No metastatic cervical adenocarcinomas in a series of p16INK4a-positive mucinous or endometrioid advanced ovarian carcinomas: an analysis of the AGO Ovarian Cancer Study Group.

Epithelial ovarian cancers may represent secondary manifestations of occult extraovarian carcinomas. Such tumors may be misdiagnosed as primary ovarian carcinomas clinically and pathologically. In a recent study, several cases of cervical cancer metastases with primary manifestation as mucinous or endometrioid ovarian carcinomas were described. In all cases, human papillomavirus (HPV) DNA and diffuse p16 immunostaining were detected in the ovarian tumor tissues. To estimate the frequency of occult metastatic endocervical adenocarcinomas in a series of mucinous or endometrioid ovarian carcinomas, 24 ovarian cancers with mucinous and 50 with endometrioid differentiation from the Arbeitsgemeinschaft Gynaekologische Onkologie OVAR-3 database were analyzed for HPV and p16 positivity. The p16 immunostaining was performed using the p16 histology kit (Dako, Glostrup, Denmark), and both nuclear and cytoplasmic staining results were considered positive. Human papillomavirus polymerase chain reaction analysis was performed using 2 consensus primer systems (GP5/GP6 and PGMY09/11) and HPV-16- and HPV-18-specific primers from the L1 and the E6 regions. Six (8%) of 74 tumors were p16-negative, 13 (18%) of 74 showed single positive cells, 28 (38%) of 74 showed focal homogeneous staining, and 27 (36%) of 74 showed complete diffuse staining. In several independent amplifications of different regions of the HPV genome, none of the 73 tumors available for analysis showed the presence of HPV DNA. No ovarian metastases of endocervical adenocarcinomas were found among mucinous and endometrioid adenocarcinomas from a large chemotherapy trial of advanced stage ovarian carcinomas. The p16 staining detected in many primary ovarian adenocarcinomas in the present series seems independent from HPV oncogene activity.     

Intestinal-type cervical adenocarcinoma in situ and adenocarcinoma exhibit a partial enteric immunophenotype with consistent expression of CDX2.

Most cases of cervical adenocarcinoma in situ (AIS) and adenocarcinoma are of the usual or endocervical type. However, intestinal types of AIS and adenocarcinoma exist. With an intestinal-type adenocarcinoma in the cervix, the question may arise as to whether one is dealing with a primary cervical neoplasm or direct or secondary spread from an intestinal adenocarcinoma. In organs such as the ovary, urinary bladder, esophagus, and gallbladder, intestinal-type glandular epithelium often expresses enteric markers, but this has hardly been studied in the cervix. The purpose of this study was to investigate whether intestinal-type AIS and adenocarcinoma in the cervix express enteric markers and to ascertain whether these antibodies are of value in the distinction from a metastatic intestinal adenocarcinoma. We compared the immunophenotype of these lesions with that of usual-type AIS and adenocarcinomain the cervix. Cases included were AIS of usual type (n = 6), primary cervical adenocarcinoma of usual type (n = 6), AIS of intestinal type (n = 21), primary cervical adenocarcinoma of intestinal type (n = 3), primary cervical adenocarcinoma with signet ring cells (n = 2), and colorectal adenocarcinoma involving the cervix (n = 5). All cases were stained with cytokeratin (CK) 7, CK20, monoclonal carcinoembryonic antigen (CEA), p16, and CDX2. Staining was categorized as negative, focally positive (<50% cells), or diffusely positive (50% or more cells). Usual-type AIS was always diffusely CK7 positive, typically diffusely CEA and p16 positive, and always CK20 negative. CDX2 was positive in 1 case. All usual cervical adenocarcinomas were diffusely CK7 and p16 positive, and all were immunoreactive with CEA. Five and 2 cases were CK20 and CDX2 positive, respectively. Intestinal-type AIS was diffusely CK7 positive (all cases) and typically CK20 negative and diffusely CEA and p16 positive. All but 1 case exhibited diffuse nuclear positivity with CDX2. In addition, usual-type AIS adjacent to intestinal type was CDX2 positive in 13 of 21 cases. The 3 cases of primary cervical intestinal-type adenocarcinoma were diffusely CK7 positive, focally or diffusely positive with CK20 and CDX2, and focally positive with CEA. One case was diffusely p16 positive, 1 focal and 1 negative. The foci of signet ring cells in the 2 primary cervical adenocarcinomas were diffusely CK7 and p16 positive and negative with CK20 and CDX2. Colorectal adenocarcinomas involving the cervix were typically diffusely positive with CK20, CEA, and CDX2; negative with CK7; and negative or focally positive with p16. Intestinal types of cervical AIS and adenocarcinoma exhibit a partial enteric immunophenotype, usually with diffuse expression of CDX2 and, in some cases, staining with CK20. They maintain their CK7 immunoreactivity and are usually p16 positive. Although there is immunophenotypic overlap, focal staining with CK20 together with diffuse CK7 and sometimes p16 positivity helps to distinguish intestinal types of cervical adenocarcinoma from involvement by a colorectal adenocarcinoma; CEA and CDX2 are of no value in this regard. CDX2 positivity in usual-type AIS adjacent to intestinal type and in occasional cases of pure usual-type AIS may be a reflection of early intestinal differentiation before this is morphologically apparent. Using a set of cases of AIS diagnosed in a single institution over a 7-year period (77 usual type; 13 intestinal type), intestinal type was more likely to be associated with early invasive adenocarcinoma than usual type (31% vs 17%), suggesting that intestinal differentiation may be a risk factor for invasion in premalignant cervical glandular lesions.     

Carcinoembryonic antigen in primary and metastatic ovarian tumors

The immunoperoxidase method and an absorbed monospecific commercial rabbit anti-CEA antiserum were used to detect CEA in 105 primary ovarian tumors and 12 metastatic ovarian adenocarcinomas of intestinal origin. Primary ovarian tumors showed CEA in foci of squamous differentiation in 9 out of 10 cases of endometrioid carcinomas and focally in areas of intestinal differentiation in 21 out of 28 mucinous tumors as well as 4 out of 5 Brenner tumors. All of the serous tumors, clear cell carcinomas, and undifferentiated carcinomas as well as 19 of the 22 mucinous tumors without intestinal differentiation lacked CEA. All metastatic ovarian adenocarcinomas showed characteristic diffuse staining of CEA. Differences in CEA staining were found to be useful for histological differentiation between primary ovarian cancers and metastatic ovarian adenocarcinomas of intestinal origin. Furthermore, these data might be helpful in the selection of patients for serial CEA evaluation.     

A panel of immunohistochemical stains, including carcinoembryonic antigen, vimentin, and estrogen receptor, aids the distinction between primary endometrial and endocervical adenocarcinomas.

The histological distinction between a primary endometrial and a primary endocervical adenocarcinoma is often difficult, especially in small biopsy specimens. A preoperative distinction is important because primary surgical management differs between the two tumors. Cases of primary endometrioid endometrial (n=30) and primary endocervical (n=26) adenocarcinoma of endocervical type were stained immunohistochemically with the monoclonal antibodies against carcinoembryonic antigen (CEA), vimentin, estrogen receptor (ER), and 34 beta E12. In all cases the origin of the adenocarcinoma was confirmed by examination of the definitive pathology specimen. There was diffuse positive nuclear staining for ER in 28 of 30 (93%) endometrial adenocarcinomas. ER was negative in 16 of 26 endocervical adenocarcinomas, and there was focal weak nuclear staining in the other cases. Vimentin was positive in 29 of 30 (97%) endometrial adenocarcinomas but in only 2 of 26 (8%) endocervical adenocarcinomas. CEA was positive in 25 of 26 (96%) endocervical adenocarcinomas, mostly with diffuse membranous and cytoplasmic staining. Positivity with CEA was present in 21 of 30 (70%) endometrial adenocarcinomas but was largely confined to squamoid areas with only 12 tumors exhibiting focal membranous staining of the glandular component. 34 beta E12 was diffusely positive in all except one cervical adenocarcinoma. In endometrial carcinomas, positivity was strongest in squamoid areas but there was positive staining, either focally or diffusely, of the glandular component in 27 cases. In summary, primary endometrioid endometrial adenocarcinomas are characterized by diffuse, strong, positive staining for vimentin and ER and negative or very focal, positive staining of the glandular component for CEA. In contrast, primary endocervical adenocarcinomas are characterized by CEA positivity, which is usually but not always diffuse, negativity for vimentin, and negativity or focal weak positivity for ER. 34 beta E12 is of no value in the distinction between endometrial and endocervical adenocarcinomas. A panel of immunohistochemical stains, comprising CEA, vimentin, and ER, generally allows confident preoperative distinction between a primary endometrial and endocervical adenocarcinoma.     

Immunohistochemical demonstration of carcinoembryonic antigen and ultrastructural features of endometrial adenocarcinoma

Determination of carcinoembryonic antigen levels in plasma (45 cases) and the immunohistochemical demonstration of tumor CEA (37 cases) were carried out in patients with endometrial adenocarcinoma. Twenty four out of 37 were also studied with the electron microscope. The plasma CEA level prior to therapy was significantly elevated (greater than 5.0ng/ml) in only one case (1/45:2.2%) of endometrial adenocarcinoma. CEA levels were more consistently elevated (4/17:23.5%) in patients with cervical adenocarcinoma. Immunoperoxidase staining of CEA (PAP method) was carried out using formalin-fixed paraffin embedded sections of 37 tumors. Tissue CEA activities were found in 9 out of 37 endometrial adenocarcinomas (24.3%) and 19 of 23 cervical adenocarcinomas (82.6%). Immunoreactive CEA was present in a high concentration on the cell surface of endometrial glands and less dense in their cytoplasm. In 9 of CEA positive endometrial carcinoma tissues, squamous metaplastic lesions were found in 4 cases and mucinous metaplasia in one case which were all CEA positive. With regard to the histopathological grade, CEA positive specimens were categorized G1 (4) and G2 (5) and all of the G3 were CEA negative. Seven of 9 cases of CEA positive specimens were examined under the electron microscope. There was no definite tendency in their ultrastructural characteristics, but all of the specimens examined revealed abundant cytoplasmic organelles suggestive of intracytoplasmic differentiation analogous to those of endometrial cells in proliferative phase. Moreover, fine structures of squamous and mucinous metaplastic cells were also described in detail.     

Evaluation of squamous epithelium in adenoacanthoma and adenosquamous carcinoma of the endometrium: immunoperoxidase analysis of involucrin and keratin localization

A study was undertaken to determine whether immunoperoxidase stains for keratin and involucrin, the latter a protein present in cells of stratified squamous epithelium that have differentiated beyond the basal stage, distinguish any differences in squamous cells present in the adenoacanthoma from those in the adenosquamous carcinoma of the uterine corpus. Forty-eight tumors were studied, of which 33 were adenoacanthomas and 15 adenosquamous carcinomas. The patients with adenoacanthomas were slightly younger (mean 61.5 vs. 64.5 years) and had tumors that were generally better differentiated than the adenosquamous carcinomas. The squamous epithelium in every tumor, regardless of histologic type, stained positively for keratin. There were no obvious differences in staining when tumors were stratified for histologic type, grade, or location within the tumor. The glandular portion of both tumor types stained irregularly, but nonetheless positively, for keratin in 71% of the cases. Involucrin was detected in 57% of adenoacanthomas and 87% of adenosquamous carcinomas. The deeper or more central portion of the squamous morules stained only if the more superficial or peripheral areas were positive. The extent of the involucrin staining was less in the adenosquamous carcinomas than in the adenoacanthomas. The glandular component of the tumors did not stain for involucrin. It is concluded that no qualitative differences in the staining reactions with respect to keratin and involucrin distinguish the adenoacanthomas from the adenoaquamous carcinoma. These findings support the argument that the adenoacanthoma and adenosquamous carcinoma represent a spectrum of squamous differentiation in a single tumor type.     

Use of hormone replacement therapy and adenocarcinomas and squamous cell carcinomas of the uterine cervix

INTRODUCTION: Exogenous hormones may influence the development of cervical adenocarcinomas. Incidence rates of adenocarcinomas and use of noncontraceptive hormones have increased since the 1970s, but few studies have investigated this potential relationship. METHODS: We conducted a multicenter case-control study of 124 women with adenocarcinomas, 139 women with squamous cell carcinomas matched on age, diagnosis date, clinic, and stage of disease (in situ or invasive) to adenocarcinoma cases, and 307 healthy community controls who were also matched on age, ethnicity, and residence to adenocarcinoma cases. Participants completed in-person interviews regarding exogenous hormone use before diagnosis and other risk factors and volunteered cervical samples for human papillomavirus (HPV) testing via a PCR-based method. Odds ratios (ORs) with 95% confidence intervals (CIs) estimated relative risks. RESULTS: Only 13 adenocarcinoma cases (10.5%), 7 squamous carcinoma cases (5%), and 20 controls (6.5%) had used noncontraceptive hormones for menopausal symptoms, irregular periods, or disease prevention; most use was short-term, former use. Ever-use was associated with adenocarcinomas (OR = 2.1, 95% CI 0.95-4.6) but not squamous carcinomas (OR = 0.85, 95% CI 0.34-2.1). No trends were seen with duration of use or ages at first use, but unopposed estrogens were positively associated with adenocarcinomas (OR = 2.7). Unopposed estrogens remained associated with adenocarcinomas (OR = 2.0) when analyses were restricted to the HPV-positive controls. Menopausal status was not associated with adenocarcinomas or squamous carcinomas and did not modify the other associations. CONCLUSION: Although small numbers warrant tentative conclusions, exogenous estrogens, especially unopposed estrogens, were positively associated with adenocarcinomas. Noncontraceptive hormones were negatively but weakly associated with squamous carcinomas.     

Ovarian mucinous and mixed epithelial carcinomas of mullerian (endocervical-like) type: a clinicopathologic analysis of four cases of an uncommon variant associated with endometriosis.

The epithelial cells of ovarian mucinous carcinomas may sometimes appear similar to those of gastrointestinal or endocervical mucinous carcinomas, but most are composed of cells that do not suggest any particular derivation. We report four cases of mucinous ovarian carcinoma in which the cells were entirely or almost entirely endocervical-like. The patients' ages were 34, 43, 44, and 50 years. Two patients had bilateral tumors confined to the ovaries at initial staging; both also had synchronous endometrial carcinomas of the mucinous type. The two other patients had unilateral tumors, both with invasive metastases in the pelvis and abdomen at initial staging. In one of the latter cases a mullerian (endocervical-like) mucinous borderline tumor (MMBT) of the opposite ovary had been removed 5 years earlier, and in this case and two other cases the ovarian carcinomas had foci resembling MMBT, suggesting that they may be an invasive counterpart to these tumors. The six tumors ranged from 4 to 19 cm; five were grossly cystic with papillary or solid areas, and one was entirely solid. They were composed of closely packed glands, cysts, and cysts containing complex papillae. There was abundant intraglandular and intracystic mucin. The epithelial cells were well differentiated with infrequent mitoses and most were tall with mucinous cytoplasm resembling normal endocervical glandular cells. In three tumors there also were round to polygonal cells with eosinophilic cytoplasm; endometrioid foci were present in three tumors and a squamous focus was present in one. One tumor had a focally infiltrative growth pattern with a desmoplastic stromal reaction; the remaining five tumors had an exclusively confluent (expansile) pattern of invasion. Endometriosis was present in residual ovarian tissue adjacent to four tumors in three patients and had marked epithelial proliferation in three. All patients were treated postoperatively with chemotherapy and were without clinical recurrence with follow-up intervals of 8 months, 1.2 years, 2.9 years, and 3.8 years. By immunohistochemical analysis the neoplastic epithelium was positive for estrogen and progesterone receptor proteins, vimentin, and cytokeratin 7, and negative or only focally positive for carcinoembryonic antigen and cytokeratin 20, a profile that differs from that of the usual mucinous ovarian carcinoma and is supportive of a mullerian derivation. As with MMBTs, there was a strong association with endometriosis, and these tumors likely arise from endometriosis, possibly through an MMBT precursor in some cases. To better understand their clinicopathologic features and pathogenesis, this uncommon variant should be separated from the usual type in future studies of mucinous carcinomas of the ovary.     

Investigation of human papillomavirus by hybrid capture II in cervical carcinomas including 113 adenocarcinomas and related lesions

Hybrid capture is an easy and highly sensitive technique for screening population due to its capacity to detect malignant and premalignant lesions of the cervix. To evaluate its sensitivity, we investigated the frequency of high-risk human papillomavirus (HPV) infection and its correlation with glandular malignant lesions, analyzing a total of 113 cases of adenocarcinomas and related lesions. High-risk HPV was investigated using a hybrid capture II (HC2) assay. Samples were collected in two different ways: either brushed directly from surgical specimens before fixation or collected from the patients. We also investigated the frequency of HPV in squamous malignant lesions, 65 squamous cell carcinomas (SCC) and 66 in situ squamous cell carcinomas (ISSCC), to compare the occurrence of HPV for these lesions. The 113 glandular lesions comprised 62 invasive adenocarcinomas (IAC), 8 in situ adenocarcinomas (ISAC), 26 IAC plus SCC, and 17 adenosquamous cells carcinomas (ASCC). The HPV-positive reactions were as follows: 51 (82.2%) in IAC, 8 (100%) in ISAC, 25 (96.1%) in IAC plus SCC, and 14 (82.3%) in ASCC. HC2-positive results in the squamous malignant lesions were as follows: 58 of 63 (89.0%) for SCC and 94 of 103 (91.2%) for ISSCC. High-risk HPV infection was quite similar for glandular and pure squamous invasive malignant lesions, 82.2% and 89.0%, respectively, indicating that high-risk HPV is also highly prevalent in glandular lesions. Although hybrid capture proved to be an excellent adjunctive technique, we do not believe its results merit replacing the Pap smear as a screening tool.     

How significant is a cervical smear showing glandular dyskaryosis?

OBJECTIVE: To evaluate the incidence, outcome and predictive value of cytology showing glandular dyskaryosis. PARTICIPANTS: Fifty-seven women with a smear diagnosis of glandular dyskaryosis registered between January 1997 and December 2001. SETTING: Colposcopy and cytopathology units in a large district general hospital. RESULTS: Sixty smears in 57 women showing glandular dyskaryosis were identified from a cohort of 135,120 smears, giving an incidence of 0.05%. Hospital records were available for 50 women. Final diagnosis included 13 cases of cervical glandular intraepithelial neoplasia (CGIN), 4 microinvasive cervical adenocarcinomas, 2 undifferentiated tumours, 1 microinvasive squamous carcinoma, 21 cases of CIN and 13 cases of endometrial pathology (8 endometrial cancers). Twelve women had coexistent squamous and glandular disease. Forty-five out of 50 women had significant pathology (positive predictive value 90%). Colposcopy was seen to be of limited value in assessment of smears showing glandular dyskaryosis. Only 1 out of 13 glandular lesions was diagnosed by colposcopy. CONCLUSION: Smears showing glandular dyskaryosis are associated with significant pathology in 90% of cases and malignancy in 32% of cases. Hence, women with a smear showing glandular dyskaryosis should be referred urgently to a colposcopy clinic and flagged up as suspected cancer. Glandular dyskaryosis should be included in the national referral criteria for suspected gynaecological cancer.     

Cervical cancer: effect of glandular cell type on prognosis,treatment, and survival

OBJECTIVE: To investigate survivals from cervical cancer, with special reference to effects of glandular histology and its influence on prognostic characteristics and management decisions. METHODS: Data on cervical cancers, diagnosed in 1984-2000, were obtained from the gynecologic oncology registry of hospitals of the University of Adelaide. Comparisons were made of disease-specific survival, age at diagnosis, diagnostic period, stage, grade, and primary course of treatment. RESULTS: The study included 544 squamous cell carcinomas, 43 adenosquamous carcinomas, five clear cell cancers, 136 other adenocarcinomas, and 19 cancers of "other" histological type. Overall survival was 72.2% at 5 years from diagnosis, decreasing to 67.5% at 15 years. Survival was lower for older ages, higher grades, and higher International Federation of Gynecology and Obstetrics stages, although equivalent for stages IIA and IIB. Unadjusted survivals varied by histological type (P =.001), with lower survivals suggested for adenosquamous and clear cell lesions and "other" histological types than for squamous cell carcinomas and other adenocarcinomas. After adjusting for age, stage, grade, and diagnostic period, adenocarcinomas had a higher case fatality than squamous cell lesions (relative risk 2.08, 95% confidence limit 1.35, 3.21), whereas the elevation in relative risk was lower and not statistically significant for a combined adenosquamous and clear cell category at 1.25 (0.69, 2.24). For stage II, both adenocarcinomas and the adenosquamous and clear cell group had lower survivals than squamous cell cancers. CONCLUSION: Relative to squamous cell carcinomas, adenocarcinomas and potentially adenosquamous cancers are becoming more common. This has implications for screening, treatment, and prognosis.     

Clear cell carcinoma of the uterine cervix: pathology and prognosis in surgically treated stage IB-IIB disease in women not exposed in utero to diethylstilbestrol

OBJECTIVE: The purpose of this research was to compare the clinical behavior, pathology findings, and prognosis of surgically treated FIGO stage IB-IIB clear cell carcinomas of the cervix with those of squamous cell carcinomas and non-clear cell adenocarcinomas. METHODS: Fifteen patients with clear cell adenocarcinomas of the cervix (8 FIGO stage IB, 7 FIGO stage IIB) were reviewed. The control group consisted of 444 squamous cell carcinomas and 59 non-clear cell adenocarcinomas. None of the patients had a history of in utero exposure to diethylstilbestrol. All patients underwent radical abdominal hysterectomy with systematic pelvic lymphadenectomy. All specimens were processed as serial giant frontal sections. The mean follow-up in the clear cell group was 83 (13-182) months. Statistical analysis was done with contingency tables, chi(2) tests, and Fisher's exact test. RESULTS: Twelve of the fifteen clear cell carcinomas (80%) were endophytic and tended toward deep cervical infiltration. Clear cell carcinomas extended to the uterine corpus significantly more often than squamous cell and non-clear cell adenocarcarcinomas (P < 0.001). The rates of parametrial involvement and pelvic lymph node involvement were 40 and 47%, respectively. Four patients (27%), all with positive pelvic nodes, developed recurrences an average of 14 (4-48) months after initial therapy. The extrapelvic sites of relapse were the lung, liver, and bone. Clear cell carcinomas had a worse 5-year survival rate (67%) than squamous cell carcinomas (80%) and non-clear cell adenocarcinomas (77%) but this was not statistically significant (P = 0.6). No significant differences were seen for age, growth pattern, parametrial and vaginal involvement, parametrial and pelvic lymph node metastases, frequency of recurrent disease, and time to first recurrence. CONCLUSION: The clinicopathologic findings and prognosis of surgically treated patients with stage IB-IIB clear cell carcinomas without exposure to diethylstilbestrol in utero are similar to those of patients with squamous cell carcinomas and non-clear cell adenocarcinomas.     

Immunohistochemical localization of keratin and secretory component in carcinoma of the uterine cervix

Carcinoma of the uterine cervix is said to frequently show a combination of squamous epithelial and glandular epithelial characteristics. In the present study, immunohistochemical localization of keratin and secretory component (SC) was studied to clarify these characteristics of cancers of the cervix, and the following results were obtained. Demonstration of the localization of keratin and SC was useful in providing functional markers of the squamous and glandular epithelium of the cervix. In epidermoid carcinomas, the squamous epithelial character of the keratinizing carcinomas was strongest and decreased in the large cell non-keratinizing, followed by the small cell non-keratinizing carcinomas. The glandular character of these lesions decreased in the same order. Subclassification of CIS did not reveal any major changes with either kind of staining. So-called bipotential differentiation was found in 21% of the epidermoid, 53% of the adenocarcinomas and 13% of the CIS. In the clinical stages of epidermoid carcinomas, the stage I and II cases more frequently showed squamous characteristics than did the stage 0 cases.     

Expression of cathepsin D and epidermal growth factor receptor in stage III cervical carcinomas

Cathepsin D and epidermal growth factor receptor (EGFR) antigens are related to tumor invasion, metastasis, progression, and recurrence. To assess the prognostic significance of the expression of these two antigens, biopsy specimens consecutively obtained from 216 patients with stage III cervical carcinomas (191 with squamous cell carcinomas and 25 with adenocarcinomas), who were treated with radiotherapy, were investigated immunohistochemically. The positive rate of cathepsin D expression in squamous cell carcinomas was 74%, significantly higher than the 47% observed in adenocarcinomas ( P  = 0.015). The EGFR positive rate in squamous cell carcinomas was 33%, somewhat higher than the 16% in adenocarcinomas ( P  = 0.088). The chi-square test and Kaplan–Meier method showed no significant relationship between the expression of either cathepsin D or EGFR and the prognosis in these patients. These results indicate that in stage III cervical carcinomas cathepsin D and EGFR expression do not correlate with prognosis.     

Immunohistochemical demonstration of HNK-1-defined antigen in gynecologic tumors with argyrophilia

Gynecologic tumors with argyrophilia were tested immunohistochemically for reactivity with monoclonal antibody HNK-1, which detects normal and neoplastic cells derived from the neuroectodermal and the amine-precursor-uptake and decarboxylation (APUD) systems. The tumors included six small cell carcinomas and four adenocarcinomas of the cervix; 23 adenocarcinomas of the endometrium (13 with type I and 10 with type II argyrophil cells); and 11 mucinous tumors (three benign, three borderline, and five malignant), eight endometrioid carcinomas (four with type I and four with type II argyrophil cells), and two carcinoid tumors (one insular and one strumal) of the ovary. HNK-1 reactive cells were found in almost every category of tumor: in four small cell carcinomas and two adenocarcinomas of the cervix; 11 adenocarcinomas of the endometrium (eight with type I and three with type II argyrophil cells); and four mucinous (two benign and two borderline), two endometrioid (one with type I and one with type II argyrophil cells), and two carcinoid tumors of the ovary. These cells corresponded to at least some of the type I argyrophil cells in endometrial and ovarian endometrioid carcinomas and to similar cells in mucinous and carcinoid tumors of the ovary and small cell carcinoma and adenocarcinoma of the cervix. However, the remaining type I and similar argyrophil cells and almost all type II argyrophil cells were HNK-1 negative, and some of the nonargyrophil tumor cells were HNK-1 positive. Although the significance of such discrepancies in reactivity with HNK-1 antibody remains unknown, the present results suggest that some of the gynecologic tumors with argyrophilia are related to APUDomas.     

Evaluation of PTEN expression in cervical adenocarcinoma by tissue microarray

PTEN, a tumor suppressor gene, appears to negatively control the phosphoinositide 3-kinase signaling pathway for regulation of cell proliferation and cell survival. Somatic PTEN mutations are involved in a variety of tumors, including endometrial carcinomas, where PTEN expression is diminished. We examined expression of PTEN in a series of cervical adenocarcinomas and precursors, using tissue microarray (TMA) technology. TMA blocks were constructed using paraffin-embedded, formalin-fixed tissues from 273 samples derived from 16 normal cervical biopsies, 119 cases of invasive adenocarcinoma, and 20 high-grade cervical glandular intraepithelial neoplasia (CGIN). Fresh 3-mum sections were cut and immunostained with PTEN, and expression was correlated with clinicopathologic variables, including histologic subtypes of adenocarcinoma. In 137 patients, PTEN expression was positive in 121 (88%). The intensity and distribution of PTEN staining in the tumor tissue were more heterogeneous than those observed in the normal tissues. There were no significant differences in distribution or intensity of PTEN expression between adenocarcinoma in situ and subtypes of invasive adenocarcinoma. Our findings show that unlike the case in most endometrial carcinomas, PTEN expression is retained during the process of carcinogenesis in the glandular cervix. There is, however, evidence of altered distribution and intensity of PTEN expression in cervical adenocarcinoma cells.     

Immunohistochemical distribution of tumor-associated antigen CA6 in gynecological neoplasms as detected by monoclonal antibody DS6.

DS6 is a murine monoclonal antibody developed using ovarian papillary serous adenocarcinoma as the immunogen. DS6 immunohistochemically reacts with a tumor-associated antigen, CA6, which has a limited range of expression in normal human tissues and is not expressed by benign mesothelium. We have studied the spectrum of immunohistochemical reactivity of antibody DS6 in 293 formalin-fixed, paraffin-embedded human gynecological neoplasms. The CA6 antigen shows strong expression in serous adenocarcinomas of the ovary (56/58 cases) and endometrium (6/6). CA6 is also expressed by the majority of ovarian endometrioid adenocarcinomas and Brenner tumors and by the majority of endometrioid adenocarcinomas, mucinous adenocarcinomas, and clear cell adenocarcinomas of the endometrium. CA6 is detected in 14% of ovarian clear cell carcinomas and is not detected in ovarian mucinous cystadenomas (0/7), mucinous intestinal-type borderline tumors (0/8), mucinous adenocarcinomas (0/10), or in malignant mesotheliomas (0/8). In neoplasms with papillary or glandular growth patterns, CA6 is detected along luminal cell membranes. CA6 is also seen along peripheral cell membranes and focally in the cytoplasm in some epithelial neoplasms. There is heterogeneity in immunohistochemical staining for DS6 both within an individual neoplasm and between neoplasms. Reactivity is not detected in neoplasms of sex cord-stromal, mesenchymal or germ cell origin.     

Primary and metastatic mucinous adenocarcinomas of the ovary: Evaluation of the diagnostic approach using tumor size and laterality

OBJECTIVE: To evaluate the usefulness of the recently proposed algorithm (Seidman JD, Kurman RJ, Ronnett BM. Primary and metastatic mucinous adenocarcinomas in the ovaries: incidence in routine practice with a new approach to improve intraoperative diagnosis. Am J Surg Pathol 2003; 27: 985-93 [5]) that classifies mucinous adenocarcinomas of the ovary as primary when they were unilateral > or =10 cm and as metastatic when they were unilateral <10 cm or bilateral. METHODS: Malignant ovarian neoplasms, which were resected in Chiang Mai University Hospital between 1992 and 2003, were histologically reviewed. Mucinous adenocarcinomas involving the ovary were identified. The medical records and radiologic materials were reviewed in correlation with the pathologic features to identify the primary site. RESULTS: There were 74 cases of mucinous adenocarcinomas; 16 were primary ovarian; 52, metastatic; and 6 of indeterminate primary site (primary versus metastatic). Primary mucinous adenocarcinomas had a mean size of 16.4 cm and bilateral involvement in 13%. Metastatic mucinous adenocarcinomas had a mean size of 11.7 cm and bilateral involvement in 77%. Excluding the 6 tumors of indeterminate primary site, the proposed algorithm correctly classified primary and metastatic tumors in 84% of 68 cases. Of 21 unilateral mucinous adenocarcinomas > or =10 cm, 62% were primary ovarian. Of 5 unilateral tumors <10 cm, 80% were metastatic. Of 42 bilateral mucinous adenocarcinomas, 95% were metastatic. CONCLUSION: The algorithm provided high accuracy in the overall prediction of primary and metastatic mucinous adenocarcinomas of the ovary, with major strength in the identification of metastatic tumors by bilaterality or size <10 cm. However, the prediction of primary mucinous adenocarcinomas by unilaterality and size > or =10 cm was less reliable than previously reported. Due to the overlapping features between primary and metastatic tumors and the higher frequency of the latter, the possibility of metastases should always be borne in mind in the evaluation of mucinous adenocarcinomas of the ovary.     

Immunohistological study of isoantigens, carcinoembryonic antigen and human chorionic gonadotropin in adenocarcinomas of the uterus

Isoantigens, carcinoembryonic antigen (CEA) and human chorionic gonadotropin (hCG) were simultaneously studied by immunohistology in the cervical and endometrial adenocarcinomas. Isoantigen loss was observed in all adenocarcinoma in situ (AIS) of the uterus. However, they appeared again in some tumor cells in 8 of 23 cervical and 4 of 41 endometrial adenocarcinomas. CEA was positive in 1 of 4 AIS and 22 of 23 adenocarcinomas of the cervix. It was distributed continuously in the apical portion and/or in the whole cytoplasm of tumor cells. On the other hand, CEA was positive only in 16 of 41 endometrial adenocarcinomas. It was strongly positive in the squamous elements, but weakly and sparsely in the apical portion and/or in the cytoplasm of some isolated glandular cells which occasionally showed a tendency to squamous differentiation. The majority of neoplastic glands, however, were negative for CEA. HCG was positive in 1 of 23 cervical and 3 of 41 endometrial adenocarcinomas. Two or 3 antigens were found concomitantly in some tumors, but localized differently from each other. It was concluded from the present study that the simultaneous examination of multiple antigens may be useful for characterization of adenocarcinomas of the uterus.