Mitsutake Yano

Clinicopathological pitfalls associated with benign uterine mesenchymal tumors: A single-center experience

Diagnosis of uterine mesenchymal tumors continues to be challenging because of their nonspecific clinicopathological presentation. Several studies have focused on the underdiagnosis/undertreatment of hidden uterine sarcomas. However, few have examined the overdiagnosis/overtreatment of benign uterine mesenchymal tumors that masquerade as uterine sarcomas. We report 4 cases of benign uterine mesenchymal tumors that were preoperatively diagnosed as having malignant potential and underwent extensive surgery. The patients had cotyledonoid-dissecting leiomyomas, uterine tumors resembling ovarian sex-cord tumors, metastasizing leiomyomas, and torsion of a subserosal uterine leiomyoma. The patients’ ages ranged from 42 to 59 years (median 51.5). All 4 cases were suspected of having a malignant tumor based on preoperative clinical imaging, and 1 case was suspected of having a malignant tumor based on preoperative imaging and pathological evaluations of biopsy. All patients underwent surgery, including a hysterectomy. One of the 4 patients (25%) underwent lymphadenectomy, and 1 (25%) underwent partial lung resection. All patients survived without evidence of disease. Overall, detailed pre- and intraoperative clinical and pathological evaluations may be insufficient for diagnosis. Physicians should be aware of the diversity of uterine mesenchymal tumors, the difficulty in diagnosing them, and how to avoid these pitfalls.

Genetic Profiling of Sebaceous Carcinoma Arising from an Ovarian Mature Teratoma: A Case Report

Ovarian mature teratomas (OMTs) originate from post-meiotic germ cells. Malignant transformation occurs in approximately 1–2% of OMTs; however, sebaceous carcinoma arising from OMTs is rare. This is the first report of a detailed genomic analysis of sebaceous carcinoma arising from an OMT. A 36-year-old woman underwent evaluation for abdominal tumors and subsequent hysterectomy and salpingo-oophorectomy. Pathologically, a diagnosis of stage IA sebaceous carcinoma arising from an OMT was established. Eight months post-surgery, the patient was alive without recurrence. Immunohistochemically, the tumor was negative for mismatch repair proteins. A nonsense mutation in TP53 (p.R306*) and a deletion in PIK3R1 were identified. Single nucleotide polymorphisms across all chromosomes displayed a high degree of homozygosity, suggestive of uniparental disomy. Herein, the OMT resulting from the endoreduplication of oocytes underwent a malignant transformation to sebaceous carcinoma via TP53 as an early event and PIK3R1 as a late event.

Therapeutic indications for antibody-drug conjugates estimated from HER2 and p53 expressions in endometrial carcinoma

While human epidermal growth factor receptor 2 (HER2) is upregulated in endometrial carcinoma-especially in the p53 aberrant type- conventional anti-HER2 therapy is not typically used for this cancer type. Recently, HER2-targeted antibody-drug conjugates have shown antitumor effects against HER2 low-expressing cancers. Therefore, we analyzed the clinicopathological characteristics of HER2-positive endometrial carcinomas including those with low expression, as well as the prognostic significance of p53 and HER2 co-expression. Immunohistochemistry for HER2 and p53 was performed in 530 patients with endometrial carcinoma; 124 cases (23%) were HER2-positive. Of the HER2-positive cases, >50% were 1+. A high prevalence of HER2 expression was observed in serous (64%), clear-cell (73%), and mixed (64%) carcinomas. Notably, 19% of endometrioid carcinomas were HER2-positive. HER2 positivity was significantly associated with age ≥60 years, high-grade histological subtype, deep myometrium invasion, stage III/IV, recurrence, and death. Univariate analysis showed that HER2-positive cases had reduced progression-free survival (PFS) (p = 0.007) and overall survival (OS) (p = 0.012). However, after adjusting for stage, HER2 positivity was not associated with survival. In the early stage, co-expression of HER2-positive and p53 aberrant types was associated with shorter PFS (p < 0.001) and OS (p < 0.001) compared with at least one negative result. Multivariate analysis of PFS showed HER2 and p53 co-expression (hazard ratio, 1.891; 95% confidence interval, 1.183-5.971, p = 0.008) as an independent prognostic factor. This study presents detailed clinicopathological characteristics and the prognostic impact of HER2-positivity in endometrial carcinomas. HER2-targeted antibody-drug conjugate therapy may be broadly applicable to endometrial carcinoma.

Vulvar neuroendocrine carcinoma that is independent of merkel cell polyomavirus and human papillomavirus suggests endometrial cancer recurrence: a case report

Abstract Background Vulvar neuroendocrine carcinomas with small cell morphology need an appropriate differential diagnosis with respect to primary Merkel cell carcinomas, primary small cell neuroendocrine carcinomas, and secondary/metastatic carcinomas. Herein, we report a woman with a history of endometrial carcinoma led to neuroendocrine vulvar carcinoma. Case presentation An 82-y-old woman with right vulvar swelling was transferred to our hospital. Computed tomography scan showed a 75 mm irregular mass in her right vulva. Three years ago, she had been diagnosed with endometrial endometrioid carcinoma stage IA and had undergone surgery. Vulvar biopsy revealed neuroendocrine carcinomas with small cell morphology. Immunohistochemical staining showed that the vulvar tumor was positive for CD56 and chromogranin A, but negative for Merkel cell polyomavirus and cytokeratin 20. Incidentally, her endometrial carcinoma was also positive for CD56 and chromogranin A. Human papillomavirus DNA typing analysis of vulvar tumor was negative. Hence, the vulvar tumor seemed to be a recurrence of the endometrial cancer rather than a primary vulvar neuroendocrine carcinoma. The patient died of the disease within a month. Conclusion We report a case of vulvar neuroendocrine carcinoma that is independent of Merkel cell polyomavirus and human papillomavirus, thereby suggesting a recurrence of endometrial cancer. Immunohistochemical and virological analyses helped in the differential diagnosis of the neuroendocrine carcinoma.

Histological classification of uterine cervical adenocarcinomas: Its alteration and current status

AbstractAdenocarcinomas (ADCs) of the uterine cervix are relatively minor compared to squamous cell carcinomas. However, ADCs are histologically and histogenetically unique, especially because they can be with or without human papillomavirus (HPV) infection. At present, ADCs are divided into tumors as HPV‐associated ADCs (HA‐ADCs) and HPV‐independent ADCs (HI‐ADCs), including adenocarcinomas in situ (AIS) as their precursor, both of which consist of variable histological types. The usual‐type accounts for the majority of HA‐ADCs, and the gastric‐type is a representative of HI‐ADCs. Notably, it is clinicopathologically significant to differentiate between HA‐ADCs and HI‐ADCs because of the discrepancy in prognosis between them. Although relatively rare in comparison with HPV‐associated AIS (HA‐AIS), HPV‐independent AIS (HI‐AIS) has gradually attracted attention since gastric‐type ADC (g‐ADC) was introduced in the World Health Organization Classification 4th ed. (2014). Occasional HA‐ADCs and HI‐ADCs, including HA‐AIS and HI‐AIS, require p16 immunostaining, in situ hybridization, or HPV testing to differentiate between them because morphological features alone cannot often be conclusive for the diagnosis. A system focusing on the infiltrative pattern has been introduced due to its clinicopathological value. Staging criteria of HA‐ADCs with polypoid/exophytic growth, recommended by the International Collaboration on Cancer Reporting, may supplement the International Federation of Gynecology and Obstetrics staging system for clinical management and treatment.

Usage of nivolumab and ipilimumab for recurrent or advanced malignant vaginal melanoma: a two-case series

AbstractImmune checkpoint inhibitors help treat malignant melanoma, but show limited use in treating malignant vaginal melanoma, an aggressive, rare gynecological malignancy. We identified two patients treated with ipilimumab and nivolumab for vaginal melanoma; both were immunonegative for programmed cell death-ligand 1 and wild-type BRAF. Case 1, a 56-year-old female who underwent radical surgery for stage 1 malignant vaginal melanoma, experienced recurrence 15 months postoperatively. She briefly responded to ipilimumab and nivolumab combination therapy before showing disease progression. Tumor shrinkage occurred with nivolumab and local radiotherapy and, 45 months postoperatively, she survives with the melanoma. Case 2, a 50-year-old female, presented with a 4-cm blackish polypoid vaginal tumor with metastatic pelvic lymph nodes. She received ipilimumab and nivolumab combination therapy for stage III unresectable malignant vaginal melanoma. The vaginal tumor shrank after the third course of treatment, and the lymphadenopathy disappeared. The patient underwent radical surgery and is currently disease-free, using nivolumab for maintenance therapy. Both patients had immune-related adverse events coinciding with periods of high therapeutic efficacy of immune checkpoint inhibitors. Neoadjuvant therapy with immune checkpoint inhibitors and radiotherapy for immune checkpoint inhibitor resensitization may effectively treat advanced or recurrent vaginal melanoma.

Immunohistochemical and molecular analysis of an α-fetoprotein-producing cervical adenocarcinoma with clear cell morphology

Adenocarcinomas with clear cell morphology may be associated with elevated serum alpha-fetoprotein levels in various organs. We report the case of an alpha-fetoprotein-producing cervical adenocarcinoma with clear cell morphology and compare it immunohistochemically, molecularly, and virologically with cervical clear cell carcinoma, gastric-type mucinous carcinoma, and ovarian clear cell carcinoma. A 51-year-old Japanese woman was initially diagnosed with cervical clear cell carcinoma. The tumor was resistant to standard surgery, radiotherapy, and chemotherapy. Serum carcinoembryonic antigen and alpha-fetoprotein were elevated. The tumor was immunohistochemically positive for alpha-fetoprotein, human chorionic gonadotropin, cytokeratin 20, spalt-like transcription factor 4, glypican 3, MUC6, and HIK1083. Gene panel testing revealed CCNE1 amplification, CDKN2A loss, and TP53 R282W. We compared the present case with 120 ovarian clear cell carcinoma cases using a tissue microarray. Only one case (0.8%) showed very limited immunohistochemical positivity for alpha-fetoprotein. Of the 54 cases in which serum carcinoembryonic antigen was measured, only one (1.9%) was elevated (19.9 ng/mL). We diagnosed the case as alpha-fetoprotein-producing cervical gastric-type mucinous carcinoma with enteroblastic differentiation. In conclusion, alpha-fetoprotein-producing cervical adenocarcinoma is a rare but aggressive tumor. Clinicians and pathologists should be aware of this unfamiliar tumor, its diagnostic clues, prognostic markers, and treatment strategies.

PPP2R1A mutations portend improved survival after cancer immunotherapy

Immune checkpoint blockade (ICB) therapy is effective against many cancers, although resistance remains a major issue and new strategies are needed to improve clinical outcomes

Human epidermal growth factor receptor 3 expression in patients with epithelial ovarian cancer: a potential target for ovarian mucinous and clear cell carcinoma

Human epidermal growth factor receptor 3 (HER3), a tyrosine kinase belonging to the HER family, is a known target for cancer therapy; recently, an anti-HER3 antibody-drug conjugate (ADC) is developing. To understand HER3 expression in epithelial ovarian cancer (EOC), this study was conducted. We investigated the expression of HER3 in 202 patients with EOC using immunohistochemistry (IHC), and the association between HER3 expression, clinicopathological features, prognosis, and treatment timing. Of all the cases, 55.4% had a HER3 IHC score ≥ 1 + . In particular, 78.0% of the patients with clear cell carcinoma (CCC) and 87.9% of the patients with mucinous carcinoma (MC) had a HER3 IHC score ≥ 1 + . Regarding clinicopathological features, early disease stage, feasibility of primary debulking surgery, no residual tumor, and low CA125 levels were more frequently observed in patients with a HER3 IHC score ≥ 1 + . Furthermore, a HER3 no-expression showed a significant association with a relatively short progression-free survival (PFS). And, for patients with mucinous carcinoma, those with a HER3 IHC score ≥ 1 + had poorer PFS and overall survival than those with a HER3 no-expression (no statistically significant difference). In addition, we analyzed HER3 expression at primary tumor and recurrence tumor in same patients. Thus, we observed the HER3 IHC score tended to change from 0 to ≥ 1 + in recurrence cases compared with primary cases. These observations suggested that patients with MC, CCC and recurrence of all histological type may potentially benefit from future clinical trials of HER3-directed therapies.