Cervical cancer was once one of the most common

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1 Special Section Fourth Princeton Integrated Pathology Symposium: Gynecologic Pathology, Part II Cervical Adenocarcinomas A Heterogeneous Group of Tumors With Variable Etiologies and Clinical Outcomes Anjelica Hodgson, MD; Kay J. Park, MD Context. 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. Objective. 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. Data sources included published peerreviewed literature and personal experiences of the senior author. Conclusions. 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. (Arch Pathol Lab Med. 2019;143:34 46; doi: / arpa ra) Cervical cancer was once one of the most common malignancies to affect women in the United States, but with the advent of Papanicolaou test screening in the mid- 20th century, a sharp decline in the rate of cervical cancer and associated deaths has been noted. Today, cervical cancer ranks as the 14th most common cancer to affect women in the United States and the third most common cancer to affect women worldwide. 1 Most cervical cancers are composed of squamous cell carcinoma caused by human papillomavirus (HPV) infection; however, adenocarcinoma of the cervix appears to be increasing in both true and relative incidence. 2,3 Unlike squamous cell carcinoma, adenocarcinoma of the cervix comprises a heterogeneous group of tumors not universally associated with HPV infection. These tumors demonstrate varying morphologies, etiologies, and prognoses. This review will cover classification of endocervical adenocarcinomas, associated precursor lesions, pathogenesis, and the latest available data of molecular and immunohistochemical findings. Where applicable, a historical perspective will also be provided. CLASSIFICATION OF ENDOCERVICAL ADENOCARCINOMAS According to the most recent WHO (World Health Organization) Classification of Tumors of Female Reproductive Organs published in 2014, endocervical adenocarcinomas are classified from descriptive morphologic characteristics, primarily cytoplasmic features. 4 This classification suffers from vague definitions and does not reflect our current understanding of endocervical glandular neoplasia. A recent novel classification system based on etiology and biologic behavior was proposed to provide an updated framework for classification of endocervical adenocarcinomas. The International Endocervical Adenocarcinoma Criteria and Classification (IECC) 5 categorizes endocervical adenocarcinomas by the presence or absence of HPV infection related features: easily identified apical mitotic figures and apoptotic bodies. HPV-associated adenocarcinomas are further subdivided by clear definitions centered around cytoplasmic features, while HPV-unassociated adenocarcinomas are subclassified based on established published criteria. 5 It has been suggested by the authors of that study that the IECC, given its etiologically based framework and clear definitions, would replace the current WHO classification should ongoing validation, genomic, and clinical outcome studies support it. The WHO and IECC systems are summarized in Table 1, and each of the known distinct morphologic subtypes is described herein. Accepted for publication June 8, From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (Dr Hodgson); and the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Park). The authors have no relevant financial interest in the products or HPV-ASSOCIATED ADENOCARCINOMAS companies described in this article. Presented in part at the 4th Princeton Integrated Pathology Usual Type Endocervical Adenocarcinoma Symposium; April 23, 2017; Plainsboro, New Jersey. Corresponding author: Kay J. Park, MD, Department of Pathology, According to both the WHO and the IECC systems, usual Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, type endocervical adenocarcinoma (UEA) is the most NY ( ParkK@mskcc.org). common subtype, 4,5 accounting for 75% of all invasive 34 Arch Pathol Lab Med Vol 143, January 2019 Cervical Adenocarcinoma: A Heterogeneous Entity Hodgson & Park

2 Table 1. Classifications of Endocervical Adenocarcinoma by World Health Organization (WHO) and International Endocervical Criteria and Classification (IECC) WHO HPV-Associated Adenocarcinomas HPV-Unassociated Adenocarcinomas Endocervical adenocarcinoma, usual type Usual type Gastric type Mucinous carcinoma, NOS Mucinous, NOS Mesonephric carcinoma Mucinous carcinoma, gastric type Mucinous, intestinal type Serous carcinoma Mucinous carcinoma, intestinal type Mucinous, signet ring cell type Clear cell carcinoma Mucinous carcinoma signet ring cell type Villoglandular type Endometrioid adenocarcinoma Villoglandular carcinoma ismile Adenocarcinoma, NOS Mesonephric carcinoma Serous carcinoma Clear cell carcinoma Endometrioid carcinoma Adenocarcinoma, NOS Abbreviations: HPV, human papillomavirus; ismile; invasive stratified mucin-producing carcinoma; NOS, not otherwise specified. endocervical adenocarcinomas. 6 Historically, these tumors were termed endocervical type, and grouped under the mucinous category. According to the current WHO classification, these tumors are characterized by round or oval glands with relative mucin depletion. Cribriform or papillary architecture may be seen. Cytologically, the tumor nuclei are enlarged and display pseudostratification, elongation, and hyperchromasia. Apical mitotic figures and apoptotic bodies are readily visible, as are prominent nucleoli. The IECC defines these tumors as having between 0% and 50% of cells with appreciable intracytoplasmic mucin, with or without benign-appearing squamous differentiation 5 (Figure 1, A and B). Owing to their relative mucin depletion and pseudostratified nuclei, confusion with endometrial endometrioid adenocarcinoma (EEA) is not uncommon. In distinguishing these lesions from UEA, tumor location, HPV status, and immunohistochemistry can be used to adjudicate tumor origin. UEA is typically positive for high-risk HPV by messenger ribonucleic acid (mrna) in situ hybridization and displays diffuse, block-like positivity for p16 by immunohistochemistry (Figure 1, C and D). Monoclonal carcinoembryonic antigen (CEA) also usually shows positivity. In contrast, EEA is typically positive for vimentin and estrogen receptor (ER)/progesterone receptor (PR). 7,8 It should be noted however, that there can be significant overlap of immunohistochemical profiles between UEA and EEA and that dependence should not be placed on a single immunohistochemical marker; rather, a panel should always be used. Deoxyribonucleic acid (DNA) mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, MSH6) may also be potentially helpful when 1 or more are lost in tumor cells, as this would indicate an EEA with microsatellite instability. Mucinous Adenocarcinoma, Including Not Otherwise Specified, Intestinal, and Signet Ring Cell Types The WHO classification for mucinous endocervical adenocarcinomas is heterogeneous, and includes both HPV-associated (not otherwise specified [NOS], intestinal, and signet ring cell types) and HPV-unassociated (gastric type) tumors. Like all HPV-associated tumors as determined by the IECC, these neoplasms have apical mitoses and apoptotic bodies. They are further subclassified by the amount of tumor cells with evident intracytoplasmic mucin into NOS (.50% of tumor cells with intracytoplasmic IECC mucin; Figure 2, A), intestinal type (.50% of cells with goblet morphology; Figure 2, B and C), or signet ring cell type (.50% of tumor cells with signet ring morphology; Figure 2, D). 5 Mucinous and usual type features often coexist. Villoglandular Adenocarcinoma Villoglandular adenocarcinoma of the endocervix is a rare, well-differentiated subtype of HPV-associated adenocarcinoma. Like villoglandular neoplasms elsewhere in the gynecologic tract, these neoplasms are microscopically characterized by thin villous and papillary cores lined by cells with usual type cytomorphology and no more than moderate atypia. No morphologically distinct precursor lesions have been described. Invasive Stratified Mucin-Producing Carcinoma Stratified mucin-producing intraepithelial lesion (SMILE) is an in situ cervical lesion that arises from reserve cells of the cervical transformation zone, and thought to be distinct from conventional adenocarcinoma in situ (AIS) and squamous intraepithelial lesions. 9 Morphologically, SMILE is characterized by immature epithelium with conspicuous intracytoplasmic mucin stratified throughout its thickness but without overt gland formation (Figure 3, A). In the original description, SMILEs were associated with other in situ lesions including AIS and squamous intraepithelial lesion (Figure 3, B), as well as different forms of invasive carcinoma; therefore, it was concluded that this lesion represented a marker for phenotypic instability. 9 Ultrastructural examination has suggested that these lesions are more closely related to endocervical glandular neoplasia rather than squamous dysplasia. 10 Several studies have evaluated the cytologic and histologic features 15 of SMILEs, and it has been recommended that these lesions should be managed like AIS, 15 with dilemmas regarding treatment acknowledged in the clinical literature. 16 A corresponding invasive form of SMILE has been recently described, termed invasive stratified mucin-producing carcinoma, or ismile. 17 In the seminal article, these invasive tumors were described as nests of stratified columnar cells with peripheral palisading, variable amounts of intracytoplasmic mucin, and evident HPV infection related features with apical mitotic figures and apoptotic bodies, similar to SMILE (Figure 3, A through F). 17 In addition, a neutrophilic Arch Pathol Lab Med Vol 143, January 2019 Cervical Adenocarcinoma: A Heterogeneous Entity Hodgson & Park 35

3 Figure 1. Usual type endocervical adenocarcinoma. A and B, Apical mitotic figures and apoptotic bodies seen at scanning magnification with round to oval glands with focal cribriform pattern, lined by cells with enlarged, pseudostratified, and hyperchromatic nuclei and mucin-depleted appearance. C, High-risk human papillomavirus (HPV) in situ hybridization positive. D, p16 positive (hematoxylin-eosin, original magnifications 340 [A] and 3100 [B]; original magnification 3100 [C and D]). infiltrate was noted in most cases (Figure 3, C and D). Subsequent studies evaluating the morphologic and immunohistochemical features, as well as HPV status of ismile, have been reported and describe a variety of patterns including pure composition or admixture with usual type, mucinous, signet ring, glassy cell, or squamoid areas.18 Immunohistochemically, most of these tumors are diffusely positive for p16 (Figure 3, G), with varying percentages of positivity for paired-box 8 (PAX8), p63, p40 (Figure 3, H), hepatocyte nuclear factor 1 homeobox B (HNF1-b), U3 small nucleolar ribonucleoprotein protein (IMP3), and GATA binding protein 3 (GATA3). Anti-mucin MGGMC-1 (clone: HIK1083), special AT-rich sequence binding protein 2 (SATB2), caudal-related homeobox gene 2 (CDX2), and androgen receptor consistently show negativity.10,18 HPV in situ hybridization detects high-risk HPV consistently in these tumors (Figure 3, I).5 Although SMILE is mentioned in the 2014 WHO classification, ismile was not described at the time of 36 Arch Pathol Lab Med Vol 143, January 2019 publication. As such, it is included as an HPV-associated adenocarcinoma in the IECC.5 NON HPV-ASSOCIATED ADENOCARCINOMAS Gastric Type Endocervical Adenocarcinoma Gastric type endocervical carcinoma (GEA) was included in the 2014 WHO classification, and recent studies have shown that these tumors are the second most common subtype of endocervical adenocarcinoma.5 It is now known that within the spectrum of gastric type adenocarcinoma is minimal deviation adenocarcinoma (MDA), also referred to as adenoma malignum. This is an entity that has long been known to be a particularly aggressive type of endocervical adenocarcinoma, in spite of its deceptively bland morphology. Remarkably, cervical lesions matching the description of MDA were described in the European literature dating back to The first report in the English literature was published in Cancer in 1963 by McKelvey and Goodlin20 who noted that, despite its innocent histological pattern, Cervical Adenocarcinoma: A Heterogeneous Entity Hodgson & Park

4 Figure 2. Human papillomavirus associated mucinous adenocarcinomas. A, Mucinous adenocarcinoma, not otherwise specified; most tumor cells (.50%) display evident intracytoplasmic mucin. B and C, Mucinous adenocarcinoma, intestinal type with goblet cell differentiation, sometimes associated with extravasated mucin imparting a colloid-like appearance. D, Mucinous adenocarcinoma, signet ring cell type; mucin vacuoles push the nuclei to the edges of the cells (hematoxylin-eosin, original magnifications 3100 [A] and 3400 [B through D]). these neoplasms were almost always fatal and were resistant to common therapeutic approaches. In 1998, Ishii and colleagues 21 published the first histochemical study to link MDA with gastric type mucin. Subsequently, the seminal article by Kojima et al 22 described mucinous adenocarcinomas of the cervix with gastric morphology and immunophenotype, showing that these tumors had poor outcomes that were significantly worse than nongastric types. They defined gastric differentiation morphologically as tumor cells that have distinct cell borders and voluminous clear or pale eosinophilic cytoplasm (Figure 4, A through C). 22 What has become evident is that there can be a wide range of morphologic features within a single tumor, with welldifferentiated MDA-like components adjacent to poorly differentiated carcinoma (Figure 4, D). In addition, there may not necessarily be abundant clear cytoplasm in much of the tumor, although it does usually tend to be found at least focally (Figure 4, E). p16 staining is usually focal or shows negativity in these tumors with a few exceptions, 23,24 and studies have proven that indeed GEAs are negative for HPV by polymerase chain reaction and in situ hybridization. 5,23 Clinically, GEA has worse outcomes than UEA, even at stage I, 25 and also presents more frequently at high stage (II or higher) as compared to other subtypes of adenocarcinoma 5,25 with unusual patterns of spread involving the omentum, peritoneum, and visceral organs. 25 A study by the Sankai Group 26 has also confirmed the chemoresistance of these aggressive tumors. The ovary and fallopian tube can also be involved by GEA and it should be particularly noted that this can mimic lesions that are primary to that site (eg, ovarian mucinous cystadenoma/borderline tumors or mucinous metaplasia/neoplasia of fallopian tube) (Figure 4, F through I). 27 Cytologically, in addition to having abundant eosinophilic or clear cytoplasm, it has been observed that GEA often has a foamy cytoplasmic quality (Figure 4, J). 28 As mentioned above, immunohistochemical studies of GEAs have shown that they are mostly p16 negative 29 ; however, diffuse p16 positivity has been described. 5,30 Therefore, it is not 100% sensitive or specific in distinguishing HPV- versus non HPV-associated endocervical adeno- Arch Pathol Lab Med Vol 143, January 2019 Cervical Adenocarcinoma: A Heterogeneous Entity Hodgson & Park 37

5 Figure 3. Stratified mucin-producing intraepithelial lesion (SMILE) and invasive stratified mucin-producing carcinoma (ismile). A. Immature epithelium with conspicuous mucin stratified throughout. Overt gland formation is not seen. B, SMILE and associated high-grade squamous intraepithelial lesion. C, ismile: invasive carcinoma with nests of stratified columnar cells and peripheral palisading. D, Evident apical mitotic figures and apoptotic bodies with prominent neutrophilic infiltrate. E, ismile with mucin-rich and mucin-poor areas and (F) corresponding mucicarmine. G, p16 positive. H, p40 positive. I, human papillomavirus positive (hematoxylin-eosin, original magnifications 3100 [A through C] and 3200 [D and E]; original magnification 3100 [F through H]; in situ hybridization, original magnification 3100 [I]). carcinomas. In addition, a few cases of endocervical adenocarcinoma have been described that have mixed features of GEA and UEA. 5,23,28,31 A recent study showed that most tumors with mixed GEA and UEA features were immunophenotypically GEA-like, while the minority were UEA-like ; no evidence of a true mixed immunophenotype was reported. 31 As such, it may be prudent to perform HPV testing if available in uncertain cases. Aberrant (overexpressed and null) phenotypes for p53 have been reported in 40% to 50% of GEAs, suggesting underlying p53 mutations. HIK1083, a marker for gastric type mucin, is relatively specific but not available for widespread use in routine practice. In our experience, it tends to be the strongest and most diffuse at the well-differentiated end of the morphologic spectrum, including in precursor lesions like lobular endocervical glandular hyperplasia (LEGH), with expression decreasing as the tumor becomes more poorly differentiated. Other positive immunomarkers include cytokeratin (CK) 7, MUC6, and CEA. 23,24,32 GEA is typically negative for ER and PR. PAX8 has shown positivity in about 68% of GEAs in one cohort, 24 which may be useful in distinguishing GEA from tumors of gastrointestinal or pancreatobiliary origin. Although the name gastric type endocervical adenocarcinoma suggests homology with gastric tumors, GEAs actually have morphologic 28 and immunohistochemical 24 overlap with pancreatic adenocarcinoma. GEAs and pancreatobiliary adenocarcinomas are typically positive for CK7, CEA, CA 19-9, with or without CK20 and CDX2 positivity, 24 while PAX8 typically shows negativity in adenocarcinomas of pancreatobiliary origin. 33,34 Therefore, PAX8 positivity could potentially be very useful in this scenario, recognizing that negativity for PAX8 does not entirely rule out GEA. In addition to the morphologic and immunohistochemical similarities described above, molecular analysis has also shown some similarities in genetic alterations between GEA and pancreatic adenocarcinoma. 35 Next-generation sequencing of GEA has shown somatic mutations in TP53, CDKN2A, ERBB2/ERBB3, and STK11. In cases without TP53 mutations, KRAS, BRAF, and GNAQ were found to be altered. Less commonly, mutations in GNAS, SMAD4, and PIK3CA were identified. 36 Minimal deviation adenocarcinoma is part of the tumor spectrum in patients with Peutz-Jeghers syndrome, an autosomal dominant inherited syndrome characterized by germline mutations in STK11, which encodes a serine/ threonine kinase that is involved in the regulation of cell polarity and is associated with numerous malignancies 38 Arch Pathol Lab Med Vol 143, January 2019 Cervical Adenocarcinoma: A Heterogeneous Entity Hodgson & Park

6 Figure 4. Gastric type endocervical adenocarcinoma. A and B, Diffusely infiltrative adenocarcinoma with well-formed but irregularly shaped glands. C, Cells with basally located nuclei, abundant foamy pale cytoplasm, and apical eosinophilic cytoplasm within same gland, distinct cellular borders, and a single mitotic figure without apoptotic bodies. D, Well-differentiated minimal deviation adenocarcinoma like gland forming tumor on the right adjacent to poorly differentiated irregular clusters and single cells on the left. E, Glands with mixture of cells containing abundant, tall apical mucin, goblet cells and mucin-poor eosinophilic cytoplasm, with nuclear grade ranging from low to high. F and G, Ovary metastasis mimicking mucinous cystadenoma. H and I, Fallopian tube metastasis with mucosal spread and focal stromal invasion. J, Foamy nature of cytoplasm in tumor cells (hematoxylin-eosin, original magnifications 320 [A and F], 340 [B, D, and H], 3200 [E, G, and I], and 3400 [C and J]. Arch Pathol Lab Med Vol 143, January 2019 Cervical Adenocarcinoma: A Heterogeneous Entity Hodgson & Park 39

7 Figure 5. Preinvasive endocervical lesions with gastric phenotype. A through C, Lobular endocervical glandular hyperplasia (LEGH) showing glandular proliferation limited to superficial portion of cervix with small acinar-like proliferation of glands surrounding central large duct-like structures lined by cells with abundant tall apical mucin and small basally located nuclei. D, Atypical lobular endocervical hyperplasia (atypical LEGH). E, Gastric type adenocarcinoma in situ (hematoxylin-eosin, original magnifications whole slide image [A], 320 [B], and 3100 [C through E]). including those arising in the breast, lung, testes, pancreas, GI tract, and gynecologic tract Typical GEA 40 has also been reported to occur in patients with Peutz-Jeghers syndrome. Parallel to our increased understanding of invasive gastric type endocervical adenocarcinoma, our understanding of preinvasive endocervical lesions with gastric phenotype has also evolved Currently, it is postulated that GEA might develop from a series of precursor lesions that begin with gastric metaplasia at one end of the spectrum, and proceed through LEGH, atypical LEGH, gastric type adenocarcinoma in situ, and finally to invasive carcinoma. There are several previously described entities that now fall into the category of noninvasive gastric lesions in the cervix in addition to LEGH and atypical LEGH. Diffuse laminar endocervical hyperplasia is cytologically identical to LEGH and in its original description was noted to often be confused with MDA. 42 Type A tunnel clusters, originally described by Fluhmann 41 in 1961, are also morphologically similar to LEGH and express gastric mucin. 41,48 LEGH and pyloric metaplasia were first described by Nucci et al 43 and Mikami et al, 44 respectively, in 1999 as distinct lobular proliferations of small to moderately sized rounded glands often centered on a larger central gland in an acinar pattern, lined by columnar mucinous cells with bland cytology, often mimicking MDA (Figure 5, A through C). Gastric AIS and atypical LEGH could be considered a form of progression whereby the lesions acquire cytologic atypia without invasion into stroma (Figure 5, D and E). 40 Arch Pathol Lab Med Vol 143, January 2019 Cervical Adenocarcinoma: A Heterogeneous Entity Hodgson & Park

8 Figure 6. Mesonephric carcinoma. A and B, Variety of architectural patterns, including tubular, solid, spindled, and papillary. C, Characteristic eosinophilic secretions within glandular luminal spaces (hematoxylin-eosin, original magnifications 320 [A], 340 [B], and 3100 [C]). These gastric lesions can present with clinical symptoms, commonly as a mass or with watery vaginal discharge,49 51 and can also be visible on imaging such as computed tomography or magnetic resonance imaging.52 The rate of malignant transformation of precursor gastric lesions to invasive carcinoma is unknown and currently there are no standards for how to manage such lesions. Mesonephric Carcinoma Mesonephric carcinoma of the endocervix is a rare malignancy arising from remnants of the Wolffian duct system, in contrast to many other neoplasms of the gynecologic tract, which are Mu llerian derived. The Wolffian duct system represents the anlage of the male reproductive tract, which gives rise to the seminal vesicles, vas deferens, ejaculatory ducts, and epididymis. In the normal female, this ductal system regresses and involutes; however, remnants may remain and can be seen deep in the lateral cervical walls, among other locations in the pelvis.53 A spectrum of benign (mesonephric hyperplasia) to malignant (mesonephric carcinoma) mesonephric proliferations is recognized.54 Morphologically, mesonephric carcinoma is characterized by heterogeneous architecture, with various patterns of growth that include glandular/tubular, papillary, retiform, sex cord like, solid, and spindled/sarcomatoid (Figure 6, A and B). Characteristically, dense eosinophilic secretions are seen within glandular luminal spaces, similar to that seen within benign mesonephric remnants (Figure 6, C). Clinically, these tumors can be aggressive and show metastases to distant sites including the lungs, with Arch Pathol Lab Med Vol 143, January 2019 outcome being stage dependent.55 To date, no specific treatment regimens for this tumor type exist. As these tumors are not associated with HPV infection, p16 immunostaining is typically patchy or negative. ER and PR also tend to show flat negativity. Cervical mesonephric carcinomas are consistently positive for PAX8 and GATA with variable staining for HNF1-b, TTF-1, calretinin, and CD10.59,60 A recent study focusing on the molecular genetics of mesonephric carcinomas has demonstrated several novel findings including canonical KRAS mutations in most tumors (81%) and a smaller number harboring activating NRAS mutations.61 Mutations in chromatin-remodeling genes ARID1A/B were also common (62% of cases). Unlike EEA, alterations in PIK3CA and phosphatase and tensin homolog (PTEN) were not identified, nor were any cases found to have microsatellite instability. Several chromosomal abnormalities have been identified in mesonephric carcinomas with copy number gains in 1q, loss of 1p, and gain of chromosomes 10 and 12 being the most common.61 In a follow-up study evaluating 10 cases of mesonephric hyperplasias, no activating mutations in KRAS or NRAS were detected.62 Clear Cell Carcinoma Clear cell carcinoma (CCC) of the endocervix, like clear cell carcinoma elsewhere in the gynecologic tract, displays heterogeneous morphology with tubulocystic, papillary, and solid architecture (Figure 7, A through C). Hobnail cells with moderate to marked nuclear atypia without pleomorphism Cervical Adenocarcinoma: A Heterogeneous Entity Hodgson & Park 41

9 Figure 7. Clear cell carcinoma. A, Papillary and tubulocystic architecture. B, Tubulocystic architecture with eosinophilic stroma. C, Solid growth pattern with clear cytoplasm. D, Cuboidal tumor cells hobnailed appearance, and uniform moderate nuclear atypia (hematoxylin-eosin, original magnifications 3200 [A and C], 3100 [B], and 3400 [D]). are characteristic (Figure 7, D). Similar to vaginal clear cell carcinomas, these rare malignancies can be associated with in utero exposure to diethylstilbestrol (DES), a synthetic estrogen given to women in the 1940s 1970s to prevent pregnancy loss and/or complications. Clear cell carcinoma of the cervix shows a bimodal age distribution (young adults versus postmenopausal women). 63 In DES-exposed patients, the peak risk of disease is at 19 years of age, although the risk persists through later years. In those patients, the anterior upper third of the vagina and ectocervix are the most likely sites of disease. In contrast, the peak age risk of disease in non DES-exposed patients is wide, and spans the pediatric to postmenopausal population with the endocervix predominantly involved. A recent 40-year follow-up study in DES-exposed patients shows that the cumulative risk for development of CCC is 1 in 750 exposed patients, and 1 in 520 when the risk was adjusted to include nonexposed patients within the same birth cohort and year of diagnosis. 64 Immunohistochemically, these tumors are positive for CK7, PAX8, HNF1-b, and napsin-a. p53 and p16 may show positivity or negativity, while ER and PR typically show negativity. 23 CEA has consistently shown negativity in these tumors, which could make it a useful marker to distinguish CCC from GEA with abundant clear cytoplasm. 23 Not much is known regarding the molecular underpinnings of cervical CCC. One study by Boyd et al 65 showed that microsatellite instability (widespread mutations in microsatellite repeats) is detected in all DES-exposed and 50% of non DES-exposed cases, while no mutations in KRAS, HRAS, WT1 (Wilms tumor 1), ER, ortp53 genes were found. Mills et al 66 evaluated several cases of endocervical adenocarcinoma including 1 case of CCC for DNA MMR deficiency; the CCC showed retained MMR proteins, and they found no association between Lynch syndrome and endocervical adenocarcinoma. One study examining various molecular pathways by immunohistochemistry showed that a proportion of cervical CCCs had loss of PTEN, positivity for pakt, and positivity for p- mammalian target of rapamycin (mtor) with 1 case showing human epidermal growth factor receptor 2 (HER2) amplification by fluorescence in situ hybridization. 67 However, no molecular analysis was performed in these cases and therefore, the correlation of these results with actual mutations is unknown. 42 Arch Pathol Lab Med Vol 143, January 2019 Cervical Adenocarcinoma: A Heterogeneous Entity Hodgson & Park

10 Figure 8. Endocervical adenocarcinoma with serous-like features. A, Usual type endocervical adenocarcinoma with serous-like papillae and slitlike spaces. B, High power shows nuclear pleomorphism, large cherry-red nucleoli, and abundant mitotic figures and apoptotic bodies. C, Micropapillary growth similar to high-grade serous carcinoma of ovary/fallopian tube (hematoxylin-eosin, original magnifications 3100 [A and C] and 3200 [B]). Serous Carcinoma Papillary serous carcinoma of the endocervix was described by Gilks and Clement 68 in 1992, with a followup study evaluating the clinicopathologic features of 18 cases in These reports highlighted a bimodal age distribution in patients (,40 years,.65 years), similar outcomes compared to UEA in patients with stage I disease, and the importance of excluding serous carcinoma of endometrial origin. One study presented in abstract form demonstrated HPV positivity in all 6 cases that were tested by polymerase chain reaction, 2 of which also showed aberrant p53 staining by immunohistochemistry. 70 Another study 71 evaluating the clinicopathologic and immunohistochemical features of so-called cervical serous carcinomas showed a number of interesting findings: (1) a bimodal age distribution was again noted with 3 premenopausal and 10 postmenopausal patients; (2) significant clinical differences were found between the 2 groups where all of the premenopausal patients were essentially cured (alive without disease after.20 years), while half the postmenopausal patients were either alive with disease or dead of disease; and (3) histologic variations were seen, with evidence of combined UEA and serous morphology in the premenopausal group but only pure serous histology in the postmenopausal group. HPV in situ hybridization was positive in both the serous and usual type areas in the 1 case that was tested in the premenopausal group. WT1 immunohistochemistry was also informative in that all premenopausal cases were WT1 negative, while 9 of 10 postmenopausal cases showed WT1 positivity. Similarly, p53 was overexpressed in 1 premenopausal case and only in the morphologically serous component, compared to aberrant expression in all postmenopausal cases. Most interesting in this series was the presence of concurrent serous tubal intraepithelial carcinoma (STIC) in 5 cases with identical TP53 missense mutations in the STIC and cervical lesions in 2/3 cases from the postmenopausal group. The systematic sectioning of the fimbriated end of the fallopian tube (SEE-FIM) has become a routine part of practice only in the last decade, which has allowed for the detection of these occult lesions that previously would have gone undetected. Another recent study showed that WT1 was not immunohistochemically detected in 12 cases of cervical serous carcinoma, with HPV 16 or 18 being detected in 4 of those cases. 72 Even micropapillary growth pattern of cervical adenocarcinoma that can mimic peritoneal serous carcinoma has been described, usually associated with a component of UEA and harboring HPV (Figure 8, A through C) The evidence suggests that serous carcinoma of the cervix most likely represents a high-grade variant of HPVassociated UEA with serous-like features and that a certain proportion of so-called cervical serous carcinomas are likely drop metastases from the adnexa (assuming there is no endometrial lesion). If one is considering the diagnosis of primary endocervical serous carcinoma, metastases from the uterine corpus and adnexa, including occult tubal primary lesions, must be rigorously excluded. As such, SEE-FIM is required in these cases. Endometrioid Adenocarcinoma Until recently, specific diagnostic criteria for primary endocervical endometrioid adenocarcinoma were lacking in the literature, leading to great variability in the reporting of its frequency with some authors suggesting that it is quite rare, 78 while others suggested that it was one of the more common subtypes. 79 Because of the lack of well-defined criteria for the endometrioid variant of endocervical adenocarcinoma, there are conflicting data regarding prevalence and association with HPV. In 2018, the IECC included specific diagnostic criteria for endocervical endometrioid adenocarcinoma. 5 The group showed that when using WHO criteria, a large percentage of tumors in their cohort would have been diagnosed as endometrioid adenocarcinoma; however, when strict evaluation for HPV-related features was conducted, only a small minority (3 of 371, 1.1%) actually fell into this category. These 3 tumors were found to be negative for HPV by in situ hybridization. The IECC used confirmatory endometrioid features to make the diagnosis, that is, at least focally identified low-grade endometrioid glands lined by columnar cells, pseudostratified nuclei demonstrating no more than moderate atypia, squamous differentiation, and/or the presence of endometriosis. HPV-associated adenocarcinoma features were lacking. Of note, there have been reports of endometrioid adenocarcinoma arising in cervical endometriosis. 80 Overall, endocervical endometrioid adenocarcinoma should not be reflexively diagnosed when evaluating a mucin-poor adenocarcinoma arising in the endocervix, as the other tumors in the differential diagnoses are much more likely, including UEA, mesonephric carcinoma, and endometrial endometrioid adenocarcinoma extending into the cervix (Figure 9, A and B). Arch Pathol Lab Med Vol 143, January 2019 Cervical Adenocarcinoma: A Heterogeneous Entity Hodgson & Park 43

11 Figure 9. True endometrioid adenocarcinoma of the cervix is rare (1%). More often they are extensions of corpus tumors extending into the cervix. A, Endometrial endometrioid adenocarcinoma involving cervix. B, Confirmatory endometrioid features, including low-grade endometrioid glands lined by columnar cells, pseudostratified nuclei with mild-moderate atypia, and squamous differentiation (hematoxylin-eosin, original magnifications whole slide image [A] and 340 [B]). Adenocarcinoma, NOS According to the IECC, this designation should be used when a tumor cannot be classified by either WHO or IECC criteria. In the IECC study, 2.4% of the studied cases were classified by consensus review as adenocarcinoma, NOS. HPV in situ hybridization and p16 results indicate that both HPV-related and non HPV-related tumors may fall into this category. Table 2. Summary of Important Points for Human Papillomavirus (HPV) Associated and Non HPV-Associated Endocervical Adenocarcinomas HPV-Associated Endocervical Adenocarcinomas Easily identifiable apical mitotic figures and apoptotic bodies; subclassified by cytoplasmic features Usual type Most common subtype Most cases are stage I Positive for p16, CEA, and HPV ISH Usually negative for vimentin, ER, and PR, though there can be considerable expression in some cases Mucinous, NOS.50% of tumor cells with evident intracytoplasmic mucin Immunophenotype as per usual type Mucinous, intestinal type 50% goblet cells in a background of usual type morphology May show at least focal enteric immunophenotype Mucinous, signet ring cell type Rarely exists in pure form, often admixed with usual type Villoglandular type Rare, well-differentiated variant of usual type Good prognosis ismile Recently described entity Along with its precursor SMILE, likely represents a marker of phenotypic instability Variety of morphologic patterns Non HPV-Associated Endocervical Adenocarcinomas Lacking easily identifiable apical mitotic figures or apoptotic bodies; subclassified by previously established criteria Gastric type Second most common subtype Adenoma malignum included in the spectrum Aggressive, with metastases to unusual sites Knowledge of precursor lesions is evolving Mesonephric carcinoma Rare neoplasm of Wolffian duct origin Positive for PAX8, GATA3, and HNF1-b KRAS, NRAS, and chromatin-remodeling gene mutations as well as copy number gains and losses Clear cell carcinoma DES-associated and non DES-associated cases Bimodal age distribution Architecture and immunophenotype as in ovary Microsatellite instability Serous carcinoma Rare (controversial existence) Diligently exclude corpus and tubo-ovarian primary tumors and other mimickers as source Endometrioid adenocarcinoma Rare Confirmatory endometrioid features helpful in making the diagnosis May arise in endometriosis Exclude extension from corpus Adenocarcinoma, NOS Used when the tumor cannot be specifically subclassified HPV ISH helpful in diagnostically challenging cases Abbreviations: CEA, carcinoembryonic antigen; DES, diethylstilbestrol; ER, estrogen receptor; HNF1-b, hepatocyte nuclear factor 1 b; ISH, in situ hybridization; ismile, invasive stratified mucin-producing carcinoma; NOS, not otherwise specified; PR, progesterone receptor; SMILE, stratified mucin-producing intraepithelial lesion. 44 Arch Pathol Lab Med Vol 143, January 2019 Cervical Adenocarcinoma: A Heterogeneous Entity Hodgson & Park

12 CONCLUSIONS Endocervical adenocarcinomas are a heterogeneous group of tumors, most of which are etiologically related to infection by high-risk HPV. However, it is now evident that a significant proportion of cervical adenocarcinomas are not driven by HPV and in the current era of HPV vaccination, it is likely that the relative incidence of HPVunassociated tumors will increase. Importantly, endocervical adenocarcinomas can be difficult to recognize during routine cervical cytologic examination and will not be detected by HPV-only screening programs. Available evidence suggests that at least a subset of HPV-unrelated tumors behave aggressively, respond differently to standard chemotherapy regimens, and have different molecular drivers from HPV-associated carcinomas. Classification schemes like the IECC emphasize our current understanding of cervical glandular neoplasia and are supported by p16 and HPV in situ hybridization results. 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