Correlation of histology and human papillomavirus DNA detection in condyloma acuminatum and condyloma-like vulvar lesions

The diagnosis of a vulvar condyloma is made when perinuclear halos are seen with nuclear atypia and binucleate forms (koilocytotic atypia). These changes are most prominent in the granular layer and are associated with the presence of human papillomavirus (HPV). However, these changes may be absent or minimal in patients with papillary vulvar lesions; this situation can thus present diagnostic difficulties. We analyzed the histologic features of 53 biopsies from 48 patients who had vulvar lesions suggestive of condylomata. Of the 26 biopsy specimens with koilocytotic atypia, 20 (77%) had sequences homologous to HPV DNA as detected by Southern blot hybridization analysis using a probe of HPV s 6/11, 16, 18, 31, 35, and 51. In cases where the histologic features were suggestive but not diagnostic of condylomata, because unequivocal koilocytotic atypia was not noted, five of 27 (19%) had detectable HPV DNA. In this latter group, we found no histologic feature to distinguish the cases that had detectable HPV DNA from those that did not. Analysis for HPV DNA by in situ hybridization in the cases that were histologically equivocal for condyloma was uniformly negative. We conclude that there is a marked decrease in the detection rate of the HPV types associated with genital tract neoplasms in vulvar lesions that lack koilocytotic atypia. Southern blot hybridization analysis was the only reliable way to distinguish the "equivocal for condyloma" cases that had HPV from those where HPV DNA was not detected.     

Human papillomavirus DNA in genital tract lesions histologically negative for condylomata. Analysis by in situ, Southern blot hybridization and the polymerase chain reaction

Koilocytotic atypia (nuclear atypia in conjunction with perinuclear halos) is diagnostic of condylomata of the lower female genital tract, over 90% of which contain human papillomavirus (HPV) DNA. Genital tract lesions may be clinically suggestive of condylomata but lack clear-cut koilocytotic atypia. Of 57 vulvar and 60 cervical lesions that lacked clear-cut koilocytotic atypia, four (7%) and two (3%), respectively, had HPV DNA detected by in situ analysis. Using Southern blot analysis, HPV DNA was detected in five of 27 (19%) and 20 of 55 (36%) vulvar and cervical lesions, respectively, that lacked koilocytotic atypia. When analyzed with the polymerase chain reaction (PCR), HPV DNA was detected in six of 22 (27%) and three of 18 (17%) vulvar and cervical lesions, respectively, that lacked koilocytotic atypia. These findings demonstrate that infection by HPV may be found in genital tract lesions that lack koilocytotic atypia. The lower detection rate of HPV in cervical lesions that lacked koilocytotic atypia with PCR as compared with Southern blot analysis may be related to the relatively high proportion of "novel" types (related to, but distinct from, the HPV types in the probe) in such lesions. The increase in the detection rate in vulvar lesions that lacked koilocytotic atypia with PCR compared with in situ hybridization suggests that about one third of such lesions are HPV related, but that in such cases the copy number of the virus is typically below the threshold of the in situ analysis.     

Is lobular endocervical glandular hyperplasia a cancerous precursor of minimal deviation adenocarcinoma?: a comparative molecular-genetic and immunohistochemical study

Although lobular endocervical glandular hyperplasia (LEGH) was originally described as a distinct hyperplastic glandular lesion of the uterine cervix, recent studies have raised a question that LEGH may be a cancerous precursor of minimal deviation adenocarcinoma (MDA) and other mucinous adenocarcinomas (MACs) of the uterine cervix. In the present study, we studied LEGH, MDA, and MAC by using molecular-genetic and immunohistochemical methods for chromosomal imbalance, microsatellite instability, human papillomavirus (HPV) infection, and gastric pyloric-type mucin secretion to clarify their relationship. Comparative genomic hybridization revealed recurrent chromosomal imbalances, that is, gains of chromosome 3q and a loss of 1p, which were common to MDA and MAC, in 3 of 14 LEGHs analyzed (21%). LEGHs with chromosomal imbalances showed a degree of cellular atypia in the hyperplastic glandular epithelium. Dual-color fluorescence in situ hybridization confirmed a gain of chromosome 3 fragment in these cervical glandular lesions. HPV in situ hybridization revealed that high-risk HPV (types 16 and 18) was positive in over 80% of MACs, but negative in all LEGHs and MDAs examined. Microsatellite instability was rarely detected in these cervical glandular lesions. Our present study results demonstrated a molecular-genetic link between LEGH and cervical mucinous glandular malignancies including MDA and MAC, and are thought to support the hypothesis that a proportion of LEGHs are cancerous precursors of MDA and/or MAC.     

Histological distribution of polymerase chain reaction--amplified human papillomavirus 6 and 11 DNA in penile lesions.

The purpose of this study was to ascertain the histological pattern of distribution of human papillomavirus (HPV) 6 and 11 DNA in penile lesions by in situ hybridization after amplification by the polymerase chain reaction (PCR). HPV DNA was routinely detected by in situ hybridization with or without PCR amplification in granular layer cells that showed perinuclear halos and nuclear atypia. Cells that lack these histological features rarely exhibited HPV DNA with conventional in situ hybridization. However, after PCR amplification, in situ analysis showed that many of the cells that lacked halos and atypia contained HPV DNA. The hybridization signal often localized to crevices in the epithelium where there was relative hyperkeratosis and a thickened granular layer. HPV DNA was not noted in the basal cells and was rarely identified in other parts of the lesion. It is concluded that penile tissues may contain HPV DNA when lacking the diagnostic features of a condyloma/low-grade intraepithelial lesions and that such tissues usually demonstrate specific histological changes characterized by a focally thickened granular layer often associated with epithelial crevices.     

Koilocytotic, virus-induced pre-neoplasia in women: a multifocal disease effectively treated with CO2-laser surgery

A superficial koilocytotic lesion progressing to dysplasia and later into an aggressive invasive cervical cancer has been demonstrated. It is thought that these lesions create an area of susceptibility to neoplasia in the cervix, vagina, and in the vulva, and are defined as preneoplastic lesions. A total of 57 young women have been examined cytologically and colposcopically at least 3, 6, and 12 months following CO2-laser surgery. In 12 women (21%) the lesions were multifocal with the same histological pattern in the cervix and in the vagina and/or in the vulva. CO2-laser effectively eradicates the koilocytotic lesions in the cervix and in the vagina; in the vulva, however, relapses are common after an initial good effect. The diagnostic accuracy of cervicovaginal cytology was low: exfoliated koilocytotic cells were found in only 26.3% out of 57 cases with histologically proven koilocytotic lesion, even when the cytological smears were reexamined.     

Detection of human papillomavirus DNA and expression of p16, Rb, and p53 proteins in small cell carcinomas of the uterine cervix

Human papillomavirus (HPV) has been implicated as an etiologic agent for the development of primary small cell carcinoma of the uterine cervix, a rare but highly aggressive malignancy. It has been shown that the HPV E6 and E7 oncoproteins are able to inactivate the tumor suppressor functions of p53 and Rb. In squamous cell carcinoma and adenocarcinoma of the cervix, HPV infection is also associated with overexpression of p16, a cyclin-dependent kinase inhibitor. In this study, 22 cases of primary small cell carcinoma of the uterine cervix were subjected to broad-spectrum HPV DNA amplification and typing, and immunohistochemically examined for the expression of p16, Rb, and p53 proteins. The results show that HPV DNA was detected in every case (100%), with 18 cases (82%) harboring type 18. The tumor cells exhibited strong nuclear staining for p16 in 20 cases (91%). This was associated with a complete loss of Rb nuclear staining in tumor cells in 16 cases (73%). The p53 protein was essentially undetectable in all cases. In contrast, HPV DNA was not detected in 9 colorectal and 8 urinary bladder small cell carcinomas included in this study for comparison. While similar p16 and Rb expression patterns were observed in these HPV-negative tumors, a different expression pattern for p53 was noted where strong nuclear staining was seen in 8 cases (47%; P = 0.0004 compared with cervical tumors). These observations indicate that different mechanisms are involved in the pathogenesis of small cell carcinomas of the uterine cervix and support the notion that nuclear p16 overexpression serves as an indication of Rb defunctioning in tumor cells, which may or may not result from high-risk HPV infection.     

Cytometric profile of the DNA content in pathologies of the uterine cervix]

Through flow cytometry, we have analysed DNA content of cervical cells recovered by scrapping the uterine cervix in 1) 103 women without human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN), 2) 42 patients with HPV infection without CIN, and 45 patients with CIN. We have observed four different DNA patterns: 1) normal DNA pattern, 2) increased and heterogeneous DNA pattern (IH), 3) increased S G2 + M phases, and 4) DNA aneuploid pattern. Statistical calculation has emphasized the significant correlation linking flow cytometric DNA pattern with cytologic diagnosis. HPV infection without CIN was associated with IH DNA pattern and CIN with increased S G2 + M phases or DNA aneuploid pattern. These results point out the interest of flow cytometric analysis of DNA content in uterine cervix pathology and in more extend in infectious or preneoplastic pathology.     

Endocervical adenocarcinomas with ovarian metastases: analysis of 29 cases with emphasis on minimally invasive cervical tumors and the ability of the metastases to simulate primary ovarian neoplasms

Most endocervical adenocarcinomas ( approximately 90%) are high-risk human papillomavirus (HPV)-related neoplasms, with the remainder being unrelated to HPV; both types infrequently metastasize to the ovaries. Clinicopathologic features of 29 cases of synchronous and metachronous endocervical and ovarian tumors (26 HPV-related, 3 unrelated to HPV) were analyzed. In 18 cases, the cervical tumors were clearly invasive; these included 5 clinically evident tumors diagnosed before the ovarian metastases (immediately preoperatively to 7 y), 11 clinically unsuspected tumors diagnosed concurrently in specimens obtained for evaluation of ovarian/pelvic masses, 1 case with concurrent clinically evident cervical and ovarian masses, and 1 clinically occult tumor diagnosed subsequent to the ovarian metastasis. In 11 cases, the cervical tumors were more limited; these included 5 tumors comprised predominantly of adenocarcinoma in situ with small foci of superficial invasion ("microinvasive carcinomas") diagnosed before the ovarian metastases (3 mo to 7 y) and 6 tumors comprised of extensive adenocarcinoma in situ lacking unequivocally recognizable stromal invasion diagnosed before (9 mo to 7 y, n=4), concurrently with (n=1), or subsequent to (n=1) the ovarian metastases. Fifteen cervical tumors involved lower uterine segment corpus endometrium or endomyometrium, including 4 tumors that were minimally invasive or not recognizably invasive in the cervix. The ovarian tumors ranged in size from 2.1 to 30.0 cm (mean/median=12.7/13.5); they were unilateral in 19 cases (65.5%) and 12 of these were unilateral and 10 cm or greater. In 26 cases, including the 19 unilateral tumors, the ovarian tumors exhibited "borderlinelike," confluent glandular, cribriform, and/or villoglandular patterns simulating primary ovarian atypical proliferative (borderline) tumors or well-differentiated carcinomas; these patterns were pure in 24 and admixed with minor infiltrative foci in 2. The ovarian tumors had features typical of metastases (bilateral and infiltrative) in only 3 cases. In all HPV-related cases the paired endocervical and ovarian tumors contained identical HPV types, establishing the ovarian tumors as metastases. Endocervical adenocarcinomas, including microinvasive forms and some not recognizably invasive, have the potential to metastasize to the ovaries; extension into the lower uterine segment/corpus endometrium may be a risk factor, with retrograde uterine/transtubal spread as a possible mechanism.     

Small-cell neuroendocrine carcinoma of the cervix. A human papillomavirus type 18-associated cancer.

Small-cell undifferentiated carcinomas comprise a rare but aggressive subset of uterine cervical neoplasms. Analogous to small-cell anaplastic carcinoma of the lung, these tumors frequently exhibit neuroendocrine differentiation. Although human papillomaviruses (HPV) types 16 and 18 are strongly associated with the development of cervical squamous carcinoma, there is as yet little information describing the relationship of these viruses to small-cell carcinomas. To address this question, we analyzed 20 cases of small-cell carcinoma of the cervix using in situ hybridization to detect HPV gene expression. In addition, immunohistochemistry was used to evaluate three markers of neuroendocrine differentiation. Eighteen of 20 tumors (90%) demonstrated some evidence of neuroendocrine differentiation; 17 of 20 (85%) expressed HPV type 16 or 18 messenger RNA. Of the neuroendocrine-positive cases, 14 of 18 expressed HPV 18 messenger RNA. In contrast, both of the cases with squamous differentiation were HPV 16 positive. These findings broaden the spectrum of HPV-associated cervical neoplasia and strongly suggest that HPV 18 is a viral type specifically associated with cervical small-cell neuroendocrine carcinomas.     

Diffuse laminar endocervical glandular hyperplasia. A benign lesion often confused with adenoma malignum (minimal deviation adenocarcinoma).

We report seven examples of a hitherto undescribed pseudoneoplastic glandular lesion of the uterine cervix that we have designated "diffuse laminar endocervical glandular hyperplasia." The patients ranged in age from 22 to 48 (mean 37) years. Only one of them had a history of hormone intake. All the lesions were incidental findings in hysterectomy specimens performed for dysfunctional uterine bleeding (five cases) or symptomatic leiomyomas (two cases). Microscopic examination revealed a proliferation of moderate-sized, evenly spaced, differentiated endocervical glands within the inner one-third of the cervical wall, sharply demarcated from the underlying cervical stroma. Reactive atypia was seen in some cases but significant cytologic atypia was absent. A marked inflammatory response was present in five of the seven cases. The main consideration in differential diagnosis was adenoma malignum (minimal deviation adenocarcinoma). Major features that helped in this distinction were a lack of irregular stromal infiltration and a desmoplastic stromal response, and an absence of focal malignant cytologic features. Follow-up for an average of 6.5 years in five of the seven cases was uneventful.     

Highly differentiated keratinizing squamous cell cancer of the cervix: a rare, locally aggressive tumor not associated with human papillomavirus or squamous intraepithelial lesions.

The purpose of this study is to report an unusual variant of cervical squamous cell carcinoma, not associated with either human papillomavirus infection or antecedent squamous intraepithelial lesions. Five women had a diagnosis of invasive cervical cancer discovered at hysterectomy performed for prolapse (two cases), leiomyoma (one case), or a vaginal fistula (two cases). The women ranged in age from 47 to 78 years (mean 59 years). Four of the five had a history of normal Papanicolaou (Pap) smears; the other had a Pap smear diagnosis of atypical squamous cells of undetermined significance (ASCUS). All had large cervical tumors (two with parametrial involvement and one with vaginal involvement) that showed extensive keratin formation, an inverted pattern of growth, and, except for one case, minimal cytologic atypia. There was extensive hyperkeratosis and parakeratosis adjacent to each tumor; none had evidence of squamous intraepithelial lesion. Human papillomavirus testing by polymerase chain reaction in situ hybridization and reverse-transcribed polymerase chain reaction in situ was negative in each case, compared with a detection rate of 107 of 108 (99%) for squamous intraepithelial lesion-associated cervical squamous cell and adenocarcinomas. Two of the women died of extensive local recurrence; two other women were recently diagnosed. We conclude that highly differentiated keratinizing squamous cell carcinoma of the cervix is a rare entity not associated with human papillomavirus infection or squamous intraepithelial lesion and thus difficult to detect on routine cervical cancer screening.     

Human papillomavirus infection related to oesophageal carcinoma in black South Africans. A preliminary study

Oesophageal specimens derived from 70 patients with established invasive squamous cell carcinoma of the oesophagus were histologically reviewed with special reference to the morphological manifestations of human papillomavirus (HPV) infection. Epithelial changes fulfilling the criteria for HPV infection were noted in 23 cases (33%). The presence of HPV antigens was demonstrated by immunohistochemical staining in 7 of these 23 cases. Although acceptable for routine diagnostic purposes, histological typing and immunoperoxidase staining methods are not entirely conclusive of HPV infection. Electron microscopy for detection of viral particles and a molecular hybridization technique have to be used for absolute confirmation and viral subtyping. The results of this pilot study will be used for prospective studies to determine the role of HPV infection in the aetiology of oesophageal carcinoma.     

Value of acetic acid screening for flat genital condylomata in men

Application of acetic acid solution to the genital skin followed by magnified examination permits the detection of grossly inapparent flat condylomata acuminata. To evaluate the accuracy of this screening method, the male sexual partners of 36 women with genital condylomata were examined by this method and biopsies were obtained when results were positive. Of 47 biopsies of acetowhite (the whitish change that occurs when an epithelial surface is stained with acetic acid) lesions there were 26 cases of histologically confirmed condylomata, 9 of koilocytotic atypia and 12 with false positive results. There were 25 men whose sexual partners had cervical condylomata and cervical dysplasia. In this subgroup, considered to be at higher risk for flat condylomata, the screening method revealed 15 cases of condylomata, 6 of koilocytotic atypia and 4 in which no changes by acetic acid could be found. The extensive involvement of genital skin with flat condylomata in this subgroup raises doubts as to the practicality of treatment. Nevertheless, before treatment is rendered a punch biopsy for confirmation of the screening test is advised.     

Lobular endocervical glandular hyperplasia, not otherwise specified: a clinicopathologic analysis of thirteen cases of a distinctive pseudoneoplastic lesion and comparison with fourteen cases of adenoma malignum.

We report 13 cases of a previously undescribed pseudoneoplastic lesion of the uterine cervix, which we have designated "lobular endocervical glandular hyperplasia, not otherwise specified." The patients' ages ranged from 37 to 71 years (mean, 45 years; median, 49 years). Three (27%) patients had a history of hormone use. Seven lesions were incidental findings in hysterectomy specimens. In the six other cases, the patient came to clinical attention because of a mucoid cervical discharge (two cases), increased vaginal discharge (two cases), abdominal discomfort (one case), or a 3.5-cm cervical mass found when being examined because of ovarian carcinoma (one case); hysterectomy was performed in each of these six cases. Microscopic examination showed a distinctly lobular proliferation of small to moderately sized rounded glands often centered around a larger central gland. The lobular proliferation was well to poorly demarcated and usually confined to the inner half of the cervical wall. Glands within the lobules were usually separated from each other by unaltered or hypercellular cervical stroma and were lined by columnar mucinous cells similar to the normal endocervix. Occasional reactive atypia of the endocervical cells and mitoses were seen, but no significant cytologic atypia was identified. Neither of the two cases stained showed cytoplasmic immunoreactivity for carcinoembryonic antigen. Follow-up of seven patients showed no evidence of recurrence of the cervical lesion, with an average length of follow-up of 3.4 years; three patients were lost to follow-up and three cases are recent. The principal consideration in the differential diagnosis was adenoma malignum (minimal deviation adenocarcinoma). The features most helpful in this distinction, in addition to the orderly lobular arrangement of the glands, were a lack of the following: irregular stromal infiltration, a desmoplastic stromal response, and focal malignant cytologic features. Lobular endocervical gland hyperplasia should be added to the list of previously described pseudoneoplastic glandular lesions of the cervix and, like them, not misinterpreted as neoplastic.     

Carcinosarcoma of the uterine cervix: a report of eight cases with immunohistochemical analysis and evaluation of human papillomavirus status

Carcinosarcomas (malignant Müllerian mixed tumors [MMMTs]) of the uterine cervix are rare neoplasms. This report describes the morphology, immunohistochemical profiles, and human papillomavirus (HPV) status of eight cervical MMMTs. Patients' ages ranged from 32 to 93 years (mean, 61 years). Seven cases showed in situ squamous cell carcinoma (SCC). The invasive epithelial component (EC) was composed of combined adenoid basal carcinoma, basaloid SCC, and adenoid cystic carcinoma (ACC) in two cases. Keratinizing SCC, large cell nonkeratinizing SCC, undifferentiated carcinoma, and basaloid SCC predominated in the remaining tumors, one of which had admixed ACC. The sarcomatous component (SC) was homologous and spindled with admixed myxoid areas in three lesions. The ECs and SCs in six MMMTs showed dual immunostaining with epithelial membrane antigen and the pan-keratin marker, MNF116. The SC was vimentin-positive in seven cases. Five tumors had a vimentin-positive EC. The SC was positive for muscle specific actin and/or smooth muscle actin in seven lesions, of which four were desmin-positive. Polymerase chain reaction (PCR) using GP5+/GP6+ L1 consensus primers detected HPV DNA in all eight cases. Nonisotopic in situ hybridization with digoxigenin-labeled probes to HPV types 6, 11, 16, 18, 31 and 33 demonstrated integrated HPV 16 in three cases, not only in the EC, but also in nuclei of the SC. This is the first study to implicate HPV in the evolution of cervical MMMTs. The above observations lend support to a metaplastic theory of histogenesis.     

Human papillomavirus (HPV) in condylomatous lesions of cervix

Ninety-seven cervical condylomata classified histologically as flat condyloma (planum), papillary condyloma (acuminatum), and endophytic condyloma were studied by transmission electron microscopy (TEM) and by immunoperoxidase technique (IPT) for the presence of human papillomavirus (HPV) particles and antigen, respectively. Both techniques localized HPV chiefly in nuclei of koilocytotic cells. HPV particles were found in 25% of the cases by TEM and HPV antigen was detected in 48% of the cases by IPT. All cases positive by TEM were also positive by IPT, thus confirming the specificity of the immunological staining. The viral antigen was detected in 56% of 68 flat condylomata, 35% of 26 papillary condylomata, and in none of 3 cases of endophytic condylomata. However, when histiotypes of virus-positive condylomata were controlled for the intraepithelial extent of koilcytotic cells, the prevalence of HPV correlated with the extent of koilocytosis rather than with the histiotype. The immunologic technique will be of value for the further characterization of cervical condylomata and of the relationship between HPV infection and cervical intraepithelial neoplasia.     

Low prevalence of human papillomavirus infection of the cervix in renal transplant recipients

BACKGROUND.: An increased risk of anogenital tract malignancies has beennoted among renal transplant recipients. A high prevalence ofhuman papillomavirus (HPV) infection of the cervix in the femalerenal-transplant population has been assumed based on increasingevidence suggesting that HPV infection is the major risk factorfor cervical intraepithelial neoplasia (CIN) and cervical cancer.It has been assumed that immunosuppression leads to either areactivation of latent HPV or a reduction in the host's abilityto contain a primary HPV infection, thereby increasing the riskof CIN and cervical cancer. The objective of this study wasto evaluate the prevalence of human papillomavirus (HPV) infectionin a population of iatrogenically immunosuppressed renal transplantrecipients. METHODS.: Twenty-one women were recruited from the renal transplant clinicat Presbyterian Hospital and underwent a gynaecological examinationwhich included colposcopy, a Papanicolaou smear, and a cervicovaginallavage. Lavage samples were analysed for HPV DNA using L1 consensusprimers and the polymerase chain reaction (PCR). RESULTS.: No cases of cervical intraepithelial neoplasia (CIN) were detectedin this cohort of 21 immunosuppressed renal transplant recipients.HPV DNA was detected in only a single patient. CONCLUSIONS.: Our data suggests that HPV infection is not highly prevalentamong older, cytologically normal renal transplant recipients,particularly those who are currently monogamous or not presentlysexually active. This study suggests that recent sexual behavioursare more important than past behaviours as a determinant ofHPV status in transplant recipients, and also suggests thateducation concerning the avoidance of high-risk sexual behaviouris an important part of the care of the female renal transplantrecipient. Our data is consistent with previous work suggestingthat the incidence of CIN is declining in transplant recipients,and it also suggests that the prevalence of HPV infection maybe declining as well.     

Human papillomavirus-associated early vulvar neoplasia investigated by in situ hybridization

Of 21 consecutive cases of early vulvar neoplasia studied at the Istituto Nazionale Tumori of Milan, 62% appeared to be related to papillomavirus infection. This conclusion is the result of the present study by in situ hybridization with DNA probes of human papillomavirus (HPV) 6/11, 16, and 18 and of previous ultrastructural and immunohistochemical investigations. The proportion of cases associated with HPV was 78.5% for those (11/14) with histologic evidence of viral infection and 33% for those without (2/6). HPV 16 was detected in all cases that were positive by in situ hybridization except for one, which showed HPV 6/11 DNA. In one case there was a mixed triple infection for HPV 6/11, 16, and 18. The patient who was positive for HPV 6/11 had a giant condyloma associated with an inguinal lymph node containing a metastatic well-differentiated squamous cell carcinoma. Three cases were positive for papillomavirus internal capsid species-nonspecific antigen (PV-Ag) (with ultrastructural evidence of virions in one of them) and were negative for HPV-DNA hybridization. They appeared to be infected with a type of HPV not identified by the available probes. Three cases, and two sites of two other cases with double infection, were HPV-DNA-positive and PV-Ag-negative. They illustrate the limitation of immunohistochemical investigation in cases with high-grade intraepithelial neoplasia. Six cases of verrucous carcinoma of the vulva were negative for HPV DNA by in situ hybridization.     

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-β

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-β staining in 3 cases. As PAX8, CA125, HMGA2, and hepatocyte nuclear factor 1-β 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.