Cervical adenocarcinoma is a heterogenous group of tumours with various aetiologies, molecular drivers, morphologies, response to treatment and prognosis. It has become evident that human ...papillomavirus (HPV) infection does not drive all adenocarcinomas, and appropriate classification is critical for patient management, especially in the era of the HPV vaccine and HPV‐only screening. Identified as one of the most important developments in gynaecological pathology during the past 50 years, the separation of cervical adenocarcinomas into HPV‐associated (HPVA) and HPV‐independent has resulted in a transformation of the classification system for cervical adenocarcinomas. HPVA has been traditionally subclassified by morphology, such as usual type (UEA), mucinous and villoglandular, etc. However, it has become evident that cell type‐based histomorphological classification is not clinically meaningful, and the newly proposed International Endocervical Adenocarcinoma Criteria and Classification (IECC) is a necessary and relevant break from this prior system. Non‐HPV‐associated adenocarcinomas can be divided by their distinct morphology and molecular genomics with very different responses to standard therapies and potential for future targeted therapies. These include gastric‐type, clear‐cell, mesonephric and endometrioid adenocarcinomas. So‐called ‘serous’ carcinomas of the cervix probably represent morphological variants of UEA or drop metastases from uterine or adnexal serous carcinomas, and the existence of true cervical serous carcinomas is in question. This review will discuss the advances since WHO 2014, and how HPV status, pattern of invasion as described by Silva and colleagues, histological features and molecular markers can be used to refine diagnosis and prognostication for patients with cervical adenocarcinoma.
In this review, we sought to address 2 important issues in the diagnosis of endometrial carcinoma: how to grade endometrial endometrioid carcinomas and how to incorporate the 4 genomic subcategories ...of endometrial carcinoma, as identified through The Cancer Genome Atlas, into clinical practice. The current International Federation of Gynecology and Obstetrics grading scheme provides prognostic information that can be used to guide the extent of surgery and use of adjuvant chemotherapy or radiation therapy. We recommend moving toward a binary scheme to grade endometrial endometrioid carcinomas by considering International Federation of Gynecology and Obstetrics defined grades 1 and 2 tumors as "low grade" and grade 3 tumors as "high grade." The current evidence base does not support the use of a 3-tiered grading system, although this is considered standard by International Federation of Gynecology and Obstetrics, the American College of Obstetricians and Gynecologists, and the College of American Pathologists. As for the 4 genomic subtypes of endometrial carcinoma (copy number low/p53 wild-type, copy number high/p53 abnormal, polymerase E mutant, and mismatch repair deficient), which only recently have been identified, there is accumulating evidence showing these categories can be reproducibly diagnosed and accurately assessed based on biopsy/curettage specimens as well as hysterectomy specimens. Furthermore, this subclassification system can be adapted for current clinical practice and is of prognostic significance independent of conventional variables used for risk assessment in patients with endometrial carcinoma (eg, stage). It is too soon to recommend the routine use of genomic classification in this setting; however, with further evidence, this system may become the basis for the subclassification of all endometrial carcinomas, supplanting (partially or completely) histotype, and grade. These recommendations were developed from the International Society of Gynecological Pathologists Endometrial Carcinoma project.
Cervical adenocarcinomas are a heterogeneous group of tumors with varying morphologies, etiologies, molecular drivers, and prognoses, comprising approximately 25% of all cervical cancers. Unlike ...cervical squamous cell carcinoma, adenocarcinomas are not uniformly caused by high-risk human papillomavirus (HPV) infection and, therefore, would not necessarily be prevented by the HPV vaccine.
To provide a review of endocervical adenocarcinoma subtypes and, when appropriate, discuss precursor lesions, etiologies, molecular genetics, and ancillary studies within the context of clinical care. Some historical perspectives will also be provided.
Data sources included published peer-reviewed literature and personal experiences of the senior author.
Endocervical adenocarcinomas are a histologically diverse group of tumors with various causes and molecular drivers, not all related to HPV infection. Distinguishing them has important implications for treatment and prognosis as well as strategies for prevention.
We sought to classify endocervical adenocarcinomas (ECAs) based on morphologic features linked to etiology (ie, human papillomavirus HPV infection), unlike the World Health Organization 2014 ...classification. The International Endocervical Adenocarcinoma Criteria and Classification (IECC criteria), described herein, distinguishes between human papillomavirus-associated adenocarcinoma (HPVA), recognized by the presence of luminal mitoses and apoptosis seen at scanning magnification, and no or limited HPVA features (nonhuman papillomavirus-associated adenocarcinoma NHPVA). HPVAs were then subcategorized based on cytoplasmic features (mostly to provide continuity with preexisting classification schemes), whereas NHPVAs were subclassified based on established criteria (ie, gastric-type, clear cell, etc.). Complete slide sets from 409 cases were collected from 7 institutions worldwide. Tissue microarrays representing 297 cases were constructed; immunohistochemistry (p16, p53, vimentin, progesterone receptor) and chromogenic in situ hybridization using an RNA-based probe set that recognizes 18 varieties of high-risk HPV were performed to validate IECC diagnoses. The 5 most common IECC diagnoses were usual-type (HPVA) (73% of cohort), gastric-type (NHPVA) (10%), mucinous adenocarcinoma of HPVA type, including intestinal, mucinous not otherwise specified, signet-ring, and invasive stratified mucin-producing carcinoma categories (9%), clear cell carcinoma (NHPVA) (3%) and adenocarcinoma, not otherwise specified (2%). Only 3 endometrioid carcinomas were recognized and all were NHPVA. When excluding cases thought to have suboptimal tissue processing, 90% and 95% of usual-type IECC cases overexpressed p16 and were HPV, whereas 37% and 3% of NHPVAs were p16 and HPV, respectively. The 1 HPV gastric-type carcinoma was found to have hybrid HPVA/NHPVA features on secondary review. NHPVA tumors were larger and occurred in significantly older patients, compared with HPVA tumors (P<0.001). The high-risk HPV chromogenic in situ hybridization probe set had superior sensitivity, specificity, and positive and negative predictive values (0.955, 0.968, 0.992, 0.833, respectively) compared with p16 immunohistochemistry (0.872, 0.632, 0.907, 0.545, respectively) to identify HPV-related usual carcinoma and mucinous carcinoma. IECC reliably segregates ECAs into HPVA and NHPVA types using morphology alone. This study confirms that usual-type ECAs are the most common type worldwide and that mucinous carcinomas comprise a mixture of HPVA and NHPVA, with gastric-type carcinoma being the major NHPVA type. Endometrioid and serous carcinomas of the endocervix are extraordinarily rare. Should clinical outcomes and genomic studies continue to support these findings, we recommend replacement of the World Health Organization 2014 criteria with the IECC 2017.
Uterine endometrioid adenocarcinomas are known for their morphologic plasticity. In addition to a multiplicity of metaplasias, uterine endometrioid adenocarcinomas may also undergo high-grade ...divergent differentiation in the form of high-grade neuroendocrine carcinoma, neuroectodermal differentiation or carcinosarcoma; others may dedifferentiate completely. Here we describe 5 cases of uterine endometrioid adenocarcinomas with high-grade divergent differentiation showing a striking morphologic and immunophenotypic resemblance to cutaneous pilomatrix carcinoma. Specifically, the high-grade component in all cases exhibited solid, basaloid morphology with conspicuous tumor cell necrosis and the presence of shadow cells, accompanied by diffusely aberrant (nuclear and cytoplasmic) β-catenin expression as well as variably diffuse CDX2 expression. In addition, the high-grade component in all cases showed loss of ER and PAX8 expression, retained MMR expression, wild-type p53 expression, patchy p16 expression, and diffusely positive cytokeratin expression (AE1/AE3 and CK7); at least focal neuroendocrine marker expression was present in all cases. CK20 was negative in all cases, with the exception of very focal staining in a single case (2% of tumor cells). All 5 of our tumors had at least a focal conventional FIGO grade 1 component. In all 4 cases tested, the low-grade component retained both PAX8 and ER expression and had, at best, focally aberrant β-catenin expression. Two of our cases had molecular analysis performed and both harbored mutations in exon 3 of CTNNB1 as expected; molecular analysis also revealed that both cases lacked POLE or TP53 mutations and showed no microsatellite instability. The tumors in this series were uniformly aggressive. Four of the 5 patients in our cohort had available follow-up information; of these, 3/4 died of their disease within 14 mo of diagnosis and the fourth patient had distant metastatic disease at presentation and is alive with disease 1 mo following diagnosis. The 1 patient without follow-up information also had distant metastatic disease at presentation and was lost to follow-up 17 mo later. The cases described in this series (1) represent a highly aggressive CTNNB1-mutated subset of the "no specific molecular profile" category of endometrioid adenocarcinomas; (2) illustrate a form of high-grade divergent differentiation resembling cutaneous pilomatrix carcinoma already described in carcinomas at other anatomic sites; and (3) underscore the difficulty in recognizing this phenotype at distant metastatic sites, which are frequent even at the time of presentation, given the consistent loss of ER and PAX8 expression and concurrent CDX2 expression.
The International Endocervical Adenocarcinoma Criteria and Classification (IECC) categorizes endocervical adenocarcinomas (ECAs) on the basis of morphologic features linked to etiology (ie, human ...papilloma virus HPV infection), resulting in separation of ECAs into HPV-associated (HPVA) and unassociated or non-HPVA (NHPVA) types. NHPVAs are reported to be large and present at high stage in older individuals. Our aim was to examine the clinical outcomes in these tumor types. Full slide sets of 205 ECAs were collected from 7 institutions worldwide and classified on the basis of IECC criteria and the presence or absence of HPV. Clinical and morphologic parameters were correlated with follow-up data. Statistical analysis of overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) were conducted using the Kaplan-Meier survival analysis and compared using the log-rank test for univariate analysis. Multivariate survival analysis was conducted, and the survival endpoints considered were OS, DFS, and PFS. Statistically significant survival differences (OS, DFS, and PFS) were found when comparing the following categoriesHPVA>NHPVA (ie, survival was superior in the setting of HPVAs), including patients treated with surgery followed by adjuvant therapy; usual-type HPVA>mucinous HPVA; FIGO grade 3 HPVA>NHPVA; HPVA>NHPVA, both with lymphovascular invasion; and HPVA>NHPVA in patients with pelvic recurrences. Although there were trends favoring HPVA outcomes over those of NHPVA, these differences were not statistically significant in the following categoriesmucinous HPVA versus NHPVA; HPVA versus NHPVA, both with lymph node metastases at presentation; and HPVA versus NHPVA in patients with distant metastasis. Survival for both HPVA and NHPVA was similar when surgery without adjuvant therapy was used. FIGO grading did not have prognostic significance in HPVAs. Multivariable analysis of HPVAs indicated nearly significant statistical associations between stage and both OS and DFS (P=0.07 and 0.06, respectively), and between Silva invasion pattern and OS (P=0.09). Multivariate analysis of NHPVAs indicated a statistically significant association between OS and age (P=0.03), stage (P=0.02) and tumor size (P=0.002), and between DFS and stage (P=0.004) and tumor size (P=0.004). Multivariate analysis of HPVAs and NHPVAs together revealed nearly significant associations between OS and HPV status and stage (both P=0.06). For DFS, stage was a significant variable (P=0.04), whereas HPV status and tumor size were nearly significant (P=0.06 and 0.07, respectively). Clinical outcome studies support the idea that the IECC classification not only separates ECAs on the basis of HPV status (usually assessed on H&E slides), but also has important clinical relevance.
We present an exceptional case of a patient with high-grade serous ovarian cancer, treated with multiple chemotherapy regimens, who exhibited regression of some metastatic lesions with concomitant ...progression of other lesions during a treatment-free period. Using immunogenomic approaches, we found that progressing metastases were characterized by immune cell exclusion, whereas regressing and stable metastases were infiltrated by CD8+ and CD4+ T cells and exhibited oligoclonal expansion of specific T cell subsets. We also detected CD8+ T cell reactivity against predicted neoepitopes after isolation of cells from a blood sample taken almost 3 years after the tumors were resected. These findings suggest that multiple distinct tumor immune microenvironments co-exist within a single individual and may explain in part the heterogeneous fates of metastatic lesions often observed in the clinic post-therapy.
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•Differential progression of metastases during off-treatment period.•Coexistence of distinct tumor-immune microenvironments within the same individual.•Tumor regression and progression correlated with T cell infiltration and exclusion.•Clonal neoepitopes elicited reactivity of circulating CD8+ T cells.
Distinct tumor immune microenvironments co-exist within a single individual and may help to explain the heterogeneous fates of metastatic lesions often observed post-therapy.
Adenocarcinomas exhibiting gastric differentiation represent a recently described and uncommon subtype of non–human papillomavirus (HPV)-related cervical adenocarcinoma. They comprise a spectrum from ...a well-differentiated variant (adenoma malignum/mucinous variant of minimal deviation adenocarcinoma) to a more poorly differentiated overtly malignant form, generally referred to as gastric-type adenocarcinoma. Rarely, such tumors have also been described as primary vaginal neoplasms. Gastric-type adenocarcinomas exhibit considerable morphologic overlap with adenocarcinomas originating outside the female genital tract, especially mucinous adenocarcinomas arising in the pancreas and biliary tract. Moreover, they often metastasize to unusual sites, such as the ovary and peritoneum/omentum, where they can be mistaken for metastatic adenocarcinomas from other, nongynecologic sites. There is little information regarding the immunophenotype of gastric-type adenocarcinomas, and knowledge of this is important to aid in the distinction from other adenocarcinomas. In this study, we undertook a detailed immunohistochemical analysis of a large series of cervical (n=45) and vaginal (n=2) gastric-type adenocarcinomas. Markers included were cytokeratin (CK)7, CK20, CDX2, carcinoembryonic antigen, CA125, CA19.9, p16, estrogen receptor, progesterone receptor, MUC6, PAX8, PAX2, p53, hepatocyte nuclear factor 1 beta, carbonic anhydrase IX, human epidermal receptor 2 (HER2), and mismatch repair (MMR) proteins. All markers were classified as negative, focal (<50% of tumor cells positive), or diffuse (≥50% tumor cells positive) except for p53 (classified as “wild-type” or “mutation-type”), HER2 (scored using the College of American Pathologists guidelines for gastric carcinomas), and MMR proteins (categorized as retained or lost). There was positive staining with CK7 (47/47—45 diffuse, 2 focal), MUC6 (17/21—6 diffuse, 11 focal), carcinoembryonic antigen (25/31—12 diffuse, 13 focal), carbonic anhydrase IX (20/24—8 diffuse, 12 focal), PAX8 (32/47—20 diffuse, 12 focal), CA125 (36/45—5 diffuse, 31 focal), CA19.9 (11/11—8 diffuse, 3 focal), hepatocyte nuclear factor 1 beta (13/14—12 diffuse, 1 focal), CDX2 (24/47—4 diffuse, 20 focal), CK20 (23/47—6 diffuse, 17 focal), and p16 (18/47—4 diffuse, 14 focal). Most cases were negative with estrogen receptor (29/31), progesterone receptor (10/11), PAX2 (18/19), and HER2 (25/26). p53 showed “wild-type” and “mutation-type” staining in 27 of 46 and 19 of 46 cases, respectively. MMR protein expression was retained in 19 of 20 cases with loss of MSH6 staining in 1 patient with Lynch syndrome. Molecular studies for HPV were undertaken in 2 tumors, which exhibited diffuse “block-type” immunoreactivity with p16, and both were negative. This is the first detailed immunohistochemical study of a large series of gastric-type adenocarcinomas of the lower female genital tract. Our results indicate immunophenotypic overlap with pancreaticobiliary adenocarcinomas but suggest that PAX8 immunoreactivity may be especially useful in distinguishing gastric-type adenocarcinomas from pancreaticobiliary and other nongynecologic adenocarcinomas, which are usually negative. Diffuse “block-type” p16 immunoreactivity in a cervical adenocarcinoma is not necessarily indicative of a high-risk HPV-associated tumor.
The International Endocervical Adenocarcinoma Criteria and Classification was developed to separate endocervical adenocarcinomas (ECAs) into 2 main categories on the basis of morphology such as human ...papilloma virus–associated (HPVA) and non-human papilloma virus–associated adenocarcinomas. We aimed to improve the diagnostic accuracy of International Endocervical Adenocarcinoma Criteria and Classification by performing a comprehensive immunohistochemical evaluation and constructing objective immunohistochemical-based algorithms for the classification of these tumors. Tissue microarrays were constructed from 297 of 409 cases used to develop the original classification. Immunostains included p16, p53, estrogen receptor (ER), progesterone receptor, androgen receptor, Vimentin, CK7, CK20, HER2, HIK1083, MUC6, CA-IX, SATB2, HNF-1beta, napsin A, PAX8, CDX2, GATA3, p63, p40, and TTF-1. High-risk human papilloma virus (HR-HPV) was detected by in situ hybridization (ISH) using probes against E6 and E7 mRNA expressed in 18 different virus types. Vimentin, ER, and progesterone receptor were expressed in a significant minority of ECAs, mostly HPVAs, limiting their use in differential diagnosis of endometrioid carcinoma when unaccompanied by HPV-ISH or p16. HR-HPV ISH had superior sensitivity, specificity, and negative and positive predictive values compared with p16, as published previously. HNF-1beta did not have the anticipated discriminatory power for clear cell carcinoma, nor did MUC6 or CA-IX for gastric-type carcinoma. HNF-1beta and napsin A were variably expressed in clear cell carcinoma, with HNF-1beta demonstrating less specificity, as it was ubiquitously expressed in gastric-type carcinoma and in the majority of HPV-associated mucinous (predominantly intestinal-type and invasive ECA resembling stratified mucin-producing intraepithelial lesion iSMILE) and usual-type carcinomas. HIK1083 was expressed in nearly half of gastric-type carcinomas, but not in the vast majority of other subtypes. GATA3 was positive in 10% of usual-type adenocarcinomas and in single examples of other subtypes. Rare gastric-type and HPVA mucinous carcinomas displayed HER2 overexpression. Androgen receptor was positive in 6% of usual-type adenocarcinomas. Aberrant p53 expression was found in only 3.6% of usual-type HPVA carcinomas, but it was more prevalent in mucinous (intestinal type and iSMILE) HPVAs and non-human papilloma virus–associates (particularly in gastric-type carcinoma, >50% of cases). The following diagnostic classification algorithms were developed with the above data. Carcinomas without overt cytoplasmic mucin (endometrioid, usual-type endocervical, clear cell, and mesonephric carcinomas) can be subclassified using HR-HPV ISH, ER, and GATA3, whereas carcinomas with easily appreciated cytoplasmic mucin (endometrioid carcinoma with mucinous features, HPVA mucinous, and gastric-type carcinomas) can be subclassified with HR-HPV ISH and ER.
Growing evidence has established two major types of vulvar intraepithelial neoplasia (VIN), which correspond to two distinct oncogenic pathways to vulvar squamous cell carcinoma (VSCC). While the ...incidence of VSCC has remained relatively stable over the last three decades, the incidence of VIN has increased. VIN of usual type (uVIN) is human papillomavirus (HPV)-driven, affects younger women and is a multicentric disease. In contrast, VIN of differentiated type (dVIN) occurs in post-menopausal women and develops independent of HPV infection. dVIN often arises in a background of lichen sclerosus and chronic inflammatory dermatoses. Although isolated dVIN is significantly less common than uVIN, dVIN bears a greater risk for malignant transformation to VSCC and progresses over a shorter time interval. On histological examination, uVIN displays conspicuous architectural and cytological abnormalities, while the morphological features that characterise dVIN are much more subtle and raise a wide differential diagnosis. On the molecular level, dVIN is characterised by a higher number of somatic mutations, particularly in TP53. Here we review the classification, epidemiology, clinical features, histomorphology, ancillary markers and molecular genetics of both types of VIN, and discuss the morphological challenges faced by pathologists in interpreting these lesions.
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