International Journal of Surgical Pathology

Intratesticular Mullerian Serous Borderline Tumor With Microinvasion: A Rare Tumor and Review of the Literature

Ovarian-type (ie, Mullerian) epithelial tumors occurring in the testicular and paratesticular regions are exceptionally rare, with only a handful reported worldwide. Serous tumors are the most frequently encountered subtype among these rare tumors. The pathogenesis of these tumors within the testicular and paratesticular regions remains a subject of intrigue and debate, with various hypotheses attempting to explain their presence in the paratestis region, where most tumors occur. However, our understanding of the pathogenesis of intratesticular tumors is limited. To date, 11 known examples of intratesticular serous Mullerian tumors have been reported globally. In this report, we present an extraordinary tumor, an intratesticular Mullerian serous borderline tumor with foci of microinvasion, in a 38-year-old male patient. This tumor exhibits histological features similar to their ovarian counterparts and is confirmed through an immunohistochemical panel. Our report underscores the extreme rarity of these tumors, emphasizes the importance of heightened awareness among clinicians and pathologists, and provides valuable insights into their complex development and histogenesis. This contribution aims to enhance diagnostic precision and optimize therapeutic strategies for similar tumors.

Primary Lesions of the Appendix in Patients Undergoing Surgery for Gynecological Tumors

Appendiceal neoplasms are an incidental finding in <1% of all appendicectomy specimens. Their incidence rates are largely based on appendectomies performed for appendicitis. Appendicectomy is often performed as part of cytoreductive surgery for gynecological malignancies. This is to reduce the risk of occult metastatic disease and to mitigate the morbidity of acute appendicitis in patients undergoing chemotherapy for cancers. The objective of this study was to investigate the incidence of primary lesions of the appendix in 2 cohorts of patients who underwent appendicectomy: patients who had surgery for mucinous neoplasms of the ovary and patients who had cytoreductive surgery for gynecological malignancies. This study looked at the histopathology reports of 581 patients covering both cohorts. Appendicectomy in the setting of mucinous neoplasms of the ovary was done in 187 patients and as part of cytoreductive surgery for gynecological malignancies in 182 patients. We used the updated 2019 WHO nomenclature to classify the appendiceal lesions. The 2 cohorts had an incidence of 13% (25/187) and 7% (12/182) of appendiceal lesions. The appendix was noted to be the frequent primary site of extraovarian mucinous tumor metastasis to the ovary with a frequency of 56% (14/25) in patients with mucinous ovarian tumors; the highest cited in literature to date. We also noted poor correlation between gross and microscopic confirmation of appendiceal lesions with 7% of all macroscopically normal appendices harboring an appendiceal pathology. The study highlights the importance of appendicectomy during surgery for ovarian mucinous neoplasms and as part of cytoreductive surgery for gynecological malignancies. It also signifies the importance of microscopic examination of the whole appendix, especially when no gross abnormality is detected.

Borderline Brenner Tumor of the Ovary Coexisting With an Ovarian Mucinous Cystadenoma With Focal Atypical Epithelial Proliferation: A Rare Case With Review of the Literature

Ovarian Brenner tumors, accounting for ∼5% of overall ovarian epithelial neoplasm, are often reported in association with mucinous neoplasm. Histogenetically, the two tumors are thought to arise from similar precursors. To date, fewer than 60 borderline Brenner tumors alone have been reported, and the concomitant presence of atypical proliferative components in Brenner and mucinous tumors is even rarer. Therefore, the clinicopathological characteristics and prognosis of patients with the borderline Brenner tumors alone or coexisting with mucinous neoplasm are extremely limited. Herein, we report a unique case of a 53-year-old woman with a unilateral ovarian borderline Brenner tumor associated with focal atypical mucinous epithelial proliferation and her clinical presentations. The clinicopathological features of the tumor are documented and the literature review along with the clinical molecular advances are summarized in this study.

Endometrial Mesonephric-Like Carcinoma With Prominent Clear Cell Carcinoma-Like Features

This report details findings from a morphologic, immunohistochemical, and molecular analysis of an example of endometrial mesonephric-like adenocarcinoma (MLA) with prominent clear cell carcinoma (CCC)-like features, with an assessment of whether such tumors represent mixed MLA/CCC or a morphologic subtype of MLA. Approximately 40% of an otherwise prototypical MLA was comprised of spatially discrete zones with prominent CCC-like morphology. The MLA-like nuclear features of both components were similar, as were their immunoreactivity patterns for estrogen receptor, progesterone receptor, SOX17, and calretinin (all negative), GATA3, and TTF1 (patchy positive). Diffuse immunoreactivity for CD10 and Napsin-A was limited to the CCC-like areas. Next generation sequencing of each macro-dissected component showed both to display the same KRAS variant (G12V), with similar variant allelic frequencies (42.5% [MLA]; 48.2% [CCC-like]). Although KRAS G12V lacks specificity for MLA, the totality of findings supports the interpretation that the CCC-like areas represent morphologic mimicry of CCC by MLA. Additional supportive factors include the similarity in nuclear features between the 2 components, absence of other architectural patterns of CCC in the CCC-like areas, co-expression of GATA3 and TTF1, as well as negativity for SOX17 in both components. This tumor highlights the potential for MLA to display striking CCC-like morphology, possibly leading to misclassification in a sampling specimen, and adds to the emerging literature on the potential for MLA to express Napsin-A.

PD-L1/PD-1 Expression in Endometrial Clear Cell Carcinoma: A Potential Surrogate Marker for Clinical Trials

Background. Endometrial clear cell carcinoma (ECCC) represents a rare subtype of endometrial cancer. Recently, immunotherapeutic drugs targeting programmed cell death protein 1 (PD-1)/programmed death ligand-1 (PD-L1) was associated with improved survival in several types of cancer (especially in patients with mismatch-repair (MMR)-deficient status). The aim of this study is to evaluate the correlation between the PD-L1/PD-1 axis and clinical and pathological features in strictly defined ECCC diagnosed at our institution. Design. Review of ECCC (diagnosed in the period of 2000 to 2017) identified 23 cases (n = 23) in our institution. The cases were reviewed by 2 gynecological pathologists. Estrogen receptor, progesterone receptor, napsin A, p16, and p53 were also performed so that only pure CCC cases were included. PD-L1 (SP142), PD-1, and MMR antibodies were performed. PD-L1 and PD-1 were scored in both the tumor and the peritumoral lymphocyte infiltration. Clinical and pathological features were recorded to correlate with the expression of the 2 markers. Results. Among the 23 cases, 20 cases were qualified for pure CCC by histology and immunohistochemistry patterns. Regarding PD-1 expression, 6/20 (30%) patients had positive expression in peritumoral lymphocyte infiltration. While 3/20 (15%) cases had PD-L1 either tumoral or peritumoral lymphocytes expression. Loss of MMR expression was present in 1 (5%) of 20 patients. PD-1 and/or PD-L1 expression cases tended to have deeper myometrial invasion and higher stage at presentation. Conclusions. Our results are suggestive of the roles of both PD-1 and PD-L1 in ECCCs as useful therapeutic biomarkers for immunotherapy.

A Case Study of a High-Grade Serous Carcinoma of the Fallopian Tube Transformed into Carcinosarcoma at the Site of Peritoneal Dissemination With Immunohistological Evidence of an Epithelial–Mesenchymal Transition

We report a patient in whom a primary high-grade serous carcinoma (HGSC) of the fallopian tube transformed into a carcinosarcoma at the site of peritoneal dissemination, and immunohistological analysis suggested the involvement of an epithelial–mesenchymal transition (EMT). The patient, a 70-year-old woman, had an abdominal mass palpated on admission, and a laparotomy was performed after a close examination. The resected right fallopian tube was cystically dilated, and a solid mass was observed in its lumen. The histological diagnosis was HGSC of the right fallopian tube with a papillary or complex tubular structure composed of tumor cells with marked nuclear irregularities. p53 was overexpressed, and no mesenchymal tumor component was observed. The resected left-sided abdominal mass of the omentum was a solid with a long diameter of 100 mm. Microscopically, the tumor exhibited a mixture of HGSC and high-grade sarcoma with nonspecific differentiation. Furthermore, a heterologous chondrosarcoma was subsequently observed from the high-grade sarcoma. The HGSC component was E-cadherin positive. The high-grade sarcoma component was positive for EMT-related proteins such as zinc finger E-box–binding homeobox 1 (ZEB1) and twist family bHLH transcription factor 1 (TWIST1). The chondrosarcoma component was ZEB1 positive and TWIST1 negative. p53 overexpression was found in all 3 components. The tumor of the omentum suggested that an EMT phenomenon was involved in the tumorigenesis. In this scenario, the primary HGSC of the fallopian tube with obvious invasion demonstrated that the conversion from carcinoma to sarcoma by EMT occurs only with peritoneal dissemination.

Nicotinamide Phosphoribosyltransferase (NAMPT) as a New Marker in Cervical Preinvasive Lesions

Objective To examine the relationship between cervical dysplasia and tissue levels of nicotinamide phosphoribosyltransferase (NAMPT). Materials and Methods Patients who underwent colposcopic biopsy due to human papilloma virus positivity were classified as normal tissue and cervical intraepithelial neoplasia (CIN) 1, CIN 2-3. These were stained with NAMPT antibodies using streptavidin-biotin peroxidase method (Invitrogen, 85-9043, CA, USA). The staining intensity was scored as: 0, 1, 2, and 3 for no, mild, moderate, and intense staining, respectively. The percentage score was classified as: 1, 2, and 3 for 1% to 33%, 34% to 66%, and 67% to 100% positivity, respectively. The product score was calculated. Totally, 86 patients were included in the study. Results The NAMPT staining scores were significantly higher in the CIN 2-3 group compared to the group with CIN 1/normal (90% vs 9%; respectively, P  < .000). No intense NAMPT staining was observed in any of the specimens with CIN 1 or normal results. The percentage score of 2 to 3 was seen in 83% and 12% for patients with and without CIN 2-3, respectively ( P  < .000). Using a cutoff value for product score of 2, the test demonstrated a sensitivity, a negative-predictive value, a specificity, and a positive-predictive value of 96%, 98%, 80%, and 71%, respectively. Although the product score was 2 and higher for 96% of CIN 2-3 specimens, 78% of those with CIN 1 or normal results had that below 2. Conclusion The NAMPT staining differs significantly among groups and may be a useful marker for distinguishing CIN 2-3 from normal tissue and CIN 1. That has potential to improve the sensitivity–specificity of diagnosing and treating cervical premalignant lesions.

Prostate Type Malignancies Arising in Ovarian Teratomas – A Report of Two Patients

The identification of benign prostatic tissue within ovarian and testicular mature teratomas is an unusual occurrence. While a few documented reports exist in the literature regarding the emergence of benign prostatic tissue within teratomas, the occurrence of prostatic-type adenocarcinoma in a mature ovarian teratoma is an exceptionally rare phenomenon. To date, only two prior reports have documented such instances, and no tumors have been previously reported with prostate-type tissue with morphologically two different malignancies. We outline our experience with two tumors involving prostatic-type carcinoma, both arising in ovarian mature teratomas. Microscopic examination of the first tumor revealed small areas of infiltrative atypical glandular proliferation within the mature teratoma. In the second tumor, prostate-type tissue exhibited a low-grade basal cell carcinoma. Additionally, adjacent minute foci of adenocarcinoma of the prostate (Gleason score 3 + 4 = 7, <5% pattern 4) were identified. Goblet cell adenocarcinoma of appendiceal type was also evident in the latter tumor. In both tumors, immunostains (NKX3.1, PSA) were performed to establish the prostatic origin of these atypical glands and PIN4 was performed to document the absence of basal cell in the atypical glands. On clinical follow-up, both patients have no signs of recurrence at 14 and 11 months after the surgery. Further reports on such neoplasms would contribute to a better understanding of the prognosis and management of such occurrences.

Myoepithelioma-Like Tumor of the Vulvar Region: A Clinicopathologic Study of Four Cases

Myoepithelioma-like tumors of the vulvar region (MELTVR) are solid tumors found in the vulva of adult women. They have a similar histopathology to myoepithelioma but differ in immunohistochemical phenotype and genetic changes. In this study, we report four examples of MELTVR, occurred in the external genitalia and mons pubis of adult women aged 32 to 39 years. The tumors presented as subcutaneous masses without obvious tenderness. The tumors were composed of a mixture of myxoid and nonmyxoid components, and myxoid areas accounted for 5% to 80% of the tumor volume. The tumor cells were spindle-shaped or epithelioid, with abundant cytoplasm, vesicular nuclei, and small nucleoli. The nuclear atypia was mild to moderate, with 0 to 10 mitotic figures per 10 high-power fields. Immunohistochemically, all four tumors showed consistent positivity for EMA, calponin and ER; three tumors exhibited PR expression. All tumors were negative for S100 protein and SMA. AE1/AE3 expression was absent in all except one tumor, which showed rare positivity. SMARCB1/INI1 expression was deficient in all tumors. EWSR1 and FUS rearrangements were absent. All tumors were treated through surgery. All patients were alive without recurrence on most recent follow-up. Together, this overview of four additional tumors of MELTVR offers further insight into this rare and poorly understood disease.

Metastasis of Clear Cell Renal Cell Carcinoma to Uterine Leiomyoma: First Case Report and Review of Literature

Metastasis of clear cell renal cell carcinoma (clear cell RCC) to the gynecologic tract is infrequent, and involvement of the uterus is extremely rare. A review of the literature identified a total of 12 reported examples with metastasis to the uterine serosa (1), endometrium (5), cervix (5) and only one with metastasis to the myometrium. This report represents the first case of tumor-to-tumor metastasis involving a clear cell RCC with metastasis to a uterine leiomyoma. The patient was a 50-year-old woman status post-radical nephrectomy for newly diagnosed unilateral clear cell RCC (stage pT3a) with negative margins, who subsequently underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy for the incidental finding of multiple uterine masses measuring up to 14.5 cm suggestive of fibroid on pelvic ultrasound. The pathologic exam of the specimen was consistent with metastatic clear cell RCC (1.2 cm) to uterine leiomyoma, confirmed with keratin, vimentin, CD10, CA9, and PAX8 immunohistochemistry. The patient's postoperative course was uneventful, and no new lesions were identified at follow-up during the past 6 months.

Primary Uterine Alveolar Soft Part Sarcoma in a Postmenopausal Woman: Histopathologic and Immunohistochemical Characteristics of a Rare Case

Background Primary uterine alveolar soft part sarcoma (ASPS) is a rare, indolent mesenchymal malignancy with less than 40 patients documented in the literature. Case We report an example of ASPS in a 61-year-old postmenopausal woman. Macroscopically, the uterus showed multiple nodular masses. Microscopic examination revealed tumor arranged in nests and alveolar pattern. The tumor cells were moderately to markedly pleomorphic, epithelioid to polygonal, with eccentrically placed nuclei, vesicular chromatin, prominent macro-nucleoli, and moderate to abundant eosinophilic cytoplasm. PAS-positive and diastase-resistant intracytoplasmic crystals were also seen in some tumor cells. On immunohistochemistry, the tumor cells showed diffuse positivity for vimentin and nuclear positivity for TFE3, a surrogate marker for ASPS. These were negative for SMA, desmin, CD10, h-caldesmon, cyclin D1, EMA, Melan A, and CD34. SMARCB1 expression was retained. Based on the histopathology and IHC, a final diagnosis of uterine ASPS was rendered. Conclusions Knowledge of the characteristic histopathologic and immunohistochemical features can help accurately diagnose such rare tumors. Knowledge of the characteristic histopathologic and immunohistochemical features can help accurately diagnose such rare sarcoma in an uncommon site with an unusual age.

Fetal Glomeruli in a Mature Ovarian Teratoma: A Developmental Anomaly Within a Developmental Anomaly?

A Case of Malignant Phyllodes Tumor of the Breast Metastasizing to the Ovary

Phyllodes tumors of the breast are uncommon, and 6.2% of phyllodes tumors behave in a malignant fashion. The metastatic spread of malignant phyllodes tumor is mainly hematogenous to lung and bone, and malignant phyllodes tumor metastasizing to the ovary is rare, with only 2 cases reported. We report the third case of metastatic malignant phyllodes tumor to the ovary with a focus on the differential diagnosis of ovarian cancer.

Cardiophrenic Lymph Node Metastasis of Ovarian High-grade Serous Carcinoma Showing Wild-type p53 Immunostaining Pattern and Aberrant CD56 Expression

Patterns of p53 immunostaining are used as a surrogate marker for tumor protein 53 ( TP53) mutations in the diagnosis of ovarian high-grade serous carcinoma (HGSC). We present a rare case of ovarian HGSC that metastasized to the diaphragm and cardiophrenic lymph nodes and showed the immunostaining pattern of wild-type p53 and aberrant neural cell adhesion molecule (CD56) expression. A 63-year-old woman developed multifocal metastases in the diaphragmatic pleura and cardiophrenic lymph nodes. Because she had a history of ovarian HGSC and pulmonary adenocarcinoma, we considered the possibility that the metastatic carcinoma was of either ovarian or pulmonary origin. Immunostaining revealed that the tumor cells were negative for thyroid transcription factor 1 but positive for Wilms tumor 1. The tumor additionally exhibited strong membranous CD56 expression and patchy p53 expression, both of which were inconsistent with the characteristics of ovarian HGSC. However, targeted sequencing analysis revealed that the tumor harbored a pathogenic mutation at the splice acceptor site of TP53 intron 9 (c.994-1G>C).

Primary HPV-Associated Enteric-Type Adenocarcinoma of Vagina: A Case Report

Primary enteric type adenocarcinomas of the vagina are extremely rare. We present a 63-year-old woman who had a polypoid mass localized to the distal vagina. The lesion was composed of a columnar glandular cell proliferation with focal cribriforming, reminiscent of tubular adenoma. Immunohistochemical stains were notable for expression of enteric markers (CDX2 and KRT20), as well as negativity for Mullerian markers (PAX8, ER, and PR), diffuse expression for p16, and positivity for high-risk HPV mRNA expression. Ultimately, a diagnosis of vaginal primary HPV-associated enteric type adenocarcinoma was rendered for this unusual lesion. To our knowledge, no prior cases of HPV-associated enteric type adenocarcinomas of the vagina have been described before.

Uterine Leiomyosarcoma Masquerading as a Malignant Perivascular Epithelioid Cell Tumor: A Diagnostic Challenge

Uterine sarcomas with myomelanocytic differentiation have been reported to be diagnostically challenging. We report a case of uterine leiomyosarcoma with extensive perivascular epithelioid cell tumor (PEComa)-like areas and extrauterine metastases. The patient was a 49-year-old gravida 3 para 2 Japanese woman with no relevant medical history. She noticed a vaginal mass with bleeding. Imaging examination revealed a uterine tumor and multiple liver and lung metastases. The vaginal tumor (3.5 cm) was resected and diagnosed as a malignant PEComa based on morphology and myomelanocytic marker expression. Clinically used targeted sequencing (FoundationOneCDx™) revealed gene alterations in RB1, TP53, and ATRX but not TSC1/2. Despite administration of an mTOR inhibitor, the tumor size increased, and subsequently, hysterectomy was performed to relieve the symptoms. The uterine tumor was composed of conventional leiomyosarcoma showing RB1 loss, wild-type TP53 staining, and retained ATRX expression, as well as adjacent predominant PEComa-like components with RB1 loss, TP53 overexpression, and ATRX loss, identical to the characteristics of the vaginal tumor. In the uterine tumor, both HMB-45 and MITF were weak to moderately positive for approximately 40% of tumor cells while Melan-A was negative. The tumor was finally diagnosed as leiomyosarcoma with PEComa-like features. This case exemplifies the tumorigenesis of diagnostically challenging tumors with myomelanocytic differentiation and demonstrates the importance of integrating multiple types of information, including genomic profiling, in making a correct diagnosis leading to appropriate treatment.

Mullerian Tissue (Endomyometriosis) and Intratumoral Bone Marrow Emboli From Long Bone in a Mature Ovarian Teratoma—A Keatsian Reminiscence

Isolated Metastasis to Fallopian Tube Mucosa by Low-Grade Appendiceal Mucinous Neoplasm: Report of Two Cases

Isolated metastases from non-gynecological cancers to the fallopian tube are rare. Recent literature suggests that mucosal alterations of the fallopian tube should be considered primary tubal lesions. This has led to a paradigm shift in the classification of ovarian tumors with studies proposing tubal origin for these tumors, and clinicians advocating distal salpingectomy to decrease rates of ovarian cancer. This is based on the theory that sole presence of tubal mucosal disease is evidence of tubal origin. We present two patients with isolated mucosal metastases to the fallopian tube from appendiceal tumors. Two 36- and 72-year-old women presented with adnexal masses. Both had a history of right hemicolectomy for low-grade appendiceal mucinous neoplasms. The tubes in both cases were distended with mucin. Microscopic examination showed multifocal low-grade mucinous epithelium with papillations and tufting, interspersed by normal tubal epithelium. The mucinous epithelium was diffusely positive for keratin 20 and CDX2, focally positive for keratin 7, and negative for ER and PAX8 in both cases. Ovaries showed acellular mucin pools. Based on morphology and immunohistochemical features, it is likely that these tumors are of primary appendiceal origin metastatic to fallopian tube mucosa. These cases are unique in that no other organs were involved by metastases raising the possibility of an in-situ lesion or benign tubal mucinous metaplasia. These cases bring up an important point that mucosal metastasis can occur and question the current practice of assigning primary origin of a tumor to the fallopian tube in the presence of “intraepithelial” tumor.

Two Components of Variant Profiles in Primary Vaginal Carcinosarcoma via Next-Generation Sequencing and a Literature Review

Primary vaginal carcinosarcoma (VCS) is an extremely rare and aggressive tumor consisting of admixed malignant epithelial and mesenchymal elements. We report a case of VCS that was subjected to analysis by immunohistochemistry and next-generation sequencing (NGS). A 53-year-old woman with post-menopausal vaginal bleeding underwent surgical excision followed by concurrent chemoradiation. A well demarcated tumor was growing in a discontinuous fashion at a location some distance from both the cervix and vulva. Microscopically, the tumor consisted of adenocarcinoma components and sarcoma components consisting of a sheet-like growth of spindle-shaped cells, and we diagnosed this tumor as primary vaginal carcinosarcoma. NGS analysis of each component identified the following variants, TP53, PIK3CA, KRAS and FBXW7. A comparison of microsatellite instability (MSI) and tumor mutation burden (TMB) showed that within both tissues the sarcomatous components had a higher MSI and TMB than the carcinomatous components. This case supports “a monoclonal theory” with the genome profile being similar to other malignant mixed Müllerian tumors.

Human Papilloma Virus 18-Positive Submucosal Small Cell Neuroendocrine Carcinoma of the Vagina: An Immunohistochemical and Genomic Study

Primary vaginal neuroendocrine carcinoma (NEC) is extremely rare among female genital tract tumors. Here, we report 2 cases of vaginal small cell NEC (SCNEC) using immunohistochemistry and next-generation sequencing (NGS) analysis. The 2 patients were in their mid-to-late 70s, presented with abnormal vaginal bleeding and had a vaginal submucosal mass. The biopsied or resected tumors showed a typical neuroendocrine morphology consisting of solid nests of atypical tumor cells, with no specific organoid patterns, and proliferating in the vaginal submucosa. Immunohistochemical analysis showed strong and diffuse expression of chromogranin A, synaptophysin, and p16, but no thyroid transcription factor 1 expression. Additionally, both cases were positive for human papillomavirus (HPV) 18. An NGS-based cancer panel analysis revealed that the tumors carried NF1 and AR mutations, but no major driver mutations were detected. The results of this study suggested that HPV18 infection is linked to vaginal SCNEC.

Metastatic Small Bowel Adenocarcinoma Mimicking a Primary Ovarian Mucinous Tumour – Clinical, Radiologic, Pathologic and Molecular Correlation

We describe an interesting case of a patient who presented with a large adnexal mass, first favored to be mucinous carcinoma of the gynecologic origin. The primary tumour site was ascertained after the patient's small bowel was resected by identifying an adenomatous component evolving into an invasive adenocarcinoma identical in morphology and immunophenotype to the ovarian tumour. Notably, both tumours were found to harbor a BRAF K601E mutation, which is extremely rare for a primary of the ovary. BRAF mutations are present in a subset of large bowel and small bowel adenocarcinoma, but our case shows the first instance of a BRAF K601E mutation being present in a small bowel adenocarcinoma, to the best of our knowledge. This case serves as a great illustration of the pivotal role of molecular diagnostics in modern pathology in arriving at the correct diagnosis. Additionally, it is an excellent example of how clinical-radiologic-pathologic-molecular correlation plays into the landscape of molecular pathology to deliver optimal care for the patient.

SMARCA4-deficient Undifferentiated Uterine Sarcoma: Clinicopathological Features of an Emerging Entity

SMARCA4-deficient undifferentiated uterine sarcoma is a recently described molecularly defined entity among the subset of aggressive undifferentiated uterine tumors. Mutation in the SMARCA4 gene is a key driver alteration, as also seen in small cell carcinoma of ovary, hypercalcemic type (SCCOHT) and thoracic undifferentiated carcinoma. Limited number of cases of SMARCA4-deficient undifferentiated uterine sarcoma has been reported in literature. We hereby describe a case of this distinct entity in a 52-year-old woman. Histomorphological examination showed sheets of monomorphic epithelioid cells with a variable proportion of cells displaying rhabdoid features, brisk mitotic activity, and lymphovascular invasion. A panel of immunohistochemical markers was required to exclude the differential diagnoses. The tumor was microsatellite stable. Loss of SMARCA4 expression and intact expression of INI1 in tumor cells by immunohistochemistry (IHC) confirmed the diagnosis of SMARCA4- deficient undifferentiated uterine sarcoma. The patient had a rapidly progressive clinical course.

Trichoblastic Carcinosarcoma Arising From the Vagina: A Case Report With Comprehensive Immunophenotypic Analysis

A 54-year-old woman presented with abdominal pain. Magnetic resonance imaging revealed an upper vaginal mass with no pelvic side wall involvement, nodal, or distant metastasis. Radical hysterectomy was performed. Histology showed trichoblastic carcinoma with hair follicle structures and malignant sarcomatous and carcinomatous components. Hair follicular differentiation was confirmed by positivity to hair follicle markers (Bcl-2, TLE1, CD56/NCAM, and TDAG51) and presence of CD10-positive trichogenic stroma. The tumor involved the vaginal muscularis only (FIGO [International Federation of Gynecology and Obstetrics] stage I) and was excised with clear margins. The patient remained disease free at 3-month follow-up. This is the first case of cutaneous-type carcinosarcoma reported in the vagina, highlighting the difference in histology, immunophenotype, and behavior compared with gynecologic carcinosarcomas.

High-grade Transformation in Adult Granulosa Cell Tumor: Potential Diagnostic Challenges and the Utility of Molecular Testing

Adult granulosa cell tumor (AGCT) is the most common sex cord-stromal tumor, accounting for about 1% of all ovarian tumors. It has a propensity for recurrences, especially late in the disease course. High-grade or sarcomatoid transformation has been rarely described in AGCT. We present a case of a 65 year old woman who presented with hemodynamic shock and bowel obstruction from a large pelvic mass. Histologic examination revealed predominantly high-grade epithelioid and spindled cells with high mitotic activity and necrosis. A minor component suggestive of AGCT was also identified. Molecular analysis confirmed the diagnosis of AGCT by revealing FOXL2 C134W mutations. Additionally, TP53 mutations were also detected which may contribute to the high-grade transformation. Our case is unique because the high-grade sarcomatous component constituted most of the tumor and the areas of “typical” AGCT were minor. Also, the clinical and operative findings did not suggest a specific site of origin leading to a broad differential diagnosis. High-grade transformation in AGCT is a rarely described phenomenon. The awareness of this presentation is helpful in reaching the correct diagnosis. Molecular analysis may be an extremely helpful adjunct in challenging cases.

Cervical Awareness Rabbit (CARA)

Vulvar Lactating Adenoma: A Rare Representation of Mammary-Like Anogenital Glands

Mammary-like anogenital glands are considered a normal constituent of the anogenital area. These glands can have epithelial components with eccrine or apocrine features. They often undergo transformation into mammary-like lesions, including lactational changes that occur during pregnancy and the breastfeeding period. When they form mass lesions they are referred to as lactating adenomas. Their appearance can clinically be mistaken for other more common benign and malignant entities in the vulva. We describe a vulvar lesion in a 26-year-old woman. The lesion was excised and determined by histologic examination to be a benign lactating adenoma. Subsequent immunohistochemistry was performed. The epithelial cells were positive for GATA3 and estrogen receptor while negative for PAX8, supporting mammary-like differentiation. The myoepithelial markers p63 and calponin were positive at the periphery of the ducts, supporting the benign nature of this lesion.

Giant Angiomyofibroblastoma With a Florid Lipomatous Component: A Report and Review of Diagnostic Considerations

Angiomyofibroblastoma is a benign, usually small neoplasm typically constituted by spindle-shaped and epithelioid cells in a vascularized, myxoid-fibrous stromal background. It is most often seen in the superficial genitalia of female patients of reproductive age. However, various clinical and histologic features have been reported, including tumors in male patients, malignant transformation, extragenital sites, huge sizes, and a prominent lipomatous pattern. We report the clinical and pathologic features of one such tumor: a 23.5 cm lipomatous angiomyofibroblastoma of the vulva in a 40-year-old female patient. We also discuss important diagnostic considerations when approaching such large tumors, particularly in the setting of a biopsy specimen.

Recurrent Primary Paget Disease of Vulva with Paget-Like Epithelial Cells in Papillary Dermis: Displaced or Invasion?

While histological diagnosis of Paget disease of vulva is mostly straightforward, identifying and confirming invasion can be challenging. Often invasion is accompanied by epidermal hyperplasia, marked inflammatory response and desmoplastic reaction. Diagnosis of invasion in Paget disease portends a poor outcome. We report findings from a recurrent primary vulvar Paget disease where overall histomorphology of possible invasive disease is unusual and raises a possibility of displacement of Paget cells in the dermis. We compare histology of the index case with known invasive vulvar Paget disease cases retrieved from our pathology archives. Unique histomorphology in the index case suggests a possibility of previous excision related dermal displacement of Paget cells.

Pediatric Vulvar Superficial Angiomyxoma: A Case Report With Clinical, Radiological, and Anatomopathological Characterization and a Comprehensive Review of the Literature

Superficial angiomyxoma is characterized as a benign, slow-growing vascular cutaneous myxoma. A 6-year-old Arab girl with no medical history presented with a vulvar tumor located on the left labia majora. The lesion was present since birth, but it had significantly increased over the last 6 months. She did not have any associated symptoms. Physical examination revealed an exophytic tumor of the left labia majora, which measured 5 cm in its major axis. Doppler ultrasound study showed a mass with abundant arterial and venous vascularization, and magnetic resonance imaging showed a highly vascular contrast-enhanced mass with well-delimited margins, which depended on the labia majora. A macroscopically complete resection was performed, achieving a tension-free primary closure. Histologically, the lesion was characterized as a well-demarcated superficial tumor with thin-walled vessels and myxoid stroma, S100 (−), CD34 (+), vimentin (+), and actin (+). The final histopathological diagnosis was superficial angiomyxoma. The literature review of this entity in the pediatric population shows a predominance of this lesion in the vulvar location. Local recurrence has been described. Loss of PRKAR1A expression may be involved in the pathogenesis of superficial angiomyxoma.

High-grade Squamous Intraepithelial Lesion of the Vulva with Obscuring Edema: A Potential Diagnostic Pitfall in Vulvar Biopsies

Pitfalls in Pathology—Nodular Hyperplasia of Bartholin's Gland

Nodular hyperplasia of the Bartholin's gland is an underreported and extremely rare entity that presents as a solid lesion potentially raising concern for malignancy clinically, most solid lesions at this location are carcinomas. They may also be mistaken for a Bartholin cyst clinically. Nodular hyperplasia is rarer than carcinoma of the Bartholin gland, and hence pathologists may not be familiar with this entity, making it a pitfall in pathologic as well as a clinical diagnosis. Here we report a case originally considered a Bartholin cyst, but raising intraoperative concern due to solid elements. Histological examination of the lesion revealed nodular hyperplasia of Bartholin's gland. Recognition of this entity is important, as it is something that may be encountered by the pathologist.

Vulvar Cutaneous Myxoma in a Patient With Carney Complex: Avoiding Pitfalls of Myxoid Lesions of the Vulva

We present the case of a 31-year-old woman who underwent surgical excision for a polypoid, vulvar lesion. Histopathological analysis showed a diffuse myxoid stroma admixed with scant collagen fibrils. Thin-walled and branching blood vessels were prominent, with a mild perivascular lymphocytic infiltrate. Cytologically bland spindle cells with inconspicuous nucleoli were immersed in a loose myxoid stroma. This combination of histopathological features along with multinodularity in the subcutaneous fat raised concern for deep angiomyxoma, a locally destructive neoplasm. Among our differential of myxoid lesions of the vulva, we ultimately favored the diagnosis of vulvar cutaneous myxoma. Upon further investigation, we learned that our patient was indeed known for the Carney complex. We highlight that vulvar cutaneous myxomas arising in the context of the Carney complex pose a significant diagnostic challenge for pathologists and should not be overdiagnosed as aggressive lesions such as deep angiomyxoma or other malignant stromal neoplasms.

Basaloid Squamous Cell Carcinoma of the Uterine Cervix: Report of a Case With Molecular Analysis

There is a lack of knowledge about molecular alterations in basaloid squamous cell carcinoma (BSCC) of the uterine cervix. A 72-year-old woman with a history of previous subtotal hysterectomy and current vaginal bleeding was referred to our hospital. Initially, adenoid cystic carcinoma (ACC) was diagnosed upon cervical cytology and biopsy. Chest imaging showed multiple metastatic lesions in both lungs. The surgical specimen showed BSCC with diffuse p16 immunoreactivity and negativity for S-100, c-kit, and neuroendocrine markers. There was a focal minor ACC component, which could have explained the previous cytology and biopsy diagnosis. Next-generation sequencing with two different panels showed coexisting PIK3CA mutation and NTRK2 fusion with 10 additional variants of unknown significance ( ATR, DAXX, FAM123B, JAK1 , KEL, MLL2, NOTCH2 , PALB2, POLD1, POLE ). The MYB gene fusions were not identified. The patient received chemotherapy with TRK inhibitor larotrectinib and carboplatin, which caused shrinkage of metastatic lung nodules. This is the first report of cervical BSCC with extensive molecular workup, which detected multiple genetic events, including targetable ones, which are potentially implicated in the development of a tumor. The accumulation of data and further studies on this tumor are necessary to define its diagnostic criteria and its clinical and biological behavior.

Pathologic Determination of Multifocality in pT1a1 Squamous Cell Carcinoma of the Cervix: A Retrospective Analysis

When more than one focus of stromal invasion is present in a superficially invasive cervical squamous cell carcinoma (SCC), determination of the tumoral lateral extent/horizontal extension, and hence tumor-nodes-metastases (TNM) staging, can be problematic. In recent years, a diagnostic approach to distinguish multifocal pT1a1 from pT1b cases has gained increased attention. These criteria call for classifying SCC as multifocal when invasive foci are separated by blocks of uninvolved cervical tissues, and/or are located on separated cervical lips in a tumor that is discontinuous, and/or are situated far apart (≥2 mm) from each other. In this study, we assess our experience with multifocal stage pT1a1 cervical SCC that was retrospectively classified as such using these criteria. Slides from the loop electrosurgical excision or conization specimens, comprising 212 pT1a1, 173 pT1a2, and 206 pT1b cases, were reviewed. Twenty-four (11%) of the 212 pT1a1 cases were classified as multifocal after review. The 24 multifocal pT1a1 cases were compared with the 188 unifocal pT1a1 cases regarding a variety of clinicopathologic parameters. Notably, these 2 groups showed no significant differences regarding all parameters that were evaluated, including patient age, recurrence rate, primary tumoral features in the primary excision specimen (rate of positive margins, median depth of stromal invasion, frequency of lymphovascular invasion), and frequency of residual disease in additional excisions. In summary, we demonstrate comparably favorable patient outcomes in both unifocal and multifocal cases of pT1a1 SCC of the cervix, and, accordingly, we conclusively affirm the validity of the aforementioned criteria for establishing multifocality.

Effect of Human Papillomavirus Subtype on the Rate of Positive Surgical Margin After Cervical Conization

Objective. Human papillomavirus (HPV) infection is a risk factor for cervical carcinoma. Over 100 types of HPV have been identified. The excisional procedures are recommended for women with high-grade cervical intraepithelial neoplasia. Surgical margin status is an important predictor of the risk of relapse. The aim of the current study was to evaluate whether HPV genotype is a predictive factor of positive surgical margin after cervical cone excision. Materials and Methods. The records of 448 HPV-infected patients who underwent loop electrosurgical excision or cold knife conization at a tertiary gynecological cancer center were retrospectively reviewed. The patients were divided into 6 groups according to HPV positivity: HPV 16 only, HPV 18 only, HPV 16/18, other high-risk HPV (hrHPV), HPV 16/hrHPV, and HPV 18/hrHPV. Results. There was no significant difference between the HPV groups in terms of age, parity, menopausal status, endocervical canal involvement, conization method, and the rates of positive margin ( P = .15, P = .49, P = .07, P = .20, P = .24, P = .39, respectively). Conclusion. The results show that HPV subtypes might not be associated with endocervical canal involvement and the rates of positive margin. In addition, margin status was not related to the conization method and the number of excised cervical tissue.

Is Endocervical Glandular Involvement Related to The Depth of Cone Biopsy?

Introduction. This study aimed to determine whether endocervical glandular involvement by squamous intraepithelial lesion would differ with respect to the depth of the excised specimen and analyze the related factors that may define endocervical glandular involvement among cases treated with cone biopsy. Methods. Between April 2016 and December 2018, women who underwent colposcopy and excisional procedures in the department of gynecologic oncology were retrospectively investigated. Patients with multiple specimens, or whose specimen depths were not measured, and a negative/unknown HPV status were excluded from the study. Also, patients with no dysplasia or microinvasive/invasive cancer in the final pathology report and those who had not undergone endocervical curettage during colposcopy were excluded. HPV genotypes, degree of dysplasia, surgical margin status, and specimen depth were documented from medical records. Further, the association of these factors with endocervical glandular involvement was evaluated. Results: A total of 321 patients who fulfilled the criteria were included in the study, with a mean age of 41.9 years. In total, 101 patients (31.5%) had endocervical glandular involvement. The mean excised specimen depth was 17.04 mm; 17.9 and 16.7 mm for the positive and negative glandular involvement groups, respectively ( p = .13). The mean ages were 42.7 and 41.6 years for these groups, respectively ( p = .32). There was no association between the HPV genotypes and glandular involvement. Conclusions: Endocervical glandular involvement is not associated with the depth of the excised specimen. A deeper cone biopsy may not necessarily enable a more effective treatment of the disease.

Gastric-phenotype Mucinous Carcinoma of the Fallopian Tube with Secondary Ovarian Involvement in a Woman with Peutz-Jeghers Syndrome: A Case Report

Peutz-Jeghers syndrome is an autosomal dominant condition characterized by the association of hamartomatous polyps in the digestive tract, mucocutaneous pigmentation, family history, and infrequently tumors of the female genital tract with one of the most characteristic being the gastric-type endocervical adenocarcinoma. We present the case of a 75-year-old woman with a history of gastrointestinal polyps and cancer of the pancreas and breast, diagnosed with Peutz-Jeghers syndrome, who clinically debuted with a primary adnexal tumor. However, on histologic examination it was found to be a gastric-phenotype primary mucinous carcinoma tubal in origin, associated to tubal mucinous metaplasia and secondary ovarian involvement. One of her daughters had a confirmed genetic diagnosis of Peutz-Jeghers syndrome and presented with mucinous metaplasia of the tubal mucosa in the pathological study of a prophylactic hysterectomy specimen. Another of her daughters died from an ovarian juvenile granulosa cell tumor, she did not have a genetic diagnosis of Peutz-Jeghers syndrome. This case intends to highlight the rarity of gastrointestinal-type mucinous carcinomas of the ovary and fallopian tube (similar to gastric-type endocervical adenocarcinoma) in Peutz-Jeghers syndrome and emphasize the importance of genetic counseling of these patients as well as the adequate sampling of surgical specimens for early detection and treatment.

Uterine Spindle Cell Smooth Muscle Tumor of Uncertain Malignant Potential With Mitotic Figures Greater Than or Equal to 15/10 High-Power Fields: A Clinicopathologic Study of 20 Patients With a Rare Tumor

Background. This study aimed to investigate the prognostic factors associated with uterine spindle cell smooth muscle tumors of uncertain malignant potential (STUMPs) with mitotic figures ≥15/10 high-power fields (HPFs). Methods. A total of 20 patients between January of 2009 and December of 2020 at the Department of Pathology of the Obstetrics and Gynecology Hospital of Fudan University were enrolled. Pathological features and immunohistochemical staining (including estrogen receptor (ER), progesterone receptor (PR), Ki67, p53, and phosphorylated histone H3 (PHH3)) were assessed, and clinical follow-up data were collected. Results. Among the 16 patients with Stage I, 3 recurrence, mitotic figures and PHH3 were associated with recurrence ( P = 0.014 and P = 0.001, respectively). Among all 20 patients, stage, mitotic figures, PHH3 and Ki67 were associated with recurrence ( P = 0.007, P = 0.003, P = 0.000, and P = 0.028, respectively). The areas under the receiver operating characteristic curve were 0.890 and 0.934 for mitotic figures and PHH3, with a cutoff value of mitotic figures 21/10 HPFs. Three patients (43%) did not experience recurrence without chemotherapy, and 6 patients (86%) did not experience recurrence after bilateral ovariectomy. Conclusions : For STUMPs with mitotic figures ≥15/10 HPFs, the higher the number of mitotic figures, the more likely it is for the tumor be extrauterine and recurrent. Recurrence could be assessed by using the diagnostic cutoff value of mitotic figures >21/10 HPFs or PHH3 >21/10 HPFs. We postulate that ovariectomy or antiestrogen therapy may be beneficial in preventing recurrence.

Ovarian Gynandroblastoma: A Rare Sex Cord-Stromal Tumor with Unique Morphological, Genetic, and Clinical Features—A Series of Two Patients with Clinicopathological and Molecular Analysis, and a Review of the Literature

Background Gynandroblastoma is an exceptionally rare ovarian sex cord-stromal tumor containing both male and female components. Due to its rarity, molecular data are limited, and its clinical behavior remains incompletely understood. Methods We retrospectively analyzed 2 tumors of gynandroblastoma diagnosed at 2 teaching hospitals. Clinicopathological data, including patient demographics, tumor characteristics, and outcomes, were collected. Immunohistochemistry (IHC) and next-generation sequencing (NGS) were performed on both tumors to evaluate for the presence of FOXL2 (Forkhead Box L2) and/or DICER1 (dicer 1, ribonuclease III) mutations. Results Both tumors were FIGO stage IA . Microscopically, tumor #1 contained well-differentiated Sertoli cell tumor (SCT) and adult-type granulosa cell tumor (AGCT) components, while tumor #2 comprised moderately differentiated Sertoli-Leydig cell tumor (SLCT) and AGCT components. Immunophenotypically, both tumors were positive for the sex cord-stromal markers calretinin and inhibin. NGS revealed the absence of FOXL2 c.402C>G (p.Cys134Trp) in both tumors. DICER1 mutations were absent in both tumors. Both patients remained disease-free during follow-up periods of 6 and 62 months, respectively. Conclusion Gynandroblastoma remains a distinct and rare entity with characteristic histopathological and molecular features. Our findings align with previous studies, emphasizing the rarity of FOXL2 mutation and the absence of DICER1 mutations in tumors with an AGCT component, regardless of the male sex cord component. Further studies are needed to better understand its molecular pathogenesis and long-term outcomes.

Serous Carcinomas Initially Diagnosed on Colon Biopsies: A Case Series Highlighting the Role of p53 to Guide Management

This case series highlights the diagnostic challenge of Müllerian carcinoma presenting as colonic metastasis. The morphology, immunohistochemical work-up, and the utility of p53 immunohistochemistry in delineating between high-grade serous carcinoma and low-grade serous carcinomas are reviewed. Four patients initially presented with metastatic tubo-ovarian carcinoma in a colon biopsy between 2012 and 2023. Specimens and immunohistochemical stains were processed following routine clinical workflows. Colon biopsies in all patients showed a malignancy exhibiting papillary morphology (+/−psammomatous calcifications and “bottom-heavy” architecture) or poorly differentiated morphology. All patients were evaluated for metastasis by immunohistochemistry to include keratins (KRT7 and KRT20 or AE1/AE3), CDX2 or SATB2 (for gastrointestinal origin), and PAX8 (for Müllerian origin). Once Müllerian origin was established, further interrogation of the tumor with WT1, p53, and KI67 was essential to establish a diagnosis of high-grade serous carcinoma or low-grade serous carcinoma. Differing clinical management between high-grade serous carcinoma and low-grade serous carcinoma is summarized. Papillary morphology, “bottom-heavy” architecture, and psammomatous calcifications should prompt a metastatic work-up in colon biopsies. When a Müllerian site of origin is identified, a follow-up panel of markers—to include p53—should be used to distinguish between high-grade serous carcinoma and low-grade serous carcinoma to guide initial management options.

The Use of Cytology Specimens in Isolation for Diagnosis of High-Grade Serous Carcinoma Prior to Initiation of Neoadjuvant Chemotherapy: A 3-Year Experience at a Large Referral Hospital

Introduction: Selected patients with pelvic high-grade serous carcinoma (HGSC) receive neoadjuvant chemotherapy prior to resection. Guidelines allow cytopathology fluids to be used to confirm this diagnosis before neoadjuvant chemotherapy, which can be less invasive and costly. This study examines how often cytology fluids are used for this purpose at our institution. Methods: Specimens of HGSC on cytology were searched for over 3 years. Results: Of 54 specimens, 44 of 54 (81%) were effusions, 10 of 54 (19%) were washings. The majority (32/54; 59%) of specimens were abdominal, the remaining were pleural (22/54; 41%). Most 32 of 54 (59%) were post therapy/diagnosis. A minority of specimens (14/54; 26%) had a concurrent surgical pathology specimen. In all, 34 of 52 (65%) patients were Stage 3, 13 of 52 (25%) Stage 4, and 5 of 52 (10%) Stage 2. Only 6 of 54 (11%) specimens were used solely for initial diagnosis with no concurrent surgical pathology specimen. All 6 were effusions; 5 of 6 (83%) were abdominal and 1 of 6 (17%) was pleural. Immunohistochemistry was performed on a majority (30/54; 56%) of specimens, with PAX8 being the most common, (30/54; 56%) and was positive in all specimens. Mutational p53 staining was noted in 20 of 21 (95%) specimens. Conclusion: Cytology fluid alone is uncommonly used for diagnosis of HGSC prior to initiation of neoadjuvant chemotherapy at our institution, possibly due to morphologic overlap on fluid specimens and relatively new implementation of neoadjuvant chemotherapy guidelines. High-grade serous carcinoma is most often encountered in effusions post-therapy. Morphology is similar in all specimens, regardless of preparation method or therapy status.

A Rare Collision of Endometrioid Adenocarcinoma and Second Recurrent Low-Grade Endometrial Stromal Sarcoma 8 Years After Hysterectomy: A Case Report and Literature Review

Low grade endometrial stromal sarcoma (LG-ESS) is a rare malignancy of mesenchymal origin in the female reproductive system, which has the characteristic of late recurrence. Endometrial carcinoma is a group of epithelial tumors, and is one of the most common gynecological malignancies among women worldwide. The coexistence of LG-ESS and endometrial carcinoma is extremely rare, and there is no relevant report about the collision of endometrial carcinoma and recurrent LG-ESS currently. In the present study, we report a tumor of recurrent LG-ESS accompanied with endometrioid adenocarcinoma in a young patient 8 years after hysterectomy. She was first diagnosed with LG-ESS at the age of 19 and received fertility-sparing therapy. During the 13-year follow-up period, she successfully delivered and experienced two recurrences of LG-ESS, and an unexpected endometrioid adenocarcinoma component was found in the second recurrent tumor. Adjuvant chemotherapy and endocrine therapy were administrated to the patient after completely removing the tumor, and no sign of disease recurrence or metastasis were found 7 months after the last surgery. This study emphasizes the importance of long-term management of LG-ESS and brings new insights to clinicians and pathologists about collision tumors involving recurrent tumor.

Ovarian Mesonephric-Like Adenocarcinoma Arising from an Endometriotic Cyst with an Identical KRAS Mutation in Both Components: A Case Report

Mesonephric-like adenocarcinoma (MLA) is a rare tumor that occurs in the uterine corpus and ovary. It shares the morphological and immunohistochemical features of cervical mesonephric adenocarcinoma. Recent reports have suggested that a majority of ovarian MLAs are associated with endometriosis. Herein, we report the novel tumor of a 54-year-old Japanese woman with a history of bilateral ovarian endometriotic cysts who presented with abdominal distension. Pelvic magnetic resonance imaging revealed a 14-cm left ovarian cystic tumor with an intra-cystic solid mass. Histological examination revealed proliferation of columnar or cuboidal tumor cells forming round tubules, irregular tubular glands, fused glands, papillary structures, and solid nests. Additionally, associated endometriosis was observed in the cyst wall. The tumor cells were diffusely positive for GATA-binding protein 3 (GATA3) and negative for estrogen receptor. The tumor cells also showed wild-type p53, with retained expression of AT-rich interactive domain-containing protein 1A (ARID1) and phosphatase and tensin homolog (PTEN). Molecular analysis revealed an identical KRAS p.G12V mutation in the tumor and the endometriotic cyst. The present tumor elucidates the pathogenesis and molecular mechanisms of ovarian MLA and demonstrates that ovarian MLA is an endometriosis-associated neoplasm. Further investigation into the pathogenesis and molecular mechanisms of ovarian MLA may assist in identifying potential therapeutic targets for this rare condition.

Ovarian Mesonephric-Like Adenocarcinoma Arising Within a Serous Borderline Tumor: Insights into the Implications of Cell Origin—A Case Report and Review of the Literature

Background Mesonephric-like adenocarcinoma (MLA) is a rare and aggressive tumor found in the uterus and ovaries, characterized by unique morphological and immunophenotypic features similar to mesonephric carcinoma. It has been suggested that some tumors of MLA may originate from Müllerian-type lesions. Tumor Presentation A 54-year-old woman presented with abdominal discomfort and adnexal mass. Laboratory results revealed elevated carcinoembryonic antigen and CA-125 levels. Surgical findings showed ovarian MLA arising within a serous borderline tumor (SBT) with metastasis to lymph nodes, classified as FIGO stage IIIA2. Pathological Findings The SBT component exhibited typical papillary architecture, while the MLA component showed admixture of various architectural patterns, with intraluminal eosinophilic secretions. Immunohistochemistry revealed positivity for GATA3, TTF-1, and CD10, and negativity for ER and WT1. Molecular analysis identified a KRAS p.G12D mutation, typical of MLA, and a SMAD4 mutation. Conclusion This tumor represents the ninth documented example of ovarian carcinoma with distinct components of MLA and low-grade serous neoplasm, SBT or low-grade serous carcinoma, providing valuable insights into the clinicopathological features and molecular characteristics of MLA, and contributing to the understanding of its origin and clinical behavior.

High-grade Endometrial Endometrioid Carcinoma: A Case Report of Complete Transdifferentiation to Pilomatrix-like Carcinoma

Introduction Endometrial endometrioid carcinomas can show multiple lines of differentiation, including pilomatrix-like high-grade endometrioid carcinoma, a recently described tumor with similarity to cutaneous pilomatrix carcinoma and associated with very aggressive clinical behavior. Methods We present a 56-year-old woman with an endometrial tumor associated with secondary involvement of both ovaries, left tubo-ovarian ligament and obturator lymph nodes. The diagnosis of high-grade endometrioid carcinoma in a previously performed curettage was confirmed in the hysterectomy specimen. Results Microscopically, the tumor exhibited a solid, nested/insular pattern with basaloid cells, predominantly seen at the periphery, ghost cell keratinization towards the center of the nests, and extensive geographic necrosis. No low-grade endometrioid carcinoma component was identified throughout the primary tumor or metastases after extensive sampling. Immunohistochemical assessment showed aberrant cytoplasmic and nuclear expression of β-catenin, and focal CDX2 expression. Tumor cells were negative for PAX8, and estrogen and progesterone receptors (ER/PR). The next-generation sequencing (NGS) analysis found a CTNNB1 pathogenic mutation (p.Ser37Phe, c.110C > T; variant allele frequency: 18.6%). Based on these morphologic, immunohistochemistry and NGS analysis, a diagnosis of pilomatrix-like high-grade endometrioid carcinoma was established. Conclusion The absence of a low-grade endometrioid carcinoma component makes this pilomatrix-like high-grade endometrioid carcinoma, a very rare tumor, even more special. This and the absence of PAX8 and ER/PR expression in an unusual morphological context proved to be diagnostically challenging. This patient's presentation at high stage is concordant with the literature's description of this tumor as aggressive. It is not yet known whether standard adjuvant therapies for high-risk endometrial carcinomas are effective.

Mesonephric-Like Adenocarcinomas, an Underdiagnosed Rare Type of Gynecological Malignancy Associated with Aggressive Clinical Behaviors: A Series of 4 Patients from Single Institution

Mesonephric-like adenocarcinoma (MLA) is a newly recognized type of carcinoma that occurs in the uterus and ovaries. MLA exhibits distinct morphological and immunophenotypical features similar to those of mesonephric carcinoma of the cervix or vagina, with the majority of reported tumors containing KRAS mutations. MLA is exceedingly rare and appears to be associated with aggressive clinical behavior. Literature regarding the clinical behavior of MLAs remains limited. Here, we report four additional MLA patients with detailed morphological and immunophenotypical analysis, as well as clinicopathological and follow-up information. Additionally, molecular study was conducted on the ovarian MLA tumor and one uterine MLA tumor. Our findings support the observation that MLA is associated with an aggressive clinical course and poor clinical outcomes. Out of four tumors presented, 2 (50%) were at an advanced clinical stage, 3 (75%) presented with metastasis (including 2 (50%) with lung metastasis), and 2 (50%) patients died of the disease. MLA is often misdiagnosed as other types of gynecological carcinoma, as indicated in the literature and evidenced in our study, where 2 (50%) were initially misdiagnosed as low-grade endometrioid carcinoma in biopsy. Therefore, an integrated approach, including careful evaluation of the morphological and immunophenotypical features of the tumor, preferably with molecular confirmation, is critical for accurate diagnosis of this aggressive malignancy.

Ovarian Mucinous Carcinoma with a Yolk sac Tumor-Like Component: A Report of Three Cases with a Literature Review for Prognostic Analysis

The most common subtype of ovarian carcinoma associated with somatically derived yolk sac tumor (YST) is endometrioid carcinoma. Only two cases of ovarian mucinous carcinomas associated with YST have been reported; herein, we present three additional patients, along with a review of previous literature and our pathology archives to analyze the tumor prognosis. The patients’ ages ranged from 38 to 53 years. Two patients had FIGO stage 1 tumors, and one patient had a stage 3 tumor. Two patients died of the disease within a year, and one patient survived with distant metastasis (32 months after surgery). In all three tumors, the YST-like component comprised less than 5% of the total tumor area. Together with the two previously reported mucinous carcinomas with a YST-like component, the prognosis of the five mucinous carcinomas with a YST-like component were compared with that of 19 conventional mucinous carcinomas resected at our hospital. The survival curves were estimated using the Kaplan–Meier method. As a result, the overall survival rate of patients with mucinous carcinomas with a YST-like component was significantly lower than that of patients with conventional mucinous carcinomas ( P = .0014). Our study indicates that the presence of a YST-like component in mucinous carcinomas would be a strong prognostic indicator.

Updated Morphological and Immunohistochemical Profile of Neuroendocrine Tumors Developing in Ovarian Teratomas: A Large Series of a Rare and Heterogeneous Disease

Introduction Ovarian neuroendocrine tumors are rare and often arise within mature teratoma of the ovary. No recent re-evaluation of the immunophenotype of these tumors with the new markers available in the field of neuroendocrine neoplasms has been performed. The objectives were to describe the morphologic and immunohistochemical characteristics of neuroendocrine tumors (NETs) arising from ovarian teratomas, to correlate them with the type of teratomatous epithelial components present and to evaluate their proliferative activity using the WHO recommendations for gastroenteropancreatic NETs. Materials and Methods This is a bi-centric retrospective study using a panel of markers (chromogranin-A, chromogranin-B, synaptophysin, CDX2, SATB2, TTF1, PAX8, islet-1, serotonin and calcitonin) and Ki-67 proliferation index. Results The 34 NETs studied were unilateral and presented when it's done four distinct immunophenotypic profiles: 8 NETs expressed serotonin and CDX2 (small intestinal profile), 12 SATB2 (colorectal profile), one TTF1 (thoracic profile) and 4 “null” tumors expressed none of the above markers. The Ki-67 index ranged from 0 to 19.82% (median: 1.51%). 28 tumors were grade 1 (85%), 5 tumors were grade 2 (15%). They were associated with squamous (n = 26), respiratory (n = 23), thyroid (n = 10) and gastrointestinal (n = 5) components. Discussion and Conclusion The main type of NET is intestinal phenotype, but rarely accompanied with digestive tissue. This suggests that the cell of origin may be a neuroendocrine precursor present in the teratoma, and confirms that primary NETs arising in ovarian teratomas should not be classified or named according to the type of the surrounding teratoma tissue.

A Rare Placental Site Nodule Involving the Ovary

Placental site nodule (PSN) is a benign lesion representing a nodular aggregate of intermediate trophoblast, embedded in a hyalinized stroma, thought to arise from noninvoluted placental site remaining from a past gestation. Uterus is the most common site of PSN. Occurrence in extrauterine sites is rare, with most examples being reported in the fallopian tubes. Here we report an example of PSN in the ovary. A 35-year-old woman, gravida 4, para 1, with history of adnexal ectopic pregnancy treated with methotrexate, at 39 weeks and 1 day of a subsequent pregnancy, underwent a scheduled C-section. The surgery was successful, and a healthy female infant was delivered. Intraoperative adnexal inspection revealed a small pedunculated mass on the right ovary, which was excised and sent for pathological examination. Gross inspection showed a soft, tan-white tissue fragment measuring 2.0 × 1.0 × 0.2 cm. Microscopic examination showed epithelioid cells with hyperchromatic, mildly atypical nuclei and abundant eosinophilic cytoplasm, embedded in a hyalinized stroma, forming a nodule. A diagnosis of placental site nodule was made. Immunohistochemical stains for keratin AE1/AE3, vimentin, and inhibin were strongly positive in the epithelioid cells, and immunostain for p63 was focally positive, supporting the diagnosis. PSN of the ovary is extremely rare. To our knowledge, there has been only one reported patient in the literature so far. Extrauterine PSNs are thought to arise from ectopic pregnancies. Our patient's ovarian PSN is most likely a consequence of her previous adnexal ectopic pregnancy, which was treated medically.

Morphological Diversity of the Endometrium in Choriocarcinoma Specimens and its Role in Differential Diagnosis

I ntroduction: The morphological characteristics of the endometrium in patients with choriocarcinoma have not been well described. We described the endometrial morphology patterns in 46 choriocarcinomas and analyzed their relationship with the clinicopathological characteristics of these patients. Methods: Forty-six patients diagnosed with choriocarcinoma that had sufficient endometrial tissues for histopathological diagnosis were selected. Diagnoses of choriocarcinoma and secretory status of endometrium were reviewed. LHCGR expression of endometrium was evaluated by immunostaining. Results: Endometrial morphology was classified as secretory or nonsecretory. The 15 secretory specimens included 2 highly secretory and 13 common secretory specimens. The 31 nonsecretory patterns included 1 hyperplasia without atypia, 7 disordered proliferations, 13 typical proliferations, and 10 resting endometria. Among these, 11 specimens with overall nonsecretory patterns showed focally weak secretory changes surrounding the choriocarcinoma lesion. Secretory patterns were observed in classic choriocarcinomas (8/17) and monomorphic choriocarcinomas (7/21) but not in scanty-trophoblast choriocarcinomas (0/8). Secretory changes appeared significantly less frequently in patients who received multi-agent chemotherapy (4/25) than in those who did not (7/14) or received single-agent chemotherapy (4/7) ( P  = 0.030). The differences in age, months since the last pregnancy, pregnancy type, recurrence, specimen type, gross diameter, human chorionic gonadotropin (hCG) levels, and expression of hCG receptors were not statistically significant. Conclusions: The endometrial morphologies in choriocarcinoma were diverse, including various proliferative and secretory changes, but rarely hypersecretory changes, compared to the prevailing hypersecretory endometrium in hydatidiform moles. The variety in endometrial morphology was the consequence of ovarian hormonal disturbances of the hypothalamic–pituitary–gonadal axis by hCG from choriocarcinoma. Therefore, the endometrium may serve as a clue for histopathological diagnosis of choriocarcinoma. Our study presents the largest cohort reported to date to describe the diverse spectrum of endometrial changes in choriocarcinoma patients.

Whole-Exome Sequencing Identifies Germline BLM Mutation in Ovarian Hepatoid Adenocarcinoma with Favorable Response to Niraparib and Anlotinib Combination Therapy—A Case Report and Literature Review

Hepatoid adenocarcinoma of the ovary represents a rare and malignant extrahepatic tumor that shares morphological and immunophenotypic similarities with hepatocellular carcinoma. Due to the ambiguous histomorphology and aggressive behavior, the diagnosis and management of hepatoid adenocarcinoma of the ovary present unique challenges. Here, we present a 67-year-old woman with massive ascites and disseminated peritoneal implants at initial diagnosis. She was treated with six cycles of neoadjuvant therapy (albumin-bound paclitaxel + nedaplatin + bevacizumab) and a debulking surgery, followed by eight cycles of postoperative adjuvant therapy (albumin-bound paclitaxel + carboplatin + bevacizumab). Elaborate pathology workup found significant involvement of angiogenesis in the tumor and confirmed the diagnosis via immunohistochemistry. Further molecular characterization of the tumor by whole-exome sequencing (WES) revealed a novel heterozygous germline mutation (NM_000057.2, c.1290_1291delinsATCAGGCCTCCATAG, p.Y430fs1) in gene BLM , likely pathogenic, suggesting a potential candidate for Poly (ADP-ribose) polymerase (PARP) inhibitors. For the maintenance therapy, she received a combination of the PARP inhibitor niraparib and the antiangiogenic anlotinib. As of now, the patient has achieved a partial response, with no apparent evidence of disease progression observed nearly 30 months. Our study sheds light on the WES-based profiling in rare cancers to screen for any treatable targets with otherwise no standard therapeutic options. The promising results with the niraparib–anlotinib combination suggest its potential as a maintenance therapy option for hepatoid adenocarcinoma of the ovary, which warrants validation in future larger cohort.

Factors Associated with Parametrial Involvement in Endometrial Carcinoma in Patients Treated with Radical Hysterectomy

Introduction Describe factors associated with parametrial involvement, and how these factors modify the prognosis of patients with endometrial carcinoma treated with radical hysterectomy. Methods Observational study in which categorized patients according to those with and without parametrial involvement. A descriptive analysis and comparative analysis were performed for associations between parametrial spread and clinical, surgical, and pathology variables. Results We analyzed 85 patients, which 18 (21%) had parametrial involvement. Pathology factors associated with parametrial involvement were the endometrioid subtype, grade 3, and variants of poor prognosis (odds ratio (OR) 3.41, 95% CI 1.09-10.64; P = 0.035), myometrial invasion of over 50% (OR 7.76, 95% CI 1.65-36.44; P = 0.009), serosal involvement (OR 17.07, 95% CI 3.87-75.35; P < 0.001), ovarian metastasis (OR 5.15, 95% CI 1.36-19.46; P = 0.016), positive peritoneal cytology (OR 3.9, 95% CI 1.04-14.77; P = 0.044), and lymph node metastasis (OR 3.4; 95% CI 1.16-9.97; P = 0.026). Five-year disease-free survival was 74% (95% CI 57.4-85.4) for the group without parametrial spread and 50.8% (95% CI 22.7-73.4) for the group with parametrial spread ( P = 0.001). Similarly, 5-year overall survival was 85.2% (95% CI 67.9-93.6) for the group without parametrial spread and 47.5% (95% CI 8.1-80.2) for the group with parametrial spread ( P = 0.002). Conclusion Factors associated with parametrial involvement were histologies of poor prognosis, tumors affecting uterine serosa, cervix, or spread beyond the uterus. Additionally, parametrial involvement directly affects prognosis by reducing overall survival, disease-free survival and increasing odds for recurrence.

Benign Adenomyoepithelioma: An Unrecognised Precursor of Ductal Carcinoma in Situ in Patient With Lynch Syndrome

Currently, there is no robust evidence demonstrating a clear association between Lynch syndrome and non-malignant breast pathology such as adenomyoepithelioma. We report a case of benign breast adenomyoepithelioma, which after recurrence was associated with ductal carcinoma in-situ (DCIS) in a 41-year-old woman with Lynch syndrome, who lacked significant family history of breast or ovarian cancer. Both, the adenomyoepithelioma and DCIS were found to have nuclear loss of MSH2/MSH6 by immunohistochemistry, while germline testing confirmed MSH2 gene mutation. Concordant loss of MSH2 in both lesions in the context of a MSH2 pathogenic variant in this patient with Lynch syndrome illustrates that the benign adenomyoepithelioma behaved as a likely precursor of DCIS. Our report provides a novel perspective that in some patients with Lynch syndrome adenomyoepithelioma may represent a pre-malignant precursor lesion of DCIS.

Uncovering the Unknown: Granulomatous Peritonitis After Right Ovarian Cystectomy at a Tertiary Care Center in South India—A Case Report

Background. Granulomatous peritonitis is a rare postoperative complication caused by a delayed hypersensitivity reaction to foreign substances. It can be challenging to diagnose owing to its vague presentations, and its possibility is often overlooked. Tubercular peritonitis and peritoneal carcinomatosis are the 2 crucial differential diagnoses that need to be taken into account. However, making a clinical differentiation between these 2 entities is challenging and necessitates a careful histopathological and microbiological analysis. Case Presentation. In this report, we present the case of a 28-year-old female who developed granulomatous peritonitis following a right ovarian cystectomy. The diagnosis was confirmed by histopathological examination. Conclusion. We must be aware of this rare entity, which, if left untreated, could have serious consequences, and consider its possibility in cases where the patient complains of abdominal pain after any abdominal procedure. We hope to provide insights into the importance of histopathological examination in aiding a confirmatory diagnosis of this entity.

A Rare Testicular Serous Cystadenocarcinoma Diagnosed in a Retroperitoneal Lymph Node Dissection Specimen With a Review of the Literature

Ovarian-type epithelial tumors of the testicular and paratesticular tissue are rare tumors that histologically resemble their ovarian counterparts. These tumors pose significant diagnostic challenges, especially to general pathologists, and may be misdiagnosed as the more commonly encountered germ cell tumors or mesotheliomas, if an appropriate immunohistochemistry panel is not applied. In this case report, we describe a serous cystadenocarcinoma in the retroperitoneal lymph node dissection specimen which was initially misdiagnosed in the primary testicular tumor as a germ cell tumor at an outside center, thus emphasizing the role of the pathologist in critically evaluating the histomorphological findings and applying a comprehensive immunohistochemistry panel to argue against the differential diagnoses at this site and reach the correct diagnosis.

Incidentally Discovered Intra-Abdominal Low-Grade Endometrioid Stromal Sarcoma Confirmed by JAZF1 Rearrangement Study

Endometrial stromal tumors comprise a spectrum of lesions ranging from benign nodules to malignant sarcomas. Endometrial stromal sarcomas are classified as either low-grade or high-grade based on morphologic, immunophenotypic, and genetic features. The majority of low-grade endometrial stromal sarcomas of the uterus are characterized by recurrent chromosomal translocations producing specific gene fusions, with JAZF1::SUZ12 being the most common. While endometrial stromal sarcomas typically originate in the uterine corpus, the neoplasm can rarely manifest as an extrauterine tumor in the absence of uterine involvement (endometrioid stromal sarcoma or extrauterine endometrial stromal sarcoma). Herein, we present a case report of a 55-year-old woman presenting with an intra-abdominal mass incidentally found on renal ultrasound performed for chronic kidney disease. Resection revealed irregular nodules of tumor permeating mesenteric soft tissue, composed of small, uniform ovoid to spindled cells expressing CD10, estrogen receptor, and WT1. Gross and microscopic evaluation of the accompanying hysterectomy specimen showed no uterine involvement by the tumor. Fluorescent in-situ hybridization (FISH) study performed on the mesenteric mass demonstrated the presence of a JAZF1 gene rearrangement. The patient was diagnosed with low-grade endometrioid stromal sarcoma and placed on adjuvant hormone therapy without clinical or imaging recurrence at 18-month follow-up. This case report underscores the utility of FISH as a potential confirmatory diagnostic tool in specimens of suspected extrauterine endometrial stromal sarcoma.

Detection of Microsatellite Instability in Endometrial Carcinoma Using a Novel Homopolymer Assay

Approximately 30% of endometrial cancers are associated with microsatellite instability (MSI) caused by deficiencies in the DNA mismatch repair (MMR) genes (dMMR). MMR testing by immunohistochemistry for MMR proteins and MSI testing by polymerase chain reaction (PCR) are routinely utilized to screen patients with colorectal cancer and endometrial cancer for Lynch syndrome and, more recently, to identify patients eligible for immunotherapy. The Biocartis Idylla™ MSI assay is a fully automated, cartridge-based real-time PCR assay. The assay uses as little as one formalin-fixed paraffin-embedded (FFPE) tumor section and is designed to detect seven novel MSI biomarkers consisting of short homopolymers located in ACVR2A , BTBD7 , DIDO1 , MRE11 , RYR3 , SEC31A and SULF2 genes. Mutation in two of these markers is considered MSI-H. FFPE of 35 ECs (25 dMMR and 10 microsatellite stable (MSS)) were used in this study. When tumor content was ≤20% on a slide, macrodissection was performed. The overall percent agreement with MMR IHC was 97% (31/32) with sensitivity = 96% and specificity = 100%. Pre-analytic evaluation of the manufacturer's recommended 20% tumor content cut-off is essential to ensure valid results. The Idylla MSI assay offers several advantages over other PCR-based assays including minimal hands-on time, rapid turn-around-time, no requirement for a paired normal sample and the use of FFPE directly without an extraction step.

Glandular Crowdings in Endometrial Polyps: Clinical Follow-Up and Possible Worrisome Features

Introduction Interpretation of changes and premalignant lesions in endometrial polyps can be challenging. We evaluated the clinical course of patients with focal gland crowdings in endometrial polyps via repeat biopsies and searched for possible morphological findings in the initial biopsy that may foresee a premalignant course. Methods Specimens diagnosed as endometrial polyp and focal gland crowding in patients who had a repeat biopsy in a 1-year period were reexamined. Morphological findings in the initial biopsies were recorded. The group whose repeat biopsies were “premalignant or malignant” (Group 1), and the group with “benign” repeat biopsies (Group 2) were compared. Results “Endometrial polyp and gland crowdings” was diagnosed in 115 specimens of which 38 patients had repeat biopsies. Among these 8 (21%) were diagnosed as “endometrial intraepithelial neoplasia (EIN)” (Group 1) and 30 (79%) as “benign” (Group 2). Morphological features in the initial biopsies were evaluated; PAX2 loss was 6 of 8 (75%) for Group 1 and 7 of 30 (23%) for Group 2 ( P = .020), and altered epithelial cytological features were present in 5 of 8 (62%) versus 4 of 30 (13%) ( P = .015), both significantly higher in Group 1. Dark intraluminal secretion, intraluminal histiocytes, intraglandular epithelial proliferation, and mean diameter of crowded gland areas were not statistically different between the 2 groups. Conclusion “Focal gland crowdings” in endometrial polyps do carry a risk of EIN in subsequent biopsies. We suggest that the loss/decrease of PAX2 and altered epithelial cytological features in these areas in the initial biopsy are indicative of a premalignant course.

Endometrial Clear Cell Carcinoma with Non-Gestational Uterine Choriocarcinoma Differentiation

Choriocarcinoma is a rare and highly malignant tumor that primarily occurs in women of reproductive age. Choriocarcinoma can be classified as gestational or nongestational, based on its pathogenetic origin. Although primary nongestational choriocarcinoma has been described in the ovaries, it is very rare in the uterus, especially in postmenopausal women. It is crucial to differentiate between gestational and non-gestational choriocarcinoma, as it affects the choice of treatment and prognosis. Endometrial clear cell carcinoma is an aggressive subtype of endometrial cancer, accounting for less than 10% of all uterine carcinomas. Trophoblastic differentiation in uterine cancer is unusual and very rare, with only three examples of the subtype of clear cell endometrial cancer with gestational choriocarcinoma reported in the literature, including only one with nongestational choriocarcinoma. Here, we present an example of clear cell carcinoma with nongestational uterine choriocarcinoma differentiation in a postmenopausal woman.

Malakoplakia of the Endometrium: A Rare Unexpected Disease Raising Clinical Concern for Malignancy

Malakoplakia is a rare disease that manifests as a histiocytic inflammatory process and most often occurs in the urinary bladder. It is caused by an impaired capacity of histiocytes to kill and digest bacteria. The typical histopathologic findings are sheets of histiocytes with granular eosinophilic cytoplasm and characteristic Michaelis–Gutmann bodies, spherical bodies with a targetoid appearance. Malakoplakia is even rarer in the gynecologic tract, and our literature search found only 21 published patients of malakoplakia involving the endometrium. Here we report a 60-year-old female patient who presented with recurrent pelvic infections and postmenopausal bleeding, which raised concern for an endometrial malignancy. Hysterectomy with salpingo-oophorectomy revealed malakoplakia involving the endometrium and also the right ovary. Michaelis–Gutmann bodies were visible on the intraoperative frozen section that was performed to rule out an endometrial malignancy. We summarize the clinicopathologic findings of the published patients of endometrial malakoplakia.

Endometrial Polyp-Like Lesions Arising From Adenomyosis: Report of 5 Cases

Clinicopathologic Features and the Loss of ARID1A Expression in Ovarian Seromucinous Borderline Tumors and Seromucinous Carcinomas

The current study highlighted the ARID1A and SALL4 expression and described histopathologic and immunohistochemical features of ovarian seromucinous tumors (SMTs) including borderline tumors (SMBTs) and seromucinous carcinomas (SMC; namely as endometrioid carcinoma with mucinous differentiation according to WHO 2020 classification). The clinicopathological and immunohistochemical features of 38 SMTs were analyzed, including ARID1A, SALL4, estrogen receptor (ER), progesterone receptor (PR), TP53, keratin 7, keratin 20, CEA, CDX2, WT1, PAX2, and PAX8. SMCs and SMBTs comprised 68.4% (n = 26) and 31.6% (n = 12) of all SMTs, respectively, studied. The mean age of diagnosis was 47.4 years and 41.4 years, and the mean size was 9 cm and 7.45 cm for SMC and SMBT, respectively. There was endometriosis or endometriotic cyst in 61.5% of SMCs and 50% of SMBTs. Immunohistochemically, loss of ARID1A staining was observed in 15 (65.2%) of 26 SMCs, and 3 (33.3%) of the 12 SMBTs. Only one SMC showed focal SALL4 positivity. All SMTs were positive for ER, PR, PAX8, and keratin 7. SMTs were negative for WT1, keratin 20, CDX2, and CEA (negative in 66.7% to 92.3% of the cases). While all SMBTs and 24 (92.3%) of 26 SMCs exhibited “wild-type” TP53 staining, 2 (7.7%) SMCs, both were stage III, showed mutant type TP53 overexpression. We indicate there is a similarity between SMC and SMBT according to the immunohistochemical features. SMBTs are keratin 7, ER, PR positive tumors, and some of them have loss of ARID1A expression and are likely to develop in the background of endometriosis similar to SMC.

Dedifferentiated Ovarian Carcinoma with ARID1A and ARID1B Mutations: A Clinicopathological Report and Literature Review

Dedifferentiated carcinoma of the female genital tract is a relatively recently recognized aggressive tumor affecting predominantly perimenopausal and postmenopausal women. In addition to having an undifferentiated component, dedifferentiated carcinoma includes a juxtaposed endometrioid adenocarcinoma, FIGO grade 1 or 2. Molecular characterization of these tumors has been a subject of discussion in multiple recent articles. We present a case of dedifferentiated carcinoma of the ovary in a 70-year-old female demonstrating concurrent inactivation of ARID1A and ARID1B. To the best of our knowledge, this is the second clinical report demonstrating dedifferentiated carcinoma of the ovary with concurrent inactivation of ARID1A and ARID1B. ARID1A and ARID1B inactivation seems to represent an alternate mechanism of switch/sucrose nonfermentable complex inactivation in the development of dedifferentiated carcinoma. Additional studies are warranted to precisely understand the molecular mechanism of cellular dedifferentiation in the dedifferentiated endometrial/ovarian carcinomas, thus guiding the development of targeted therapy.

Tumor Budding is an Independent Prognostic Factor to Predict Overall Survival in Endometrial Endometrioid Carcinoma: A Retrospective Study

Objective. Tumor budding defined as a tumor cell nest away from the main tumor, has been found to be associated with prognostic parameters in many cancer types. We aimed to investigate the relationship between tumor budding and clinicopathological parameters in endometrioid endometrial carcinomas, as well as its prognostic importance. Materials and Methods. One hundred four patients who underwent surgical resection with diagnosis of endometrioid endometrial carcinomas between June 2011 and May 2020 were included. The area where tumor budding was the most prominent was determined, and tumor budding was counted from hematoxylin and eosin-stained section at one high power field (X 200). By performing ROC analysis, the cut off value was obtained in order to divide the patients into low and high tumor budding groups. Results. The cut off value was determined as 1/0.95 mm2 according to the ROC analysis. Tumor budding was observed in 24 (23%) patients. Tumor budding significantly associated with poor overall survival ( P < .001), distant metastasis ( P = .001), presence of angiolymphatic invasion ( P < .001), lymph node metastasis ( P = .024), cervical invasion ( P < .001), high FIGO grade ( P < .001), large tumor size ( P = .004). In multivarate analysis, tumor budding and age were found to be an independent risk factor for overall survival ( P = .003, P = .014 respectively). Conclusion. Tumor budding is a significant morphological parameter independent of other prognostic parameters in endometrioid endometrial carcinomas. Standardizing the assesment and scoring of tumor budding, as well as including this entity in routine pathology reports could light the way for ideas in the risk analysis of patients.

The Prognostic Effect of HER2 Gene Amplification in High-Grade Endometrial Carcinomas and its Correlation with Protein Overexpression

Introduction. New therapeutic agents and biomarkers are needed for the treatment of aggressive endometrial cancer subtypes. Recently, HER2 has been recommended to be tested routinely in serous endometrial cancers. The aim of this study is to investigate the correlation between HER2 (ERBB2) protein overexpression and HER2 gene amplification and the relationship of HER2 gene amplification with prognosis in cancers with serous morphology. In addition, the concordance of HER2 testing in paired curettage and hysterectomy specimens is also investigated. Methods. Twenty five serous carcinomas and 8 carcinosarcomas with a serous morphology were included in the study. HER2 staining was performed on whole tissue sections by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). The system, which was proposed by Fader et al was used to evaluate the stainings. Results. Protein overexpression was detected in 27.3% (n = 9) of the cases, and gene amplification in 30.3% (n = 10). A significant positive correlation was found between the two methods ( P < .0001). HER2 IHC revealed a heterogeneous staining pattern, such as intense complete membranous in solid areas, and basolateral in papillary and glandular areas. HER2 gene amplification was significantly associated with shorter overall ( P = .005) and disease-free ( P = .014) survival. The concordence of the results in curettage and hysterectomy specimens was also significantly high. Conclusion. HER2 is an important prognostic and predictive marker for endometrial cancers with serous morphology. HER2 IHC/ISH testing can be performed by using diagnostic curettage specimens which contain enough viable tumor cells. However, pathologists should be aware of the intratumoral heterogeneity for HER2 staining.

High-grade Endometrial Stromal Sarcoma: Morphologic and Clinical Features, the Role of Immunohistochemistry and Fluorescence in Situ Hybridization in Diagnosis

Introduction. High-grade endometrial stromal sarcomas (HGESS) are rare malignant mesenchymal tumors of the uterus with aggressive poor clinical outcome, which frequently exhibit YWHAE::NUTM2 and ZC3H7B::BCOR fusions. In this study, we aimed to investigate HGESSs with YWHAE and BCOR translocations through our archive materials, and to identify morphological, immunohistochemical and molecular features of these tumors. We also assessed the diagnostic value of BCOR immunohistochemistry (IHC) in HGESSs, low-grade endometrial stromal sarcomas (LGESS) and uterine leiomyosarcomas. Methods. One hundred fifty-one uterine sarcomas diagnosed between 2000-2019 were reevaluated, and tumors of 39 patients with specific features were included in the study. Fluorescence in situ hybridization (FISH) studies using YWHAE and BCOR break-apart probes and BCOR IHC were performed. BCOR IHC was also performed in 20 leiomyosarcomas and 19 LGESSs. Results. In six HGESSs, translocations involving YWHAE or BCOR were detected. Five tumors showed high-grade morphology and revealed YWHAE translocation. One HGESS with myxoid morphology revealed BCOR translocation. In immunohistochemistry, three (3/4) YWHAE translocated HGESSs showed BCOR expression. However, the BCOR translocated HGESS was BCOR negative. The study showed that all LGESSs were immunohistochemically negative with BCOR. Although 15% (3/20) leiomyosarcomas reveal focal weak-moderate BCOR expression. Conclusion. BCOR IHC is a useful marker to distinguish LGESS from HGESS. A small percentage of uterine leiomyosarcomas reveal BCOR expression; however, it is not as diffuse and strong as in HGESSs. Strong and diffuse BCOR IHC expression is highly suggestive for HGESS. The diagnosis of HGESS should be supported by molecular studies such as FISH.

Spindle Cell Sarcoma of the Uterus Harboring MEIS1::NCOA1 Fusion Gene and Mimicking Endometrial Stromal Sarcoma

MEIS1::NCOA1/2 sarcomas are a newly recognized group of exceedingly rare low-grade spindle cell sarcomas that often involve the genitourinary and gynecologic tracts. Due to its deceptively low-grade morphology and the non-specific immunoprofile, these neoplasms may pose a diagnostic challenge by histologically mimicking other entities such as endometrial stromal sarcoma, smooth muscle tumor, or uterine perivascular epithelioid cell tumor (PEComa). Histologically, MEIS1::NCOA1/2 sarcomas typically show spindle cell proliferation with hyperchromatic nuclei and a generalized cytologic uniformity, arranged in short fascicles and exhibiting alternating zones of hypo- and hypercellularity. Among the previously reported cases, molecular analysis revealed the MEIS1::NCOA2 fusion as the most commonly detected fusion gene, whereas the MEIS1::NCOA1 fusion gene has been reported in only a single case that involved kidney. Herein we report the first case of uterine sarcoma harboring the MEIS1::NCOA1 fusion gene that was initially misclassified as low-grade endometrial stromal sarcoma, demonstrating its clinicopathologic features, and highlighting the essential role of molecular pathology to arrive at the accurate diagnosis that may alter disease classification and inform therapy.

Pelvic Carcinosarcoma Showing a Diverse Histology and Hierarchical Gene Mutation with a Common POLE Mutation to Endometrial Endometroid Carcinoma: A Case Report

POLE mutation-type endometrial cancer is characterized by an extremely high tumor mutation burden. Most POLE mutation-type endometrial cancers are histologically endometrioid carcinomas, and POLE mutation-type carcinosarcomas are rare among endometrial cancers. We report a case of endometrial and pelvic cancer in a 53-year-old woman who was analyzed using next-generating sequencing. The endometrial lesion harbored a p.T457del POLE mutation with an elevated tumor mutation burden and low microsatellite instability. The pelvic lesion showed divergent histological features, consisting of high-grade endometrioid carcinoma, neuroendocrine carcinoma, and chondrosarcoma. In addition to the common POLE mutation detected in the endometrial lesion, the pelvic lesion in each element showed additional gene mutations in a hierarchical manner. Therefore, it is indicated that the p.T457del POLE mutation is a pathogenic mutation and may be related to POLE mutation-induced carcinogenesis and divergent morphogenesis in endometrial cancer.

Role of the Immunohistochemical ZEB1 Expression in Uterine Mesenchymal Neoplasms

The distinction of mesenchymal tumors of the uterus is a frequent diagnostic challenge in gynecologic pathology. Especially, distinguishing low-grade endometrial stromal sarcoma (ESS) from leiomyoma or distinguishing low-grade ESS from high-grade ESS can be difficult. Epithelial-mesenchymal transition (EMT) is a physiological and pathological process in which epithelial cells lose their morphological features, become elongated and acquire mesenchymal traits. The signaling pathway of Zinc finger E-box binding homeobox 1 (ZEB1) is one of the most significant pathways involved in the EMT process and it has a crucial role in cancer progression, metastasis, and therapy resistance. We studied a series of 69 uterine mesenchymal neoplasms including 18 endometrial stromal sarcomas (10 cases of low grade and 8 cases of high grade endometrial stromal sarcomas), 26 leiomyosarcomas (8 cases of grade 1 and 19 cases of grade 2-3 leiomyosarcomas), 15 leiomyomas, and 10 rhabdomyosarcomas, using an antibody ZEB1. We graded the leiomyosarcomas depending on the FNCLCC grading system. It was observed that leiomyosarcoma was more intensely stained with ZEB1 than leiomyoma (P < 0.001) and high-grade ESS was significantly more intensely stained with ZEB1 protein than low-grade ESS (P < 0.004). It also was observed that high-grade leiomyosarcoma was significantly more intensely stained with ZEB1 protein than low-grade leiomyosarcoma (P < 0.000). Our data suggest that Zeb1 can be used to differentiate high-grade sarcomas from their low-grade counterparts as well as benign and malignant smooth muscle tumors of the uterus.

Extragenital endometrial stromal sarcoma of transverse mesocolon: A diagnostic conundrum

Endometrial stromal sarcoma (ESS) is a rare uterine neoplasm infrequently arising in extra-genital sites. Herein, we report an extremely rare case of primary extra-genital ESS of transverse mesocolon occurring in a 51-year-old female presenting with gradually increasing abdominal mass. The clinical diagnosis considered was a gastrointestinal stromal tumor. Intra-operatively, the mass was confined exclusively to the transverse mesocolon. Microscopy revealed a cellular tumor composed of oval to elongate neoplastic cells with hyperchromatic nuclei, inconspicuous nucleoli and were immunoreactive for CD10, progesterone receptor (PR), estrogen receptor (ER), and PAX8; negative for KIT, CD34, SMA, S100, synaptophysin, chromogranin, WT1, and calretinin. A distinct arborizing network of arterioles along with foci of endometriosis was also seen. We present this case for its extreme rarity and the challenges entailed in its diagnosis.

Endometrial Stromal Expression of ER, PR, and B-Catenin Toward Differentiating Hyperplasia Diagnoses

Background. The interpretation of histopathological changes of endometrial hyperplasia with or without atypia can be challenging. We aim to investigate the role of specific immunohistochemical markers in the endometrial stroma to classify endometrial hyperplasia in difficult cases. Methods and Results. We retrospectively reviewed and reclassified (WHO 2014): 47 specimens with endometrial hyperplasia without atypia, 33 with atypical hyperplasia (AH), and 13 endometrioid adenocarcinomas. We performed IHC for B-catenin, E-cadherin, p16, estrogen receptors and progesterone receptors, and B-cell lymphoma 2 (BCL2). Percentage of positive stromal cells was calculated. B-catenin was equally expressed in the stroma of both hyperplasia and AH (mean 60%, 50%; P = .17) and was absent from adenocarcinoma (0%, hyperplasia vs adenocarcinoma; P < .0001, AH vs adenocarcinoma; P < .0001). E-cadherin was not expressed in the stroma of any lesion, while p16 expression levels were not statistically different (hyperplasia vs AH; P = .46, hyperplasia vs adenocarcinoma; P = .22, AH vs adenocarcinoma; P = .48). Estrogen and progesterone were highly identified in stromal cells of hyperplasia (80%) and diminished in AH (respectively, at 30% and 60%, hyperplasia vs AH; P < .0001), and in adenocarcinoma (0% and 40%, respectively). Finally, BCL2 was not differentially expressed (hyperplasia vs AH; P = .33, hyperplasia vs adenocarcinoma; P = .17, AH vs adenocarcinoma; P = .36). Conclusion. Estrogen and progesterone were strongly expressed in stroma exclusively of hyperplasia, while B-catenin was particularly expressed in hyperplasia and AH. Use of these markers can be useful in the differential diagnosis of hyperplasia from AH, and AH from adenocarcinoma in challenging cases.

Molecular Analysis of an Abdominal Wall Cesarean Section Endometrioid Carcinoma

Malignant transformation of endometriosis is rare, and most cases concern the ovaries, while extraovarian cases are mostly found in the rectovaginal septum. Incisional adenocarcinoma is extremely rare, with only few cases reported in the literature, while their molecular profile remains unknown. Thus, we report on an abdominal wall cesarean section scar endometrioid adenocarcinoma studied by next-generation sequencing and microsatellite instability analysis.

Pitfalls in Frozen Section: A Case of Incidental Papillary Mesothelioma

Well-differentiated papillary mesothelioma is an uncommon benign, although potentially recurrent mesothelial lesion that occurs in the peritoneum of women over a wide age range. We recently encountered an incidental case sent for frozen section at the time of hysterectomy for endometrial carcinoma. Familiarity with this lesion will help prevent overinterpretation as a serous carcinoma.

Keratin Granulomas in the Peritoneum on Frozen Section: A Case Report with Multiple Suspects and the Search for the Culprit

Keratin granulomas in the peritoneum are a rare finding with multiple etiologies and can be especially challenging for both the pathologist and the surgeon when these lesions are grossly visible. We report a case of a unique frozen section diagnostic scenario of evaluation of keratin granulomas in the peritoneum of a 47-year-old woman in the setting of multiple potential culprits: endometrial endometrioid adenocarcinoma following fertility sparing treatment, and a concurrent dermoid cyst. We discuss the various etiologies of keratin granulomas in the peritoneum, mechanism of their formation, diagnostic significance, as well as implications of fertility sparing treatments. To the best of our knowledge, this is the only case of keratin granulomas in the peritoneum with multiple distinct potential pathologic culprits as well the only case following fertility sparing treatment.

Ever Expanding Morphologic Patterns of Mesonephric-like Adenocarcinomas of the Uterine Corpus: A Report of Two Tumors and a Brief Review of the Literature

Mesonephric-like adenocarcinoma (MLA) of the endometrium shows a variety of morphologic appearances, including small glands, tubules with eosinophilic materials in the lumen, prominent papillary patterns, spindled cells, solid formations, and corded and hyalinized patterns. Unique morphology, characteristic immunohistochemical staining patterns, molecular alterations, and awareness of the pathologists make it possible to identify this tumor accurately. This report of two additional morphologic patterns, intestinal goblet cells mimicking intestinal-type mucinous carcinoma and squamous differentiation with spindle and epithelioid cells mimicking carcinosarcoma of the endometrium will expand the literature on MLA.

High-Grade Endometrioid Carcinoma of the Endometrium With a GATA-3-Positive/PAX8-Negative Immunophenotype Metastatic to the Breast: A Potential Diagnostic Pitfall

This report describes clinicopathologic findings from the case of a patient with a breast mass that was ultimately diagnosed as a metastatic high-grade endometrioid carcinoma of endometrial origin. The breast lesion as well as the solid areas of the endometrial lesion displayed a similar immunoprofile: GATA3-positive; synaptophysin positive; negative for mammaglobin, gross cystic disease fluid protein-15, chromogranin, estrogen receptor, progesterone receptor, and HER2/neu; and intact expression of the DNA mismatch repair proteins MLH1, MSH2, MSH6, and PMS2. The breast lesion was negative for PAX-8, whereas the solid areas of the endometrial lesion showed focal weak positivity. A review of the literature on GATA-3 expression in endometrial carcinomas found a reported frequency of expression that ranged from 0% to 13% of cases, typically in a patchy, focal, and generally restricted pattern. However, GATA-3 may be diffusely expressed in high-grade endometrial carcinomas. Since the potential for PAX-8 expression to be lost in high-grade endometrioid carcinomas is well known, a GATA-3-positive/PAX8-negative immunoprofile may be encountered in high-grade endometrioid carcinomas of the endometrium, and this composite immunoprofile is a potential diagnostic pitfall when such a lesion is being evaluated in a breast metastasis.

Collision Tumor of Endometrial Large Cell Neuroendocrine Carcinoma and Low-Grade Endometrial Stromal Sarcoma: A Case Report and Review of the Literature

Large cell neuroendocrine carcinoma (LCNEC) of the endometrium is an exceedingly rare histologic subtype of endometrial cancer (0.8%). These tumors are highly aggressive with a propensity for metastasis and have a poor prognosis. Among the 17 cases reported to date, 9 cases were pure large cell neuroendocrine tumors and 8 were collision tumors of LCNEC with endometrial carcinomas (7 endometrioid and 1 serous). In this article, we report a case of collision tumor composed of an endometrial LCNEC and a low-grade endometrial stromal sarcoma (LGESS). The patient was a 48 year-old woman who presented with a large abdominal mass for about 10 years and underwent total hysterectomy, bilateral salpingo-oophorectomy, and tumor debulking. Microscopic evaluation demonstrated an LGESS with extensive osseous metaplasia that penetrated through the myometrium and invaded into pelvic and abdominal cavity, forming a 40.0-cm mass. Cytogenetic analysis of the LGESS revealed an abnormal female karyotype (45, XX) with multiple structural abnormalities. Incidentally, small foci of LCNEC were identified within the endometrium. The LCNEC focally invaded the myometrium with involvement of the endocervix, extensive lymph-vascular space invasion, and metastases to bilateral ovaries. Subsequently, the patient was treated with cisplatin/etoposide chemotherapy and had been doing well for about a year until presenting with recurrence of LCNEC in the abdomen. She passed away a month later due to medical complications. This report reveals an extremely rare endometrial collision tumor with unusual pathologic features and clinical presentations.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia, Mimicking Pulmonary Metastasis

A Deceptive Spread: Myoinvasion of Endometrial Carcinoma Imitating Adenoma Malignum

Endometrioid type of endometrial carcinoma is the most common form of uterine malignancy. The majority of patients in the developed world present with the low-grade, low-stage type of this malignancy. The current treatment of early-stage endometrioid carcinoma provides most patients with a favorable outcome. One of the important factors that determine the outcome of early-stage endometrial carcinoma is the involvement of cervical stroma. One of the very rare forms of cervical stromal involvement by endometrioid carcinoma is termed “adenoma malignum type” invasion due to its similarity to the infamously deceptive type of cervical adenocarcinoma called adenoma malignum. Since adenoma malignum is often discovered incidentally, finding adenoma malignum type of myoinvasion may deceive a pathologist to diagnose the simultaneous presence of endometrial carcinoma and adenoma malignum in the same patient as 2 separate entities. Also, this type of myoinvasion may be missed altogether for its subtle nature. In this article, we report a case of low-grade, low-stage endometrioid carcinoma with adenoma malignum type of myoinvasion. We have pointed out the subtle nature of this lesion and the important features to remember to successfully identify it.

Clear Cell Endometrial Carcinoma In Situ (CCEIC) Exists!

Serous Tubal Intraepithelial Carcinoma–Like and Pagetoid Tubal Metastasis of an Ovarian Large Cell Neuroendocrine Carcinoma: Peculiar Metastatic Growth Patterns of a Rare Tumor

A large cell neuroendocrine carcinoma of the ovary is presented because of tubal metastases with peculiar growth patterns: pagetoid and serous tubal intraepithelial carcinoma–like. The possibility that a tubal intraepithelial carcinoma could represent a metastasis should be considered by pathologists.

Atypical Cells in Peritoneal Cleft: A Pitfall in Diagnosis of Colorectal Adenocarcinoma

Atypical cells in peritoneal clefts are usually either reactive mesothelial cells or pT4 colonic adenocarcinoma in colon specimen removed for primary colon cancer. However, rarely if ever are these atypical cells metastasis from other primary visceral malignancy due to “sac-like” anatomic structure of this area. We present a case where these atypical cells were determined to be metastasis of gynecological origin by judicious use of immunohistochemical stains. A final diagnosis of serous tubal intraepithelial carcinoma of right fallopian tube was diagnosed only after total abdominal hysterectomy bilateral salpingo-oophorectomy. To our knowledge, this is the first report of a serous tubal intraepithelial carcinoma presenting as stage 4 colonic adenocarcinoma. The importance of this interesting case is 2-fold. It highlights the peritoneal cleft as an anatomic region not often recognized or discussed as well as tumor presentation in this region. In addition, this example stresses the need for additional mesothelial markers in addition to WT-1 workup of atypical mesothelial proliferation.

A Focus of Differentiated Myeloid Sarcoma in a Ligation Specimen of the Fallopian Tube: No Evidence of Hematologic Abnormality in 18 Years of Follow-up Despite Absence of Treatment

A 0.2-cm intramural focus composed predominantly of myelocytes and metamyelocytes, many CD3+, CD43+ T-lymphocytes, scanty CD20+ B-lymphocytes, rare mast cells, but no eosinophils or myeloblasts was incidentally found in a ligation specimen of the left fallopian tube. The myeloid cells were positive for chloroacetate esterase, myeloperoxidase, myeloid marker BM2, and CD43, and they were negative for CD30, CD34, CD117, ERG, and TDT. The findings in the left fallopian tube were consistent with the diagnosis of differentiated myeloid sarcoma. The right fallopian tube was normal. No hematologic abnormalities were found elsewhere in the body. Curiously, the patient remains free of any hematologic abnormality for 18 years despite absence of treatment.

Primary Uterine Angiosarcoma Presenting With Omental Metastasis, Lymph Node Involvement, and Demonstrating a Null p53 Mutational Staining Pattern

In this report, we present a 51-year-old woman with months of heavy vaginal discharge, pain, nausea, and vomiting. Magnetic resonance imaging showed a large necrotic mass expanding the uterus with extension through the myometrium. Initial biopsy showed a malignant spindle cell neoplasm with high mitotic activity and necrosis. Immunohistochemistry (IHC) suggested a high-grade sarcoma, and further surgical resection confirmed a diagnosis of primary uterine angiosarcoma with positive ERG and CD31. Whole exome and whole transcriptome sequencing revealed pathogenic variants for CDKN2A (p.W110*; c.330G > A) and TP53 (c.782 + 1G > T; c.782 + 1G > T). Unfortunately, despite aggressive surgical management, the patient experienced rapid progression and succumbed to her disease within 5 months. Primary uterine angiosarcomas are exceedingly rare and clinically aggressive mesenchymal malignancies, with fewer than 30 tumors reported in the English literature. This report highlights the diagnostic challenges posed by primary uterine angiosarcomas, particularly due to their nonspecific high-grade morphology and focal vascular features. A broad IHC panel and molecular analysis can aid in accurate diagnosis.

Giant Cell Tumor of the Uterus: A Report and Review of the Literature

Giant cell tumors are neoplasms that usually occur in the long bones of young adults. They can rarely present in the soft tissue and may display malignant behavior. Giant cell malignancies have previously been reported as tumors primary of the uterus but are exceptionally rare. Although uncommon, it is important to consider when a neoplasm with osteoclast-like giant cells is encountered. In this report, we describe a 70-year-old female patient with an unremarkable past history who presented with an enlarged uterus. Transvaginal ultrasound demonstrated multiple fibroids and a thickened endometrium. A biopsy diagnosis of a highgrade sarcoma was rendered and further refined in the surgical resection as malignant giant cell tumor of the uterus. In this case report, we describe the findings of this case and discuss the differential diagnosis of this entity.

Endocervical Adenocarcinoma With Micropapillary Component, a Distinct Histological Subtype Associated With Aggressive Behavior and Poor Prognosis: A Clinicopathologic Study of 10 Patients

Objective. Endocervical adenocarcinoma (ECA) with a micropapillary component is considered to be associated with aggressive behavior and poor prognosis. So far, only limited studies investigated this histological subtype of ECA in the literature. In this study, we present a clinicopathological analysis of 10 such tumors. Methods. We retrieved ten ECAs with a micropapillary component between January 2014 and July 2023 and analyzed their clinicopathologic features. Results. At diagnosis, nine tumors (90%) were of advanced clinical stage (FIGO stage ≥ IIA), nine tumors (90%) exhibited deep stromal invasion (≥2/3 of the cervix), and three tumors (30%) showed parametrial involvement. Lymphovascular invasion was evident in all tumors (100%), and lymph node metastasis was found in eight tumors (80%). Among the 10 patients, six were alive without disease (60%), one had a recurrent/later metastatic tumor (10%), and three died from the disease (30%). Furthermore, eight tumors were positive for PD-L1 expression (80%), while only one tumor showed HER2 overexpression (10%), and one tumor exhibited p53 mutant-type staining (10%). Conclusion. Endocervical adenocarcinomas with micropapillary components are associated with aggressive clinical behavior and a poor prognosis, which can be found in various conventional histological types of ECAs regardless of the HPV status. The high prevalence of PD-L1 expression suggests that patients with micropapillary ECAs may be good candidates for PD-L1 inhibitor treatment.

Fumarate Hydratase-Deficient Abdominal Wall Leiomyoma Presenting a Decade Post-Fumarate Hydratase-Deficient Uterine Leiomyoma Excision: An Incidental or Syndromic Association?

Background: The occurrence of fumarate hydratase-deficient leiomyoma of the abdominal wall is exceptionally rare. Case Presentation: A 50-year-old female patient with a past medical history of fumarate hydratase-deficient uterine leiomyoma presented with a left lower quadrant abdominal mass that has been present for the past 2 years. An ultrasound revealed a 3.5 cm oval hypoechoic mass. A subsequent CT scan showed a 3.5 cm hyperdense mass within the left internal oblique musculature. No family history is noted. A biopsy of the mass exhibited bundles of spindle cell neoplasm exhibiting bizarre ovoid nuclei and eosinophilic cytoplasm. No evidence of mitotic figures or tumor necrosis was noted. Immunohistochemical staining showed positive staining for desmin and smooth muscle actin (SMA), but negative staining for MART-1, S100, and CD34. Lesional cells showed expression of 2-succinocysteine and loss of fumarate hydratase expression. A diagnosis of fumarate hydratase-deficient leiomyoma was rendered. Conclusion: This report reinforces the importance of considering genetic testing for fumarate hydratase mutations in the evaluation of extra-uterine leiomyomatous lesions. Comprehensive follow-up and clinical screening in individuals with new lesions and a known history of fumarate hydratase-deficient neoplasms is mandatory. Recent recommendations support the integration of morphology-based evaluation along with immunohistochemical staining and genetic testing as a part of the standard evaluation for all uterine leiomyomas.

Gastric Type Endocervical Adenocarcinoma With Concurrent High-Grade Squamous Intraepithelial Lesion: A Clinicopathologic Study of Three Patients

Objective: We investigate gastric-type endocervical adenocarcinoma (ECA), a prominent HPV-independent adenocarcinoma, and its coexistence with high-grade squamous intraepithelial lesion (HSIL) through the examination of three such tumors. Methods: In this study, we conducted an in-depth review of three patients with gastric-type ECA, each associated with high-risk HPV infection as detected on Pap smears. We detailed the clinical and pathological features of each patient and utilized RNAscope for high-risk HPV testing to ascertain HPV status in both gastric-type ECA and HSIL components. Immunohistochemistry with p16, p53, and other biomarkers was also applied. Results: The gastric-type ECA component, characterized by well-differentiated glands with abundant, clear to eosinophilic cytoplasm, distinct cellular borders, and pale nuclei with conspicuous nucleoli, tested negative for both p16 and high-risk HPV, unlike the concurrent HSIL components which were positive. Additionally, two tumors showed aberrant p53 protein expression in the gastric-type ECA areas, and elevated carbohydrate antigen19-9 levels were noted in two patients. Treatment consisted of total abdominal hysterectomy and bilateral salpingo-oophorectomy, supplemented by chemotherapy and/or radiation, with disease-free intervals of 24, 12, and 40 months post-treatment, respectively. Conclusion: This study highlights the critical need for meticulous diagnostic protocols that combine morphological examination, immunohistochemistry, and HPV RNA in situ hybridization. The rarity of gastric-type ECA coexisting with HPV infection underscores the necessity for continuous research and vigilant monitoring in the field of gynecological oncology.

Ovarian Mesonephric-Like Adenocarcinoma With Recurrent Liver Metastases: A Case Report with Analysis of Therapeutic Molecular Targets

Ovarian mesonephric-like adenocarcinoma (MLA) is a rare cancer subtype. We describe a patient with ovarian MLA wherein liver metastases developed 1 month after surgery. A phenotypic analysis of the tumor was performed to identify molecular therapeutic targets. A 53-year-old woman, without any symptoms, underwent uterine cancer screening. Transvaginal ultrasonography revealed an ovarian mass, and subsequent pelvic magnetic resonance imaging showed a 13 × 10 cm multicystic ovarian lesion with a solid part. No extra ovarian lesions were observed and a staging laparotomy was performed. Pathological examination revealed an MLA of the left ovary (stage IC1). The tumor comprised tumor cells in a tubular pattern with intraluminal eosinophilic material, as well as mixed glandular and papillary, cord-like, and solid patterns. Endometriosis was also observed. Immunohistochemically, the tumor cells were positive for PAX8, GATA3 (focal), TTF1 (focal), and CD10 (luminal) and negative for the estrogen receptor, progesterone receptor, and WT1. One month after surgery, computed tomography revealed multiple liver metastases. Additional immunohistochemistry for therapeutic targets revealed that the tumor cells were weakly positive for human epidermal growth factor receptor 2 (focal; score 1+), pan-tropomyosin receptor kinase-negative, programmed death-ligand 1-negative, and PMS2 and MSH6 intact. The companion homologous recombination deficiency test (MyChoice®) showed homologous recombination repair proficiency. These findings suggest that poly(ADP-ribose) polymerase inhibitors and immune checkpoint inhibitors may not be effective treatment options. A literature review revealed that data on therapeutic targets in MLA are scarce. In summary, we report a patient with ovarian MLA showing an aggressive clinical course and the phenotypic analysis of the tumor may contribute to the identification of therapeutic targets for MLA.

Mixed Mesonephric-like Adenocarcinoma, Clear Cell Carcinoma, and Endometrioid Carcinoma Arising from an Endometriotic Cyst

Mesonephric-like adenocarcinoma is a rare neoplasm of the uterine corpus and ovary. Unlike prototypical mesonephric adenocarcinoma of the uterine cervix, which is considered of Wolffian origin, recent evidence suggests that mesonephric-like adenocarcinoma is a Mullerian tumor associated with endometriosis. We report here on a 48-year-old woman with a mixed carcinoma of the ovary that consisted of mesonephric-like adenocarcinoma, clear cell carcinoma, and endometrioid carcinoma, arising from an endometriotic cyst. The mesonephric-like adenocarcinoma consisted of cuboidal cells with vesicular nuclei presenting with a tubular, ductal, papillary, and solid architecture forming nodules. Each component showed distinct immunophenotypes that were consistent with their morphology. The mesonephric-like adenocarcinoma showed diffuse positive staining for paired box 8 and GATA binding protein 3, and negative staining for estrogen and progesterone receptors. A p53 stain exhibited wild-type immunoreactivity. A complete loss of AT-rich interactive domain-containing protein 1A (ARID1A) expression was suggestive of an ARID1A mutation. Manual macrodissection and Sanger sequencing revealed identical KRAS and PIK3CA mutations in all three components. To the best of our knowledge, this is the first report of mesonephric-like adenocarcinoma combined with a clear cell carcinoma and endometrioid carcinoma, which supports the hypothesis that mesonephric-like adenocarcinoma is an endometriosis-associated neoplasm. The report also highlights a potential pitfall in diagnosing mesonephric-like adenocarcinoma combined with clear cell carcinoma.

Uterine Angioleiomyoma: Clinical and Histopathologic Differentiation of an Underrecognized Mimicker of Uterine Leiomyoma

Angioleiomyoma is an uncommon benign neoplasm of mesenchymal origin that arises from perivascular smooth muscle cells. This soft tissue neoplasm usually occurs in the dermal or subcutaneous tissues of the extremities, head and neck, or trunk with fewer than 40 reported angioleiomyomas arising in the uterine corpus. Herein we report a uterine angioleiomyoma in a 44-year-old G5P4 Hispanic woman with a longstanding history of recurrent abdominal pain, pelvic organ prolapse, abnormal uterine bleeding, anemia, and hypertension. The patient underwent surgical treatment with total laparoscopic hysterectomy with bilateral salpingectomy and a uterosacral ligament suspension. Uterine angioleiomyoma was diagnosed post-operatively based on gross and microscopic features. The location of the uterine angioleiomyoma within the myometrium corresponded with contrast enhancement apparent on preoperative imaging. This and other uterine angioleiomyomas have characteristic imaging, macroscopic, and microscopic features which distinguish it from leiomyoma. Enhancing awareness of this underrecognized entity will facilitate precise diagnosis and thereby enable improved understanding of the clinicopathological characteristics of uterine angioleiomyoma.

A Curious Case of Omental Oxalate Crystals in a Patient With Struma Ovarii: Pointers to an Unusual Clinicopathological Scenario

Percutaneous image-guided biopsies are becoming increasingly common in routine pathology practice, with the greater omentum emerging as a common target. We present herein an account of a middle-aged lady with a complex ovarian mass, omental thickening, and raised serum CA125; clinically suspected to have advanced ovarian malignancy. Fine needle aspiration cytology (FNAC) from the ovarian mass was inconclusive. Omental biopsy revealed only refractile, birefringent crystalline material with surrounding foreign body giant cell reaction; thus surprising the clinical team. Subsequent resection of the ovarian mass showed a teratoma composed exclusively of thyroid tissue, diagnosed as struma ovarii. The omental crystals, interpreted as calcium oxalate crystals, were possibly a consequence of colloid seeding during the ovarian mass FNAC.

Ovarian Mucinous Tumor Presenting Atypical Lobular Endocervical Glandular Hyperplasia-Like Appearance in a Patient With Germline STK11 p.F354L Variant: A Case Report

Peutz-Jeghers syndrome (PJS) is associated with female genital lesions, such as cervical gastric-type adenocarcinoma and lobular endocervical glandular hyperplasia (LEGH). However, ovarian mucinous borderline tumors (OMBT) with atypical LEGH-like histology have not been described. The patient was a 60-year-old female with PJS clinically diagnosed at 23 years old with gastrointestinal polyposis. Abdominal distension was noted, and computed tomography scan revealed bilateral breast masses, multiple lung nodules, and a multicystic ovarian tumor. A needle biopsy revealed invasive ductal carcinoma of the breast. For the ovarian tumor, simple hysterectomy and bilateral salpingo-oophorectomy were performed. The left ovarian tumor was 25 × 20 × 12 cm in size and a multicystic tumor containing yellowish mucus without a solid part. Histologically, the cyst wall was covered with mucus cells with focal mild-to-moderate cellular atypia, forming LEGH-like architectures. The glandular cells were immunohistochemically positive for MUC5AC, MUC6 (focal), HIK1083 (focal), and HNF4α. Stromal invasion was not observed. Cervical lesions were not observed. The final pathological diagnosis was OMBT showing atypical LEGH morphology. Targeted sequencing of nontumor tissues revealed the germline STK11 p.F354L variant. Six months later, peritoneal dissemination of adenocarcinoma showing features similar to those of the ovarian tumor was observed, and the patient died of the disease. In summary, we report a case of OMBT with an atypical LEGH-like appearance in a patient with germline STK11 p.F354L variant. This case provides us with unresolved questions regarding the pathogenicity of this STK11 variant and the malignant potential of OMBT with this unusual morphology.

Adenoid Basal Carcinoma with Adenoid Cystic Carcinoma Component of the Uterine Cervix: A Case Report and Literature Review

Adenoid basal carcinoma (ABC) is rare cancer with a favorable prognosis. However, some ABCs are associated with other histological types, such as squamous cell carcinoma. Here, we present a case of a mixed tumor of ABC and adenoid cystic carcinoma (ACC) of the cervix, with a detailed immunohistochemical study and literature review. We describe a case of a 66-year-old woman who underwent cervical cancer screening that led to the detection of a 0.7 cm nodular lesion. Cervical punch biopsies revealed a high-grade squamous intraepithelial lesion. Cervical conization revealed a mixed carcinoma composed of ABC and ACC, showing stromal invasion, lymphovascular invasion, and positive resection margins. Immunohistochemically, the ACC components were positive for KIT and αSMA and negative for NKX3.1. The tumor presented with proficient mismatch repair (MMR) and was negative for HER2, PD-L1, and TRKA (NTRK1). Subsequent radical hysterectomy with pelvic lymph node dissection revealed the presence of residual tumor cells in the cervix. Our literature review identified six similar cases, including one patient who died of disease recurrence. We report a rare tumor comprising both ABC and ACC. Prognostic data on mixed tumors are scarce; however, given the aggressive nature of ACC, attention should be paid to the detection of mixed tumors. Since ABC and ACC histology may overlap, adequate sampling and IHC for detecting ACC would be helpful.

Expression of p16 Tumor Suppressor Protein in Malignant Ovarian Germ Cell Tumors; Immunohistochemical Study

Background Malignant ovarian germ cell tumors represent small percentage of malignant ovarian neoplasms but they affect significantly young age group. Aim of the study To investigate the immunohistochemical expression of p16 tumor suppressor protein in malignant ovarian germ cell tumors. Materials and Methods Twenty-two malignant ovarian germ cell tumors (five dysgerminoma, eight immature teratoma, and nine yolk sac tumors), twenty mature cystic teratoma tumors and twenty normal ovarian tissue were immunohistochemically stained with p16 monoclonal antibody. Ki67 immunohistochemical staining was done for malignant ovarian germ cell tumors to assess proliferation. Results We found that p16 tumor suppressor protein is overexpressed in all malignant ovarian germ cell tumors in both nuclear and cytoplasmic locations compared to control and to mature cystic teratoma ( p-value <0.001). Cytoplasmic p16 expression was significantly correlated to Ki67 proliferation index in malignant ovarian germ cell tumors ( p-value = 0.033, r = 0.445). Conclusion Overexpression of p16 in malignant ovarian germ cell tumors denotes that dysfunction of the cyclin dependent kinase pathway is involved in tumorigenesis of malignant ovarian germ cell tumors.

Bilateral Peutz–Jeghers-Associated Sex Cord Tumor With Annular Tubules Combined With Unilateral Adult Granulosa Cell Tumor: A Case Report

Sex cord tumor with annular tubules (SCTATs) is a rare sex cord stromal tumor in the ovary. SCTAT combined with adult granulosa cell tumor (AGCT) is even rarer. Here, we report a unique case of ovarian tumors with mixed AGCT and SCTAT components. Due to the unusual coexistence, molecular testing was separately performed on each ovary. Both SCTAT and AGCT components were found to have STK11 germline mutation. Furthermore, the AGCT component had an additional FOXL2 somatic mutation. Based on medical history and molecular testing we conclude that the ovarian tumors were associated with Peutz–Jeghers syndrome (PJS). Thus, we present the first report of bilateral PJS-associated SCTAT combined with unilateral AGCT.

Diagnostic Discordance in Intraoperative Frozen Section Diagnosis of Ovarian Tumors: A Literature Review and Analysis of 871 Cases Treated at a Japanese Cancer Center

Background This study examined the accuracy and pitfalls associated with frozen section diagnosis of primary ovarian tumors and ovarian metastases based on the 2014 World Health Organization classification (WHO) criteria and proposed improvements from a pathologist’s perspective. Methods We microscopically reviewed 871 cases of primary ovarian tumor (N = 802) and ovarian metastasis (N = 69) and compared the results of frozen sections with the final diagnosis. Malignant potential concordance (benign, borderline, or malignant) and specific discordant diagnosis rates were analyzed. Finally, we conducted a unique literature review of specific diagnostic errors in the frozen section diagnosis of primary ovarian tumors. Results Of 802 primary ovarian tumors, 50 (6.2%) cases showed discordant diagnoses in which mucinous carcinoma (40.5%), low-grade serous carcinoma (LGSC; 31.3%), and mucinous borderline tumor (18.4%) were frequently misinterpreted. Of 69 ovarian metastases, all 4 cases of low-grade appendiceal mucinous neoplasm (LAMN) were misdiagnosed as primary ovarian mucinous tumor. A literature review revealed that mucinous/serous borderline tumor or carcinoma accounted for approximately 70% of 217 reported discordant diagnoses. Conclusion In the present study, the concordance rate of malignant potential of the tumor was comparable to that previously reported. Even in the 2014 WHO classification, primary ovarian mucinous borderline tumor/carcinoma and LGSC still comprised the majority of discordant cases. Grossing methods that reduce sampling error are required. LAMN was frequently misinterpreted as a benign or borderline ovarian mucinous tumor. To prevent this error, a differential algorithm integrating clinical information and gross findings should be developed.

Sex Cord Tumor With Annular Tubules–Like Histologic Pattern in Adult Granulosa Cell Tumor: Case Report of a Hitherto Unreported Morphologic Variant

Adult granulosa cell tumor (AGCT) and sex cord tumor with annular tubules (SCTAT) are distinct sex cord stromal tumors with different molecular signatures. We present a unique case of an incidental ovarian tumor with mixed AGCT and SCTAT morphologic patterns. Due to the unusual co-occurrence, molecular testing was separately performed on both components. Despite minimal overlap in morphology, both the SCTAT and AGCT components were found to have an identical mutation profile, including the prototypical FOXL2 p.C134W mutation characteristic of AGCT. We thus present the first report of AGCT with SCTAT-like pattern.

Small Cell Carcinoma of the Ovary: Clinicopathologic and Immunohistochemical Analysis of 7 New Cases of a Rare Malignancy

Background Small cell carcinoma of ovary (SCCO) is extremely rare. Two types of SCCO are recognized, the pulmonary type (SCCOPT) and the hypercalcemic type (SCCOHT). Establishing an accurate diagnosis is challenging, owing to its rarity and paucity of data describing the distinctive histopathologic and immunohistochemical (IHC) features. Methods This was a retrospective study conducted over a period of 4 years. All cases reported as SCCO on histopathology were retrieved. All the available clinical, histopathological, and IHC features were studied in detail. Results A total of 7 cases of SCCO were diagnosed during the study period. There were 4 cases of SCCOPT and 3 cases of SCCOHT and with mean age of 57.25 and 22 years, respectively. All the cases presented as stage IV disease. Among the SCCOPT cases, 3 showed bilateral involvement with 1 showing concurrent uterine endometrioid adenocarcinoma. Microscopy revealed small hyperchromatic cells with brisk mitosis and multifocal necrosis. On IHC, these were consistently positive for chromogranin, CD56, and synaptophysin. All the SCCOHT cases showed unilateral involvement. Microscopically, in addition to small hyperchromatic cells, larger “rhabdoid” tumor cells were also seen. On IHC, chromogranin was negative, with positivity for vimentin and epithelial membrane antigen. The expression of SMARCA4/BRG1 was lost while SMARCB1/INI1 was retained in all cases. All of these patients developed recurrence and died due to disease progression despite treatment. Conclusions SCCO is an extremely infrequent ovarian malignancy with poor prognosis. Knowledge about its characteristic features is important for accurate tissue diagnosis and appropriate management.

Metaplastic Potential of Müllerian Epithelia in Full Display!

A Hairbrained Mature Cystic Ovarian Teratoma: With Bone Marrow, Meninges, and Intraglial Hair

Ovarian Fibroma With Bizarre Nuclei: A Rare Finding

Gynecologic Tract Lymphomas: A Clinicopathological Analysis of a Single Institution Case Series

Background Lymphomas involving gynecologic organs often occur in the ovaries, and uterine cervix. Uterine corpus, vagina, and vulva are less common locations involved. Although female genital tract lymphomas are uncommon, it is important for the gynecologists and pathologists to be aware of this entity as it potentially could be the first presenting location of lymphoma or involved secondarily. Methods Pathology of lymphomas first diagnosed in and secondarily involving gynecologic organs from January 2005 to January 2024 were retrieved from our institution's pathology databases, and their clinicopathological features were reviewed. Results A total of 19 patients with lymphomas involving the gynecological organs were identified with 17 patients being first-time diagnosed with lymphomas on gynecologic surgical pathology specimens and 2 patients with prior history of lymphoma. The average age of patients with lymphoma diagnosed initially in the gynecologic tract was 59.2 years (range 20-83 years). The two patients with prior lymphoma histories had diffuse large B-cell lymphomas (DLBCL) with one transformed from prior retroperitoneal low-grade follicular lymphoma. The cervix was the most frequent location of first-time diagnosed lymphomas, comprising 8 of 17 specimens (47%), followed by bilateral ovaries and fallopian tubes (41%), endomyometrium (12%), and vagina (6%). The types of first diagnosed gynecologic lymphomas were DLBCL (65%), follicular lymphoma (18%), lymphoplasmacytic lymphoma (6%), Burkitt lymphoma (6%) and extranodal marginal zone B-cell lymphoma (MZBCL) (6%). When the criteria of defining primary gynecologic lymphomas were applied, 7 of 17 first-time diagnosed lymphomas in the gynecologic tract were actually primary gynecologic lymphomas without distant disease, peripheral blood or bone marrow involvement, including 5 cervical primary, one endometrial primary and one vaginal primary lymphoma. Conclusion Our study confirmed that the most common lymphomas involving the gynecologic tract were DLBCL and follicular lymphoma, with rare incidence of Burkitt lymphoma, extranodal MZBCL and lymphoplasmacytic lymphoma. Misdiagnosing gynecologic lymphomas as high-grade/undifferentiated carcinoma or sarcoma is a real risk for surgical pathologist, especially during frozen sections.

Lactating Vulvar Adenoma Associated With Fibroadenoma

Ectopic breast is found to occur most commonly in the axilla, but also less commonly on the vulva and on sites outside the “milk line” like the face, neck and chest. Vulvar adenofibroma developing on ectopic breast tissue in the vulva is exceptionally rare. More precisely, vulvar adenofibroma associated with adenoma with lactating changes has only been documented three times to our knowledge. We herein report a vulvar mass specimen consistent with vulvar lactating adenoma associated with vulvar fibroadenoma occurring in a 36-year-old woman in the postpartum period.

Pagetoid Squamous Intraepithelial Neoplasia of the Vulva as a Mimicker of Vulvar Extramammary Paget Disease: Two Cases with Basal Layer Sparing

Human papillomavirus-associated vulvar intraepithelial neoplasia (high-grade squamous intraepithelial neoplasia [HSIL] or VIN of usual type) is a lesion characterized by atypia extending from the basal layer to the upper epidermis. There are only rare reports of vulvar intraepithelial morphology exhibiting a pagetoid pattern of intraepithelial dissemination. We herein report two cases of vulvar HSIL in which a pagetoid pattern of spread and a largely uninvolved basal layer represented a diagnostic pitfall for extramammary Paget disease. Nuclear atypia reminiscent of HSIL in addition to expression of p16, KRT5/6, and p40 were however in favor of pagetoid HSIL. Although there is morphological and immunohistochemical overlap between these two entities, an accurate diagnosis is important, since an erroneous diagnosis of vulvar extramammary Paget disease may lead to an extensive workup comprising radiological imaging, colonoscopy, and cystoscopy.