Simona Stolnicu

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.

Role of human papillomavirus status in the classification, diagnosis, and prognosis of malignant cervical epithelial tumors and precursor lesions

Cervical cancer ranks as the fourth most common malignant tumor in the female genital tract. Despite numerous efforts to reduce both the incidence and mortality in recent decades, it is still considered a major health issue worldwide. Previous classifications and diagnostic criteria relied on morphologic features only, lacking clinical and/or pathogenetic correlations. The present review focuses on some new developments regarding the significant role of human papillomavirus (HPV) status for the diagnosis, classification, and prognosis of the most frequent malignant cervical epithelial tumors (squamous cell carcinoma and endocervical adenocarcinoma) and their precursor lesions. The current World Health Organization (WHO) 2020 classification and morphologic criteria proposed by the International Endocervical Classification and Criteria (IECC) in 2018 are detailed. Ancillary studies to help the differential diagnosis are presented, including the critical role of p16, HPV test, and, more recently, p53. Although the management of HPV-associated and HPV-independent cervical cancer is similar at present according to current international guidelines, recent studies have highlighted the significance of HPV status for determining patient survival and response to treatment. As a consequence, personalized management approaches based on these factors could enhance treatment outcomes. Future national screening programs should integrate the information on recently described HPV-independent squamous and glandular precursor lesions.

Cervical Human Papillomavirus–Independent Squamous Cell Carcinoma: A Clinicopathological Review and Outcomes Analysis Compared With Human Papillomavirus–Associated Squamous Cell Carcinoma

Human papillomavirus (HPV)-independent cervical squamous cell carcinomas (HPVI SCCs) represent a poorly characterized entity. We aimed to explore the clinicopathological and survival features in the largest series of HPVI SCCs and compare them to HPV-associated (HPVA) SCCs. Eighty-nine cases of SCC previously tested negative for high-risk and low-risk HPV were collected from 22 institutions. A total of 363 HPVA SCCs were retrieved from a previously published database. Demographic and clinicopathological features, including p16 and p53 immunohistochemistry, and follow-up data were recorded. Forty-nine of 89 cases were classified as "true" HPVI SCC (HPV-/p16-), whereas 40 were equivocal HPVI SCC (HPV-/p16+ or HPV-/p16 not performed) and were excluded. The median age of true HPVI SCCs was 68 (range, 36-88) years and 38 (77.6%) patients were diagnosed aged 60 years or older. Seven (14.2%) had a history of uterine prolapse. Compared with HPVA SCC, patients with HPVI SCCs were older (P < .001), had larger tumors (P < .001), were diagnosed at higher Federation of Gynecology and Obstetrics stage (P < .001), recurred more frequently (P < .001) and had worse survival (P < .001). True HPVI SCCs also more frequently had keratinizing histology (P = .001) and abnormal p53 (P < .001). In a bivariate analysis adjusted for Federation of Gynecology and Obstetrics stage, HPVI p53-abnormal SCC had a higher risk of recurrence (P = .068; P < .001) and death of disease (P = .062; P < .001) than HPVI p53-wild type SCC and HPVA SCC. Survival outcomes (recurrence and disease-specific survival) in HPVI SCC and HPVA SCC differed significantly when comparing surgically treated HPVI SCC and HPVA SCC (P < .0001 for both). Even with the challenges associated with an analysis of a heterogeneous study set, we confirm that HPVI cervical SCCs have distinctive clinicopathological features. p53-Abnormal and p53-wild type HPVI SCC neoplasms exist in the uterine cervix, and p53-abnormal tumors are more aggressive. Although HPVI SCC is more frequently keratinizing than HPVA SCC neoplasms, there is substantial morphologic overlap, so HPV testing (or p16 at least) and p53 should be considered in cervical SCC, especially in patients over the age of 60 years.

The evolving spectrum of endocervical adenocarcinoma in situ (AIS)

Horizontal tumor extent (HZTE) has limited prognostic significance in 2018 FIGO stage I endocervical adenocarcinoma (ECA): a retrospective study of 416 cases

The 2018 International Federation of Gynecology and Obstetrics (FIGO) update on cervical cancer staging eliminated horizontal tumor extent (HZTE) as a staging parameter in stage IA (microscopic) disease. We aimed to determine whether HZTE correlates with outcomes in early stage ECAs and FIGO should reinstate HZTE as a staging parameter in futures updates. We retrospectively analyzed 416 FIGO 2009 stage I ECAs from 17 institutions and re-assigned stage using FIGO 2018. Correlation between HZTE, overall (OS) and recurrence free survival (RFS) was performed using univariable and multivariable analyses. Re-staging 416 cases resulted in 126 (30.3%) IA and 290 (69.7%) IB cases; 85 (67.5%) IA tumors had HZTE ≤ 7 mm, while 41 (32.5%) were > 7 mm; 32 (11%) IB tumors had HZTE ≤ 7 mm, while 258 (89%) were > 7 mm (p = 0.0001). Four (3.2%) IA (1 IA1, 3 IA2) patients developed recurrence (3 ≤ 7 mm, 1 > 7 mm) compared to 41 (14.1%) IB patients (p = 0.002). Fourteen IB and no IA patients died of disease (8 IB1, 1 ≤ 7 mm). Cox univariate analysis demonstrated that only RFS is significantly influenced by HZTE (p = 0.01), while OS and RFS were not influenced by HZTE on multivariate analysis. HZTE has limited prognostic value in early stage ECAs and is only associated with RFS on univariate but not multivariate analysis. HZTE does not improve prognostication of patients with stage I ECAs as per 2018 FIGO staging. Consequently, the rationale to remove this variable from FIGO staging is justified for ECAs.

Squamous and Glandular Epithelial Tumors of the Cervix

Squamous cell carcinoma is the most frequent epithelial malignant tumor of the cervix and among the most frequent neoplasm in women worldwide. Endocervical adenocarcinoma is the second most common malignancy. Both tumors and their precursors are currently classified based on human papillomavirus status, with prognostic and predictive value. Various prognostic biomarkers and alternative morphologic parameters have been recently described and could be used in the management of these patients. This pragmatical review highlights recent developments, emerging issues as well as controversial areas regarding the cause-based classification, diagnosis, staging, and prognostic parameters of epithelial malignant tumors of the cervix.

Incidence and Clinicopathologic Characteristics of Human Papillomavirus–independent Invasive Squamous Cell Carcinomas of the Cervix

We aimed to determine the frequency of human papillomavirus–independent (HPVI) cervical squamous cell carcinoma (SCC) and to describe clinicopathologic characteristics. Among 670 patients with surgically treated SCCs in an established multi-institutional cohort, 447 had available tissue. Tissue microarrays were constructed and studied by in situ hybridization (ISH) for high-risk and low-risk human papillomavirus (HPV) mRNA and immunohistochemistry for p16 and p53. Tumors were HPVI if negative by HPV ISH and they failed to show diffuse p16 positivity by immunohistochemistry, and human papillomavirus–associated (HPVA) if positive by HPV ISH. Ten HPVI SCCs and 435 HPVA SCCs were identified; 2 cases were equivocal and excluded from analysis. The overall rate of HPVI SCC was low (2%) but was higher among older patients (7% in patients above 60 y of age and 17% in patients above 70 y of age). Compared with HPVA, patients with HPVI SCC were significantly older (median age, 72 vs. 49, P&lt;0.001) and diagnosed at a higher stage (40% vs. 18% with stage III/IV disease, P=0.055). p53 expression was varied; 2 cases (20%) had null expression and 8 (80%) had wild-type expression. HPVI SCCs were heterogenous, with keratinizing, nonkeratinizing, and warty morphologies observed. Several cases had a precursor lesion reminiscent of differentiated vulvar intraepithelial neoplasia, with prominent basal atypia and hypereosinophilia or a basaloid-like morphology. Two patients (20%) had distant recurrences within 12 months, and 3 (30%) died of disease during follow-up. HPVI SCCs are rare tumors that are more common among older patients with higher stage disease and have important clinical and histologic differences from HPVA SCCs.

Presence and extent of lymphovascular invasion in surgical stage I squamous cell carcinoma of the cervix: a comprehensive, international, multicentre, retrospective clinicopathological study

The aim of this study was to determine whether the presence and extent of lymphovascular invasion (LVI) is prognostic in surgical stage I cervical squamous cell carcinoma (SCC). All available tumour slides and/or paraffin blocks from 426 patients with stage I cervical SCC treated surgically with curative intent were collected from 18 institutions and retrospectively analysed. Presence and extent of LVI (focal <5 spaces, extensive ≥5 spaces) were assessed on scanning magnification in large haematoxylin and eosin slide sets in 366 cases. Progression-free survival (PFS) was calculated as the time from surgery to first progression or death or last follow-up, whichever occurred first. Overall survival (OS) was defined as the time from surgery to death or last follow-up. Clinicopathological and statistical analyses were performed on 97 patients with the International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IA and 329 patients with stage IB SCC of the cervix. LVI, both focal and extensive, was more frequent in stage IB than in stage IA (p<0.001). Patients with stage IB carcinomas with extensive LVI had worse PFS [hazard ratio (HR) 2.86; 95% confidence interval (CI) 1.49, 5.49; p=0.005] and OS (HR 2.88; 95% CI 1.38, 6.02; p=0.012) than those with focal or no LVI. In stage IA, in contrast, the presence and extent of LVI did not associate with PFS (p=0.926) or OS. Extensive LVI was not statistically correlated with PFS and OS in substages IA1, IA2 or IB2. PFS (HR 3.7; 95% CI 1.61, 8.46; p<0.001) and OS (HR 4.18; 95% CI 1.58, 11.04; p=0.002) in stage IB1, and PFS (HR 7.78; 95% CI 0.87, 69.82; p=0.039) in stage IB3 were diminished in the presence of extensive LVI. In conclusion, in patients with FIGO stage I cervical SCC, the presence and extent of LVI has prognostic significance in stage IB carcinoma, and quantifying LVI is recommended.

Cervical intraepithelial neoplasia: the expanding spectrum of cervical squamous intraepithelial lesions with focus on morphologic and molecular nuances.

Cervical squamous cell carcinoma (SCC) is classified by the World Health Organization based on its association with human papillomavirus (HPV) into HPV-associated (HPVA) and HPV-independent (HPVI) categories. HPVI SCCs can be p53 wild-type or p53 abnormal, the latter harboring a driver alteration in TP53 and portending worse survival. Recent developments have expanded the spectrum of squamous intraepithelial lesions (SILs) in the cervix. In the HPVA category, seborrheic keratosis-like lesions are now established as having an aetiological association with HPV42, a common low-risk HPV type. Papillary immature metaplasia, a further low-risk HPVA lesion, also falls into this category. More recently, potential HPVI squamous precursor lesions have been described; these form a wide morphologic spectrum and are difficult to diagnose, with the use of p16, p53, and HPV testing mandatory. When these ancillary tests are used, the HPVI SILs, similar to their invasive counterparts, stratify into p53 abnormal and p53 wild-type categories. Different genomic alterations are seen within the two groups, supporting their neoplastic nature. In this review, we provide a historical perspective and comprehensive description of all cervical SILs, with a focus on emerging entities and premalignant lesions, and appraise the terminology used over past years and that recently proposed for new entities. Key clinical, colposcopic, and morphologic features, differential diagnosis, treatment, follow-up, and prognosis are discussed. Special attention is paid to ancillary studies that assist in resolving differential diagnoses and their interpretation in light of recent scientific publications and international guidelines. We also discuss the clinical impact of a pathologic diagnosis of HPVA versus HPVI SILs.