ER-positive endocervical adenocarcinoma mimicking endometrioid adenocarcinoma in morphology and immunohistochemical profile: A case report of application of HPV RNAscope detection.

RATIONALE: Usual-type endocervical adenocarcinoma (ECA), high-risk HPV associated, is the most common type of glandular carcinoma in the endocervix. Mucin-depleted usual-type ECA is 1 end of morphological lineage of usual-type ECA and morphologically may show endometrioid features, which could cause diagnostic challenge with uterine endometrioid adenocarcinoma (EEC) and primary endometrioid ECA, especially in the setting of small biopsy and endocervical curettage (ECC). PATIENT CONCERNS: A 37-year-old women presented with dyspareunia for 1 year, showing atypical glandular cell on a liquid-based Pap TCT examination and positive for HPV16 detection. ECC showed EEC in another hospital based on its "endometrioid" morphology and immunohistochemical profiles (ER/PR/PAX8 strongly positive, though p16 also strongly positive). DIAGNOSES: The specimen of hysterectomy in our hospital displayed a lesion confined to the uterine cervix showing the same morphology and immunohistochemical profiles as ECC. Finally, we successfully performed HPV RNAscope and detected high-risk human papilloma virus (HPV) E6/E7 mRNA particles in tumor cells in situ, which warranted usual-type ECA with mucin-depleted feature, a rare deviation of usual-type of ECA. INTERVENTIONS: The patient underwent total hysterectomy with lymph node dissection. OUTCOMES: To date, 14 months after surgery, the patient is well without recurrence or distant metastasis, and undergoes regular reexamination. LESSONS SUBSECTIONS: We report a rare case of mucin-depleted usual-type ECA showing overlapping morphological and immunohistochemical profiles with EEC. The pathological diagnosis was confirmed by high-risk HPV RNAscope detection which is superior than immunohistochemistry to identify usual-type ECA, warranting an important role in assisting the diagnosis of morphological vague cases.

HPV DNA integration site as proof of the origin of ovarian metastasis from endocervical adenocarcinoma: three case reports.

BACKGROUND: Most endocervical adenocarcinomas are human papillomavirus (HPV)-related cancers associated with p16 immunostaining. Ovarian metastasis from cervical cancer is a rare phenomenon, the mechanism of dissemination remains unclear. The diagnosis of metastasis may be difficult to establish when the ovarian neoplasm presents features consistent with primary tumor. Immunohistochemical expression of p16 in ovarian tumors can guide the diagnosis of metastasis from HPV-related cervical cancer, but p16 positivity is nonspecific. Identical HPV genotype in the paired endocervical and ovarian tumors is a better marker for cervical origin, which may also be confirmed by identical HPV integration site. CASE PRESENTATION: Two women presented with HPV18 cervical adenocarcinoma. No signs of disease were visible on MRI after treatment. After several years of follow-up, mucinous ovarian tumors were discovered in both patients. Molecular analyses showed that the ovarian lesions were HPV18-positive; indicating a primary cervical origin. A third woman was diagnosed with grade 1 ovarian endometrioid carcinoma with no peritoneal carcinomatosis. Final histological examination and HPV genotyping revealed HPV18-related in situ endometrioid adenocarcinoma in the endocervix and HPV18-related invasive endometrioid adenocarcinoma in the endometrium and both ovaries. Additional molecular analyses performed in two patients identified the same HPV integration sites in both the ovarian and cervical tumors, confirming that the ovarian mass was a metastasis from the cervical adenocarcinoma. CONCLUSION: We report three new cases of ovarian neoplasia in which the diagnosis of metastasis from cervical cancer was supported by the same HPV genotype and the same integration site in the paired cervical and ovarian tumors. To our knowledge, this is the first report of molecular evidence of the cervical origin of an ovarian metastasis. HPV screening should be performed in ovarian tumors for all patients with history of cervical neoplasia.

Panel of Villin, Pro-Ex-C, Estrogen Receptor and Progesterone Receptor Expressions Could Help in Differentiation Between Endocervical and Endometrioid Adenocarcinoma.

OBJECTIVE: Endocervical and endometrioid adenocarcinoma have marked overlapping features and the differentiation between them is important for their accurate management. Villin is an actin-binding protein which has an important role in the maintenance of microvilli in epithelial cells and epithelial cell-specific anti-apoptotic protein processes. Pro-Ex-C is a marker for higher-risk human papilloma virus (HPV) which targets the cell cycle proteins causing their overexpression. The aim of the study was to clarify the diagnostic and predictive role of villin, Pro-Ex-C, estrogen receptor (ER) and progesterone receptor (PR) expression in endocervical and endometrioid adenocarcinoma. MATERIAL AND METHOD: We evaluated villin, Pro-Ex-C, ER and PR expressions in 15 cases of endocervical adenocarcinoma and 30 cases of endometrioid adenocarcinoma. We analyzed the diagnostic and predictive role of that panel in both carcinoma subtypes. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. RESULTS: Positive villin and Pro-Ex-C expressions were positively correlated with the presence and pattern of cervical stromal invasion (p < 0.05). ER was positive in all cases of endometrioid adenocarcinoma. PR was detected in most cases of endometrioid adenocarcinoma. The differences of villin, Pro-Ex-C, ER and PR expression in endocervical and endometrioid adenocarcinoma was statistically significant (p < 0.05). This methodology for distinguishing endocervical and endometrioid adenocarcinoma had a sensitivity of 100%, a specificity of 100% and a significant prognostic and predictive role. CONCLUSION: In conclusion, villin, Pro-Ex-C, ER and PR expressions have diagnostic and predictive roles in endocervical and endometrioid adenocarcinoma.

Cervical Adenocarcinoma: Diagnosis of Human Papillomavirus-Positive and Human Papillomavirus-Negative Tumors.

CONTEXT: - Cervical adenocarcinomas span a diverse group of tumors with several distinct histologic tumor types, which include endocervical, endometrioid, intestinal, villoglandular, gastric, signet ring, serous, clear cell, and mesonephric. Diagnosis of cervical adenocarcinoma, especially early diagnosis, poses a significant challenge. OBJECTIVE: - To review the pathogenesis, diagnostic criteria, immunohistochemical markers, and differential diagnosis of various subtypes of human papillomavirus (HPV)-positive and HPV-negative cervical adenocarcinomas. The paper presents a concise summary of the issues that may be particularly difficult in histopathologic diagnosis, such as differentiating neoplastic lesions from benign mimics, determining the tumor type, differentiating early invasive lesions from adenocarcinoma in situ, measuring the depth of invasion, and, finally, differentiating primary cervical adenocarcinoma from uterine endometrioid adenocarcinoma and tumors metastatic from other primary sites. DATA SOURCES: - The study employed a PubMed search of recently published reports. CONCLUSIONS: - Early detection of HPV-positive tumor types may be aided with the expansion of HPV testing; however, early diagnosis of HPV-negative cervical adenocarcinomas will continue to pose a challenge and may require the development of additional molecular testing techniques.

Endometrial endometrioid adenocarcinoma of the uterine corpus involving the cervix: some cases probably represent independent primaries.

The majority of endometrial endometrioid adenocarcinomas involving the cervix have tumor morphology that is similar in the endometrium and the endocervix. There are, however, some cases in which the morphology of the tumor in the endocervix is different from the endometrial carcinoma, in which it is more invasive than the endometrial carcinoma, or in which invasion only occurs in the endocervix while there is no or only minimal myometrial invasion. The goal of this study was to investigate whether tumors involving the endometrium and the endocervix are similar or 2 independent primaries by hematoxylin and eosin stain, immunohistochemistry (IHC), human papillomavirus (HPV) DNA in situ hybridization, RNA reverse transcriptase in situ polymerase chain reaction (PCR) analyses to reveal HPV, and DNA clonality studies. We selected 14 cases of endometrial endometrioid adenocarcinomas involving the cervix with complete pathology material available from the years between 1968 and 2004. Immunohistochemical studies for vimentin, carcinoembryonic antigen, estrogen receptor, progesterone receptor, and p16 were performed in 12 cases; HPV DNA/RNA analyses in 4 cases; and clonality studies in 9 cases. The patients' ages ranged from 42 to 81 years (mean: 62 y). Follow-up information was obtained in 11 patients. Histologic features varied between the tumors in the endometrium and the endocervix in 8 cases, and 5 of these cases had uniform, dilated glands having a microcystic appearance in the cervix. In 6 cases, the tumors in the endometrium and the endocervix had similar histologic features. The immunohistochemical studies showed some differences between the endometrial and endocervical adenocarcinomas in 8 of the 12 cases, independent of differing or similar histologic features. HPV testing in 4 of the cases (3 with similar and 1 with different histology) yielded similar results in the endometrium and endocervix: 2 cases were negative, 1 was positive and 1 was equivocal for HPV DNA/RNA analyses. Clonality studies showed differences between the adenocarcinoma in the endometrium and the endocervix in 7 cases, including 5 cases with different histologic appearances; 2 cases had similar loss of heterozygosity patterns. In conclusion, as suggested by clonality studies, coexisting endometrial and endocervical carcinomas with different histologic features are most likely independent neoplasms. Endometrial and endocervical carcinomas that have similar appearances can represent either the same neoplasm or independent primaries. Clonality tests may help determine their relationship. IHC studies may not be helpful for synchronous endometrial and endocervical tumors, especially those of endometrioid type. It is possible that IHC identifies cell differentiation, rather than site of origin. HPV studies are important to identify endocervical tumors associated with high-risk HPV. However, endometrial tumors involving the cervix and endocervical tumors unrelated to HPV are both negative for high-risk HPV.

Cytosolic accumulation of HPV16 E7 oligomers supports different transformation routes for the prototypic viral oncoprotein: the amyloid-cancer connection.

E7 is the major transforming activity in human papillomaviruses, a causal agent for cervical cancer. HPV16 E7 is a small protein with a natively unfolded domain for which dozens of specific cellular targets were described, and represents a prototypical oncoprotein among small DNA tumor viruses. The protein can form spherical oligomers with amyloid-like properties and chaperone activity. Conformation specific antibodies locate endogenous oligomeric E7 species in the cytosol of 3 model cell lines, strongly co-localizing with amyloid structures and dimeric E7 localizes to the nucleus. The cytosolic oligomeric E7 appear as the most abundant species in all cell systems tested. We show that nuclear E7 levels are replenished dynamically from the cytosolic pool and do not result from protein synthesis. Our results suggest that long-term events related to de-repression of E7 would cause accumulation of excess E7 into oligomeric species in the cytosol. These, together with the known target promiscuity of E7, may allow interactions with many of the non-pRb dependent targets described. This hypothesis is further supported by the detection of E7 oligomers in the cytosol of cancerous cells from tissue biopsies.

Expression of multiple human endogenous retrovirus surface envelope proteins in ovarian cancer.

Individual classes of human endogenous retrovirus (HERV) genes and proteins are expressed in cancer, but expression of more than one type of HERV is rare. We report here the expression of multiple HERV genes and proteins in ovarian cell lines and tissues. Expression of HERV-K env mRNA was greater in ovarian epithelial tumors than in normal ovarian tissues (N = 254). The expression of this protein on the surface and in the cytoplasm of ovarian cancer cells was confirmed using anti-HERV-K specific antibody by flow cytometric analysis. The frequency of expression of HERV-K env protein in multitissue microarrays (N = 641) was determined by immunohistochemistry and a significant correlation with tumor histotype was found. A significantly increased expression of HERV-K was observed in tumors with low malignant potential and low grade, relative to expression in normal ovarian tissues. The increase in expression of HERV-K env protein took place in a stepwise fashion in serous papillary adenocarcinoma. Interestingly, we found that other classes of HERV env mRNAs, including ERV3 and HERV-E, are expressed in the same ovarian cancer tissues that expressed HERV-K. Furthermore, anti-HERV antibodies including anti-ERV3 (30%), anti-HERV-E (40%) and anti-HERV-K (55%) were detected in patients with ovarian cancer, but not in normal female controls. HERV env proteins are frequently transcribed and translated in ovarian epithelial tumors, and multiple HERV families are detectable in ovarian cancer. HERV env proteins, and especially those expressed on the cell surface, may serve as novel tumor targets for detection, diagnosis and immunotherapy of ovarian cancer.

Association of PTEN mutation with HPV-negative adenocarcinoma of the uterine cervix.

Serous, mucinous, endometrioid, and clear cell adenocarcinomas arise from reproductive organs of mullerian origin. Although the mutation of PTEN, a tumor suppressor, is known to be involved in tumorigenesis of endometrioid adenocarcinomas of the endometrium and ovary, the role of PTEN alteration in endometrioid adenocarcinoma of the cervix remains to be investigated. To elucidate the molecular pathogenesis of cervical adenocarcinoma and adenosquamous carcinoma, and in particular to examine the potential role of PTEN mutation in endometrioid-type cancer of the cervix, we analyzed 32 cervical adeno- or adenosquamous carcinomas (8 endometrioid adenocarcinomas, 14 mucinous adenocarcinomas and 10 adenosquamous carcinomas) for PTEN mutations and HPV infections. PTEN mutation was detected in 2 of 8 (25.0%) endometrioid cases, 2 of 14 (14.3%) mucinous cases, and none of 10 (0%) adenosquamous cases. HPV DNA was detected in 11 out of 18 (61.1%) PTEN wild-type adenocarcinomas and 8 out of 10 (80.0%) adenosquamous carcinomas. Among 11 HPV-negative adenocarcinomas, 40.0% (2/5) endometrioid cases and 33.3% (2/6) mucinous cases were shown to be PTEN mutated, while no cases (0/21) were PTEN-mutant in the remainder (i.e. adenosquamous carcinomas and HPV-positive adenocarcinomas). The current observations suggest that PTEN mutation is frequently detected in HPV-negative adenocarcinomas of the cervix and the most prevalent occurrence of PTEN mutation in endometrioid subtype is keeping with endometrial and ovarian carcinomas.

Detection of human papillomavirus-16 in ovarian malignancy.

Human papillomavirus is the causal factor for cervical cancer. However, the role of HPV infection in ovarian cancer is unclear. This study aimed to determine the presence of human papillomavirus-16 (HPV-16) in ovarian cancer tissues. Archived human ovarian cancer tissues (N=54 cases, 50 are epithelial cancer, four are nonepithelial cancer) embedded in paraffin blocks were used. Controls are 30 nonmalignant ovarian tissue blocks. In situ hybridisation (ISH) and immunohistochemistry (IHC) were used to detect the presence of HPV-16 and p53 expression. In all, 52 or 36% of the epithelial ovarian tumours detected by ISH or IHC, respectively, were HPV-16 E6 positive. In contrast, only 6.7% of normal ovarian tissues were HPV-16 positive proved by ISH. Human papillomavirus-16 infection was significantly higher in cancer tissues compared to controls with an odds ratio of 16.7 (95% confidence interval [CI]=3.2-71.4, P<0.01). No significant correlation between HPV-16 infection and histological types of cancer was found (P>0.05). p53 gene expression was detected in 42% epithelial ovarian cancers. No correlation between p53 expression and HPV-16 infection was found. The results showed the presence of HPV-16 E6 in ovarian carcinoma, suggesting that HPV infection might play a role in ovarian carcinogenesis.

Metastatic endocervical adenocarcinoma presenting as a virilizing ovarian mass during pregnancy.

BACKGROUND: We report a case of metastatic endocervical adenocarcinoma that presented as a virilizing ovarian mass in a young pregnant woman and simulated a primary ovarian endometrioid tumor. CASE: A 34-year-old woman underwent cesarean delivery and right salpingo-oophorectomy at 34 weeks' gestation for a 32-cm androgen-producing ovarian mass. The ovarian tumor, initially interpreted as a primary ovarian endometrioid carcinoma, was demonstrated to represent metastatic endocervical endometrioid adenocarcinoma based on detection of human papillomavirus 16 (HPV-16) deoxyribonucleic acid in the tumor by in situ hybridization. The hysterectomy specimen demonstrated an endocervical adenocarcinoma associated with adenocarcinoma in situ that also contained HPV-16. CONCLUSION: Human papillomavirus is considered an etiological agent in the development of endocervical adenocarcinomas, having been demonstrated in greater than 90% of tumors. In contrast, recent studies have concluded that HPV is unlikely to play an etiological role in ovarian neoplasia. The demonstration of HPV-16 in both the endocervical and ovarian carcinomas in this patient supports the interpretation that the ovarian tumor is a metastasis.

Human papillomavirus detection of endometrioid carcinoma with squamous differentiation of the uterine corpus.

Many studies have shown a link between human papillomavirus (HPV) and cervical carcinoma. However, studies on the association of HPV with endometrioid carcinoma of the corpus uteri are sparse and controversial. In this study, 33 formalin-fixed, paraffin-embedded tissue samples of endometrioid carcinoma with squamous cell differentiation in grade 1 (adenoacanthoma) and 10 additional samples of endometrioid carcinoma with less squamous cell differentiation in grade 2 or 3 (adenosquamous carcinoma) were examined by the hybrid capture system for the presence of the 14 most common anogenital HPV types, consisting of low-risk HPV types 6, 11, 42, 43, and 44, and intermediate- and high-risk HPV types 16, 18, 31, 33, 35, 45, 51, 52, and 56. No evidence of high-risk HPV DNA types was found in any of these samples. The low- risk HPV DNA types were found in three samples and showed borderline results (+/-) in 6 samples by the hybrid capture system. The 43 samples were tested by dot blot hybridization with HPV probes 6/11, 16/18, and 31/33/35. Only 1 sample was positive for HPV 6/11. The results of this study did not indicate an association between HPV infection and endometrioid carcinoma with squamous cells, though the endometrial mucosa of the corpus uteri is anatomically connected to the endocervical epithelium, and in some cases HPV has been postulated to possibly cause squamous cell differentiation of the endometrium. Our findings are in accord with the concept that HPV infection leading to malignancy is highly site- and tissue-specific. In conclusion, the endometrium may not be a suitable host epithelium for HPV replication and maturation.

Association of human papillomavirus with malignant and premalignant lesions of the uterine endometrium.

The possible association of human papillomavirus (HPV) with endometrial hyperplasia and endometrial adenocarcinoma was investigated. DNA from frozen tissues of 30 endometrioid carcinomas of Japanese patients was tested for HPV DNA by Southern blot hybridization analysis. Screening with HPV type 58 probe under low stringency conditions showed the presence of HPV DNA in two of 30 endometrioid carcinomas. High stringency hybridization identified HPV type 16 in the two positive specimens. The presence of HPV was further analyzed by polymerase chain reaction (PCR)-Southern blot analysis of DNA from archival tissue blocks of the initial 30 endometrioid carcinomas as well as an additional 17 endometrioid carcinomas and 13 atypical hyperplasias of the endometrium from Japan and 38 endometrioid carcinomas from the United States. Polymerase chain reaction amplification using type 16-specific HPV primers for a portion of the E6 open reading frame was positive in six of 47 (13%) endometrioid carcinomas from Japan, including two in which HPV 16 was not detected by Southern blot analysis and two of 38 (5%) endometrioid carcinomas from the United States. Polymerase chain reaction amplification using L1 consensus sequence primers was positive for HPV in two of 13 (15%) endometrial hyperplasias, 13 of 47 (28%) endometrioid carcinomas from Japan, and six of 38 (16%) endometrioid carcinomas from the United States. Slot blot hybridization identified HPV type 16 in seven of the L1 PCR products, including all but one specimen testing positive for HPV type, 16 using E6 type specific primers. In situ hybridization was positive for HPVs 16/18 in glandular epithelial tumor cells in six of the PCR-positive specimens. An additional specimen showed staining for HPVs 16/18 in acellular luminal debris in association with squamous metaplasia of the tumor, but staining was negative in the glandular cells of the tumor. Human papillomavirus was not detected by in situ hybridization in the remaining specimen, which was PCR positive for HPV 16. In situ hybridization was weakly positive for HPVs 31/33/35 in one specimen and was weakly positive for HPVs 6/11 in benign endometrial epithelial cells but not in tumor cells of another specimen that tested positive for HPV by L1 PCR. Two dimensional gel electrophoresis performed on two specimens showed that HPV DNAs were integrated into cellular DNA with no episomal coexistence. These findings suggest that HPV, especially HPV 16, may play an etiologic role in a fraction of endometrioid adenocarcinomas.

Uterine atypical polypoid adenomyoma and ovarian endometrioid carcinoma: metastatic disease or dual primaries?

Atypical polypoid adenomyoma (APA) is an uncommon uterine tumor that rarely metastasizes, although it closely resembles a well-differentiated endometrioid carcinoma. A 37-year-old woman with a history of pelvic endometriosis and oral contraceptive use developed an APA and later presented with bilateral ovarian endometrioid carcinomas. DNA ploidy analysis and human papilloma virus (HPV) typing of the APA and ovarian carcinomas were performed to characterize the primary or metastatic nature of the tumors. Both tumors were aneuploid. The APA had a DNA index of 1.53, compared with 1.19 for the ovarian carcinoma. The APA contained HPV 18, and the ovarian carcinoma a mixed infection of HPV 6, 11, 16, and 18, with types 6 and 11 predominating. These differences in DNA index and HPV type supported the autonomous nature of the APA and the ovarian carcinomas. The report affirms the benign outcome of APA, highlights its complication by a second malignancy, and suggests an etiological role for endometriosis, steroid hormones, and possibly the HPV in the formation of one or both tumors.