Pelvic and Ovarian Recurrence of Small HPV-associated Cervical Adenocarcinoma With Transformation to Neuroendocrine Carcinoma.

The phenomenon of small human papillomavirus-associated cervical adenocarcinomas involving the ovary via a transuterine and transtubal route is uncommon but well described in the literature. We report a unique case of a small human papillomavirus-associated cervical adenocarcinoma spreading to both ovaries and the pelvis via this route 22 mo after loop excision and trachelectomy and developing into a high-grade neuroendocrine carcinoma in the metastasis.

Multiple Epidermolytic Acanthomas: Rare Vulval Lesions Which May be Mistaken for Viral Warts.

Epidermolytic acanthoma is a rare benign lesion that most often presents as a solitary or multiple small papular lesions on the trunk, face, limbs or external male genitalia. Only a small number of cases have been reported occurring on the vulva and clinically and histologically they may mimic and be misdiagnosed as viral warts. We report 2 cases of multiple epidermolytic acanthomas localized to the vulva. Molecular tests (in situ hybridization and polymerase chain reaction) showed no evidence of human papillomavirus infection and p16 staining was negative. We stress the need for pathologists to consider epidermolytic acanthoma in the differential diagnosis of multiple vulval lesions resembling viral warts.

Human Papillomavirus (HPV)-associated Lymphoepithelioma-like Carcinoma of the Vagina and Anal Canal: A Rare Variant of Squamous Cell Carcinoma.

Lymphoepithelioma-like carcinoma (LELC) is an uncommon variant of squamous cell carcinoma, which is histologically identical to lymphoepithelial carcinoma of the nasopharynx. LELCs have been reported at a variety of sites, including the stomach, salivary gland, thymus, cervix, endometrium, breast, skin, bladder, and lung. We report 2 LELCs of the vagina and 1 of the anal canal, the first report of LELC at the latter site. All 3 neoplasms were diffusely positive with p16 (block-type immunoreactivity) and the anal canal lesion contained high-risk human papillomavirus type 16; the 2 vaginal neoplasms underwent human papillomavirus testing but were unsuitable for analysis. All cases were Epstein-Barr virus negative. In reporting these cases, we highlight the potential for misdiagnosis and suggest an association with human papillomavirus infection similar to LELCs in the uterine cervix.

Cervical Squamous Carcinomas With Prominent Acantholysis and Areas Resembling Breast Lobular Carcinoma: An Aggressive Form of Dedifferentation.

There have been occasional reports of primary cervical adenocarcinoma with areas of dedifferentiation resulting in morphologic mimicry of breast lobular carcinoma. We describe 4 cases of primary cervical squamous carcinoma with prominent acantholysis (3 cases), areas resembling breast lobular carcinoma (3 cases) or both (2 cases). All 4 tumors showed positivity with p63 and CK5/6 and 3 of 4 exhibited block-type immunoreactivity with p16. Two of the 4 cases contained high-risk human papillomavirus (types 16 and 18) on molecular testing; of the 2 cases which were human papillomavirus negative, 1 exhibited patchy nonblock immunoreactivity with p16. All cases exhibited some degree of loss of E-cadherin membranous staining in the areas of acantholysis and foci resembling breast lobular carcinoma. Three of 4 patients had extracervical spread at diagnosis; the fourth patient developed extracervical recurrence on follow-up. The initial FIGO stages were IB1, IIB (2 cases) and IVB. The 2 patients whose neoplasms were human papillomavirus negative developed distant metastases (supraclavicular, meningeal, and lung) during the course of their disease; the same 2 patients died of disease at periods of 4 mo and 1 yr after diagnosis. Cervical squamous carcinomas with acantholytic features and areas resembling breast lobular carcinoma are an unusual morphologic variant of squamous carcinoma. We consider the acantholysis and mimicry of breast lobular carcinoma to be part of a spectrum of morphologic changes, possibly related to loss of E-cadherin. These features can be regarded as a form of dedifferentiation which indicates a potential for aggressive behavior.

The prevalence of viral agents in esophageal adenocarcinoma and Barrett's esophagus: a systematic review.

BACKGROUND AND AIMS: Human papilloma virus (HPV), which may reach the esophagus through orogenital transmission, has been postulated to be associated with esophageal adenocarcinoma (EAC). A systematic review of the literature investigating the prevalence of infectious agents in EAC and Barrett's esophagus (BE) was carried out. METHODS: Using terms for viruses and EAC, the Medline, Embase, and Web of Science databases were systematically searched for studies published, in any language, until June 2016 that assessed the prevalence of viral agents in EAC or BE. Random-effects meta-analyses of proportions were carried out to calculate the pooled prevalence and 95% confidence intervals (CIs) of infections in EAC and BE. RESULTS: A total of 30 studies were included. The pooled prevalence of HPV in EAC tumor samples was 13% (n=19 studies, 95% CI: 2-29%) and 26% (n=6 studies, 95% CI: 3-59%) in BE samples. HPV prevalence was higher in EAC tissue than in esophageal tissue from healthy controls (n=5 studies, pooled odds ratio=3.31, 95% CI: 1.15-9.50). The prevalence of Epstein-Barr virus (EBV) in EAC was 6% (n=5, 95% CI: 0-27%). Few studies have assessed other infectious agents. For each of the analyses, considerable between-study variation was observed (I=84-96%); however, sensitivity analyses did not show any major sources of heterogeneity. CONCLUSION: The prevalence of HPV and EBV in EAC is low compared with other viral-associated cancers, but may have been hampered by small sample sizes and detection methods susceptible to fixation processes. Additional research with adequate sample sizes and high-quality detection methods is required.

HPV prevalence and type-distribution in cervical cancer and premalignant lesions of the cervix: A population-based study from Northern Ireland.

Assessment of Human papillomavirus (HPV) prevalence and genotype distribution is important for monitoring the impact of prophylactic HPV vaccination. This study aimed to demonstrate the HPV genotypes predominating in pre-malignant and cervical cancers in Northern Ireland (NI) before the vaccination campaign has effect. Formalin fixed paraffin embedded tissue blocks from 2,303 women aged 16-93 years throughout NI were collated between April 2011 and February 2013. HPV DNA was amplified by PCR and HPV genotyping undertaken using the Roche(®) linear array detection kit. In total, 1,241 out of 1,830 eligible samples (68.0%) tested positive for HPV, with the majority of these [1,181/1,830 (64.5%)] having high-risk (HR) HPV infection; 37.4% were positive for HPV-16 (n = 684) and 5.1% for HPV-18 (n = 93). HPV type-specific prevalence was 48.1%, 65.9%, 81.3%, 92.2%, and 64.3% among cervical intraepithelial neoplasias (CIN) Grades I-III, squamous cell carcinomas (SCC) and adenocarcinoma (AC) cases, respectively. Most SCC cases (81.3%) had only one HPV genotype detected and almost a third (32.0%) of all cervical pathologies were HPV negative including 51.9% of CIN I (n = 283), 34.1% CIN II (n = 145), 18.7% of CIN III (n = 146), 7.8% of SCC (n = 5), and 35.7% of AC (n = 5) cases. This study provides important baseline data for monitoring the effect of HPV vaccination in NI and for comparison with other UK regions. The coverage of other HR-HPV genotypes apart from 16 and 18, including HPV-45, 31, 39, and 52, and the potential for cross protection, should be considered when considering future polyvalent vaccines.

A rare case of HPV-negative cervical squamous cell carcinoma.

It is generally assumed that virtually all cervical squamous cell carcinomas are associated with persistent infection by high-risk human papillomavirus (HPV), although it is well known that unusual variants of cervical adenocarcinoma are mostly HPV negative. We report a case of a well-differentiated cervical squamous cell carcinoma in a 54-yr-old woman, the morphologic features of which suggested a non-HPV-related neoplasm. The tumor was p16 negative. HPV was also negative by 2 methods, including the highly sensitive SPF-10 system. Further study of additional cases is needed to establish the etiological and pathogenetic factors that underlie very rare non-HPV-related cervical squamous cell carcinoma.

Type-specific HPV prevalence in invasive cervical cancer in the UK prior to national HPV immunisation programme: baseline for monitoring the effects of immunisation.

AIMS: To establish the human papillomavirus (HPV) type-specific prevalence in cervical cancer and high-grade cervical lesions in the UK prior to the introduction of national HPV vaccination. METHODS: Specimens of cervical cancer (n=1235) and cervical intraepithelial neoplasia (CIN)3 (n=2268) were tested for HPV genotypes in England, Scotland, Wales and Northern Ireland. Data were pooled and weighted estimates presented. RESULTS: Among cervical cancer cases, 95.8% were positive for at least one high-risk (HR) HPV type. Restricting to those with HR HPV, the proportion positive for HPV16 and/or HPV18 was similar across countries (weighted overall prevalence 83.0%). This proportion decreased with increasing age at diagnosis (p=0.0005). HPV31, HPV33, HPV45, HPV52 and/or HPV58 were detected in 16.1% of HR HPV-positive cervical cancers and there was no significant association with age for these types. For HR HPV-positive CIN3 cases, there was a similar age-specific pattern with the highest positivity of HPV16 and/or HPV18 in the youngest age group (77.2%). The proportion of HR HPV CIN3 cases positive for HPV31, HPV33, HPV45, HPV52 and/or HPV58 was 36.3% in those aged <30 years at diagnosis. CONCLUSIONS: The prevalence of HPV 16 and/or 18 was high in all UK countries and highest in those diagnosed at a younger age. The UK is well placed to monitor the impact of HPV vaccination on type-specific HPV prevalence in cervical disease.

Prevalence of human papillomavirus in women attending cervical screening in the UK and Ireland: new data from northern Ireland and a systematic review and meta-analysis.

There is substantial international variation in human papillomavirus (HPV) prevalence; this study details the first report from Northern Ireland and additionally provides a systematic review and meta-analysis pooling the prevalence of high-risk (HR-HPV) subtypes among women with normal cytology in the UK and Ireland. Between February and December 2009, routine liquid based cytology (LBC) samples were collected for HPV detection (Roche Cobas® 4800 [PCR]) among unselected women attending for cervical cytology testing. Four electronic databases, including MEDLINE, were then searched from their inception till April 2011. A random effects meta-analysis was used to calculate a pooled HR-HPV prevalence and associated 95% confidence intervals (CI). 5,712 women, mean age 39 years (±SD 11.9 years; range 20-64 years), were included in the analysis, of which 5,068 (88.7%), 417 (7.3%) and 72 (1.3%) had normal, low, and high-grade cytological findings, respectively. Crude HR-HPV prevalence was 13.2% (95% CI, 12.7-13.7) among women with normal cytology and increased with cytological grade. In meta-analysis the pooled HR-HPV prevalence among those with normal cytology was 0.12 (95% CIs, 0.10-0.14; 21 studies) with the highest prevalence in younger women. HPV 16 and HPV 18 specific estimates were 0.03 (95% CI, 0.02-0.05) and 0.01 (95% CI, 0.01-0.02), respectively. The findings of this Northern Ireland study and meta-analysis verify the prevalent nature of HPV infection among younger women. Reporting of the type-specific prevalence of HPV infection is relevant for evaluating the impact of future HPV immunization initiatives, particularly against HR-HPV types other than HPV 16 and 18.

Mesonephric adenocarcinomas of the uterine cervix and corpus: HPV-negative neoplasms that are commonly PAX8, CA125, and HMGA2 positive and that may be immunoreactive with TTF1 and hepatocyte nuclear factor 1-ß.

Mesonephric adenocarcinomas are rare neoplasms that most commonly arise in the uterine cervix and exceptionally rarely in the uterine corpus. Although the morphologic features of these neoplasms are well described, there has been relatively limited investigation of the immunoprofile. We report a series of 8 mesonephric adenocarcinomas arising in the uterine cervix (7 cases) and corpus (1 case) and undertake a comprehensive immunohistochemical analysis. This includes markers that have not been investigated previously in mesonephric adenocarcinomas but that are commonly used in gynecologic pathology and may be undertaken when other, mainly Mullerian, adenocarcinomas are considered in the differential diagnosis. Linear array human papillomavirus (HPV) genotyping was also performed. Our results broadly confirm the immunohistochemical profile demonstrated in previous studies with the majority of mesonephric adenocarcinomas staining positively with CD10 (6 of 8), epithelial membrane antigen (8 of 8), vimentin (8 of 8), and calretinin (7 of 8). Estrogen receptor was positive in 2, carcinoembryonic antigen in 3, and inhibin in 4 cases. p16 was positive in 5 cases (1 diffuse and strong), despite all being HPV negative (in 1 case, there was insufficient DNA for HPV analysis). Novel findings in our study were the demonstration of nuclear positivity with PAX8 and HMGA2 in 7 cases, CA125 immunoreactivity in all 8 cases, and TTF1 and hepatocyte nuclear factor 1-ß staining in 3 cases. As PAX8, CA125, HMGA2, and hepatocyte nuclear factor 1-ß are commonly positive in a variety of Mullerian adenocarcinomas arising in the female genital tract, this may result in diagnostic confusion. All cases were WT1 negative.

Inverted papilloma of the cervix and vagina: report of 2 cases of a rare lesion associated with human papillomavirus 42.

We report 2 cases of a lesion that we term inverted papilloma of the lower female genital tract, occurring in the cervix and upper vagina of 60- and 50-year-old women, respectively. Microscopically, the features were similar to those of inverted transitional papilloma of the urinary bladder with interconnecting islands, trabeculae, and solid sheets of bland transitional epithelium with an inverted growth pattern. There were small foci of squamous and glandular differentiation in the cervical case. Linear array human papillomavirus genotyping revealed human papillomavirus type 42 in both cases. Inverted papilloma in the lower female genital tract is extremely rare with, as far as we are aware, only 3 previously reported similar cases in the cervix and none in the vagina. Our results suggest that these neoplasms when occurring in the lower female genital tract may be associated with low-risk human papillomavirus, perhaps specifically human papillomavirus 42.

p16 Immunoreactivity in unusual types of cervical adenocarcinoma does not reflect human papillomavirus infection.

AIMS: The association between human papillomavirus (HPV) and cervical carcinoma is well known, with HPV being identifiable in almost all cervical squamous carcinomas and most adenocarcinomas. However, the prevalence of HPV in unusual morphological types of cervical adenocarcinoma has not been investigated extensively. The aim was to determine HPV status in a series of primary cervical adenocarcinomas, enriched for unusual morphological types. The relationship between HPV and p16 immunoreactivity in these neoplasms was also investigated, as it is generally assumed that in cervical neoplasms diffuse p16 expression is predictive of the presence of high-risk HPV. METHODS AND RESULTS: Sixty-three cervical adenocarcinomas, comprising those of usual type (n = 43), minimal deviation type (n = 4), gastric type (n = 3), intestinal type (n = 3), mesonephric type (n = 3), clear cell type (n = 4), serous type (n = 2) and hepatoid type (n = 1) underwent linear array HPV genotyping and immunohistochemistry for p16. Overall, HPV was identified in 32 of 56 cases (57%) in which sufficient DNA was present for analysis. The most common HPV types were 16 and 18, with these being identified in 20 and 18 cases, respectively, either alone or in combination. Seventy-eight per cent of usual-type adenocarcinomas were HPV-positive, as was the single serous carcinoma in which there was sufficient DNA for analysis. In contrast, all minimal deviation adenocarcinomas and those of gastric, intestinal, mesonephric and clear cell types were HPV-negative, as was the single hepatoid carcinoma. All usual-type adenocarcinomas exhibited p16 immunoreactivity (diffuse staining in all but one case), as did 11 of 20 of those of unusual morphological type (five focal, six diffuse). CONCLUSIONS: Most, but not all, cervical adenocarcinomas of usual type contain HPV, but those of unusual morphological type are almost always HPV-negative. This has implications for the efficacy of HPV vaccination in the prevention of cervical adenocarcinoma. A significant proportion of cervical adenocarcinomas are p16-positive in the absence of HPV, illustrating that in these neoplasms diffuse p16 immunoreactivity is not a reliable surrogate marker of the presence of high-risk HPV.

Cervical adenocarcinoma in situ recurring as vaginal adenocarcinoma 16 years after hysterectomy.

We report a case in which a vaginal adenocarcinoma was discovered in a 67-year-old woman 16 years after hysterectomy for cervical adenocarcinoma in situ. Both the vaginal and cervical lesions exhibited morphologic and immunohistochemical (CDX2-positive) features of intestinal differentiation. Linear array human papillomavirus genotyping demonstrated the vaginal adenocarcinoma to contain human papillomavirus 45. We believe the vaginal adenocarcinoma to be related to the cervical adenocarcinoma in situ and to represent recurrence of this. This is an extremely rare phenomenon with, as far as we are aware, only one previous report in the literature.

Vulval intraepithelial neoplasia with mucinous differentiation: report of 2 cases of a hitherto undescribed phenomenon.

We report 2 cases of classic vulval intraepithelial neoplasia (VIN) with collections of cells throughout the full epithelial thickness and within epithelial downgrowths containing intracytoplasmic mucin. The mucinous cells were bland with eccentrically placed small regular nuclei and were positive with CAM5.2, carcinoembryonic antigen, epithelial membrane antigen, and cytokeratin 7, markers that are typically positive in the neoplastic cells of Paget disease. Both cases were strongly positive with p16 and linear array genotyping demonstrated the presence of high-risk human papillomavirus type 16. As far as we are aware, mucinous differentiation has not been described in VIN, although mucinous metaplasia has rarely been reported in non-neoplastic vulval skin and in cutaneous squamous cell carcinoma in situ at extravulval sites. The main differential diagnosis of the cases we describe is Paget disease or coexistent VIN and Paget disease and the immunophenotype of the mucinous cells may further highlight the potential for misdiagnosis. Other possible differential diagnoses include Pagetoid squamous cell carcinoma in situ (Pagetoid VIN), basal cell carcinoma with sebaceous differentiation, and VIN involving skin appendage structures. The mucinous cells are likely to be metaplastic and a result of aberrant differentiation in a premalignant squamous lesion.