Takako Kiyokawa

Gastrointestinal immunophenotype in adenocarcinomas of the uterine cervix and related glandular lesions : a possible link between lobular endocervical glandular hyperplasia/pyloric gland metaplasia and 'adenoma malignum'

Gastrointestinal phenotype in cervical adenocarcinomas was examined by immunohistochemistry and correlated with morphologic features. Antibody panels included anti-MUC2, MUC6, CD10, chromogranin A (CGA) and HIK1083. In addition, expression of p16INK4, a cyclin-dependent kinase inhibitor which is expressed in a variety of high-risk HPV-related conditions, was studied. A total of 94 invasive adenocarcinomas including 20 minimal deviation adenocarcinomas (MDAs) and 72 adenocarcinomas in situ (AIS) were examined. MDAs were most frequently positive for HIK1083 and/or MUC6, two representative gastric markers, with a rate of 95%, followed by intestinal-type adenocarcinomas (IAs) with a rate of 85% whereas only 27% of 56 usual endocervical-type adenocarcinomas (UEAs) were positive. MUC2, a goblet cell marker, was positive in 85% and 25% of IAs and MDAs, respectively, while in only 14% of UEAs. CD10 was positive in 15% of IAs, indicating incomplete intestinal differentiation without a brush border in most of the cases. CGA-positive cells were frequently seen in MDAs and IAs with rates of 60% and 62%, respectively. Nuclear and cytoplasmic p16INK4 positivity was identified in 93% of UEAs, whereas 30% of MDAs were positive for p16INK4. Results in AISs were comparable to their invasive counterparts, but morphologically usual-type AISs identified in eight cases of MDA were frequently positive for HIK1083 (75%) and MUC6 (63%), and p16INK4. Of note was the existence of lobular endocervical glandular hyperplasia (LEGH) with atypical features including cytologic abnormalities, and/or papillary projection, which were identified in this study in pure form (n=3) or in association with MDAs (n=6), but not in cases of other types of adenocarcinomas. These observations indicate that gastrointestinal phenotype is frequently expressed in MDAs and IAs, and there seems to be a possible link between MDA, and LEGH and morphologically usual-type AIS with gastric immunophenotype in histogenesis. Frequent absence of p16INK4 expression in MDAs suggests a possibility that high-risk HPV does not play a crucial role in development of MDAs, in contrast to the majority of endocervical adenocarcinomas. p16INK4 immunohistochemistry appears to be a promising diagnostic tool, but pathologists should be aware of frequent negative staining in MDAs, which can be a source of erroneous diagnosis.

Unusual endocervical adenocarcinomas: an immunohistochemical analysis with molecular detection of human papillomavirus.

BackgroundEndocervical adenocarcinomas of the usual type are etiologically related to infection with oncogenic human papillomaviruses (HPVs). These tumors are typically diffusely positive for p16 and carcinoembryonic antigen (CEA) immunostains. The goal of our study was to determine the HPV status and immunohistochemical profiles of unusual histologic subtypes of endocervical adenocarcinoma. MethodsThe study consisted of a total of 26 cases of unusual subtypes including clear cell carcinoma (CCC, n=9), gastric-type adenocarcinoma (GAS, n=11), minimal deviation adenocarcinoma (MDA, n=3), mesonephric adenocarcinoma (MSN, n=1), serous adenocarcinoma (SER, n=1), and malignant mixed Müllerian tumor (n=1). In addition, 5 cases of usual-type endocervical adenocarcinoma (UEA) were included in the study as a control group. The cases were tested for HPV using SPF-10 PCR and LiPA assays, and immunostained for p16, HIK1083, hepatocyte nuclear factor 1-&bgr;, p53, CEA, estrogen receptor (ER), and progesterone receptor (PR). ResultsHPV DNA was not detected in any of the unusual adenocarcinoma subtypes, with the exception of a single case of SER in which HPV16 was detected. p16 positivity did not correlate with HPV status, as 42% of HPV-negative tumors showed patchy/diffuse p16 overexpression; however, p16 positivity was uncommon in GAS/MDA. HIK1083 positivity was limited to GAS and MDA, indicating relative specificity for tumors with gastric mucin expression. Hepatocyte nuclear factor 1-&bgr; was positive in the majority of CCCs and also in other tumor variants and in some UEA as well, indicating a lack of specificity for clear cell differentiation. CEA was consistently negative in CCCs and in a single MSN, but positive in GAS, MDA, SER, and UEA, suggesting that it may serve as a negative marker of clear cell differentiation. p53 was diffusely positive in almost half of the GAS cases, whereas UEA showed mostly negative staining and other variants showed focal staining. PR was negative in all variant cases and in all UEA. ER expression, although mostly negative, showed focal staining in a few variant cases and UEA. ConclusionsUnusual variants of endocervical adenocarcinoma are not related to HPV infection, with only rare exceptions, and p16 overexpression in non-UEA does not correlate with HPV status. Negative staining for PR and ER may serve as a general marker of endocervical neoplasia. GAS/MDA may be differentiated from all other adenocarcinomas with either positive HIK1083 stain or negative/focal p16 stain. Positive CEA stain differentiates GAS/MDA from CCC and negative PR and ER stains differentiate GAS/MDA from benign endocervical glands. CCC may be distinguished from all other adenocarcinomas, except MSN, with a negative CEA stain. Strong and diffuse p53 positivity in SER may be useful in differentiation from UEA. MSN may be identified with negative CEA, ER, and PR stains.

Absence of High-Risk Human Papillomavirus (HPV) Detection in Endocervical Adenocarcinoma with Gastric Morphology and Phenotype

A subset of endocervical-type mucinous adenocarcinomas (ACs) of the uterine cervix exhibit a gastric phenotype and morphology, as reported in cases of minimal deviation AC in which the presence of human papillomavirus (HPV) has been rarely detected. To investigate the HPV-independent pathway of carcinogenesis in cases of gastric-type AC, we investigated the common high-risk HPV (hr-HPV) status in 52 nonsquamous cell carcinomas, using a PCR-based typing method and immunohistochemistry of p16INK4a (a cyclin-dependent kinase inhibitor that is overexpressed in both cancerous and precancerous cervical tissue, making it an ideal biomarker for cervical cancer cases). Using novel morphological criteria, seven of 52 (13.5%) carcinomas were designated as gastric-type ACs, all of which were negative for both hr-HPV DNA and p16INK4a. Nongastric-type ACs were frequently positive for both hr-HPV DNA (90%, 28/31) and p16INK4a (94%, 29/31) with adenosquamous and neuroendocrine carcinomas demonstrating the presence of hr-HPV DNA in 86% (6/7) and 83% (5/6) of cases, respectively. In these two types of carcinoma, 86% (6/7) and 100% (6/6) were positive for p16INK4a, respectively. Our data suggests that gastric-type AC appears to represent an oncogenic hr-HPV-independent neoplasm and therefore is a potential pitfall of HPV DNA testing and vaccination.

Effects of metformin on endometrial cancer cell growth in vivo: A preoperative prospective trial

Metformin, an antidiabetic drug, decreases the incidence of various cancers in diabetic patients. Metformin‐induced inhibition of cancer cell proliferation has been confirmed in vitro but not in humans. Because endometrial cancer is associated with insulin resistance, the authors investigated whether a diabetes‐therapeutic metformin dose inhibits cancer cell growth in patients with endometrial cancer.

Gastric-type Endocervical Adenocarcinoma: An Aggressive Tumor With Unusual Metastatic Patterns and Poor Prognosis.

Gastric-type adenocarcinoma of the uterine cervix (GAS) is a rare variant of mucinous endocervical adenocarcinoma not etiologically associated with human papillomavirus (HPV) infection, with minimal deviation adenocarcinoma (MDA) at the well-differentiated end of the morphologic spectrum. These tumors are reported to have worse prognosis than usual HPV associated endocervical adenocarcinoma (UEA). A retrospective review of GAS was performed from the pathology databases of 3 institutions spanning 20 years. Stage, metastatic patterns, and overall survival were documented. Forty GAS cases were identified, with clinical follow-up data available for 38. The tumors were subclassified as MDA (n=13) and non-MDA GAS (n=27). Two patients were syndromic (1 Li-Fraumeni, 1 Peutz-Jeghers). At presentation, 59% were advanced stage (FIGO II to IV), 50% had lymph node metastases, 35% had ovarian involvement, 20% had abdominal disease, 39% had at least 1 site of metastasis at the time of initial surgery, and 12% of patients experienced distant recurrence. The metastatic sites included lymph nodes, adnexa, omentum, bowel, peritoneum, diaphragm, abdominal wall, bladder, vagina, appendix, and brain. Follow-up ranged from 1.4 to 136.0 months (mean, 33.9 mo); 20/38 (52.6%) had no evidence of disease, 3/38 (7.9%) were alive with disease, and 15/38 (39.5%) died of disease. Disease-specific survival at 5 years was 42% for GAS versus 91% for UEA. There were no survival differences between MDA and non-MDA GAS. GAS represents a distinct, biologically aggressive type of endocervical adenocarcinoma. The majority of patients present at advanced stage and pelvic, abdominal, and distant metastases are not uncommon.

Reappraisal of synchronous and multifocal mucinous lesions of the female genital tract: a close association with gastric metaplasia

Aims:  To describe the gastric phenotype of synchronous mucinous metaplasia and neoplasms of the female genital tract (SMMN–FGT).

Immunohistochemical Comparison of Ovarian and Uterine Endometrioid Carcinoma, Endometrioid Carcinoma With Clear Cell Change, and Clear Cell Carcinoma.

Accurate distinction of clear cell carcinoma (CCC) from endometrioid carcinoma (EC) has important clinical implications, but, not infrequently, EC demonstrates clear cell change (EC-CC), mimicking CCC. We examined whether a panel of immunomarkers can help distinguish between these tumors. Sixty-four CCCs (40 ovarian and 24 uterine), 34 ECs (21 ovarian and 13 uterine), and 34 EC-CCs (6 ovarian and 28 uterine) were stained for HNF1&bgr;, BAF250a, Napsin A, ER, and PR. Intensity and extent of immunoreactivity was assessed. Fifty-seven of 64 (89%) CCCs, 14/34 (41%) EC-CCs, and 16/34 (47%) ECs expressed HNF1&bgr;, and 56/64 (88%) CCCs, 4/34 (12%) EC-CCs, and 1/34 (3%) ECs stained for Napsin A. Most CCCs demonstrated at least moderate and diffuse staining for both markers, whereas only focal and weak expression was identified in most EC-CC/EC. Compared to HNF1&bgr;, Napsin A showed increased specificity (93.0% vs. 55.9%, P<0.0001) and similar sensitivity (87.5% vs. 89.1%) in distinguishing CCC from EC-CC/EC. Thirteen of 64 (20%) CCCs, 6/34 (18%) EC-CCs, and 2/34 (6%) ECs showed loss of BAF250a. ER was expressed by 10/64 (16%) CCCs, 30/34 (88%) EC-CCs, and 33/34 (97%) ECs, whereas PR positivity was identified in 9/64 (14%) CCCs, 26/34 (77%) EC-CCs, and 33/34 (97%) ECs. The majority of EC and EC-CC demonstrated diffuse staining for ER/PR, whereas most CCCs showed very focal positivity. There is a statistically significant difference in HNF1&bgr;, Napsin A, ER, and PR immunoexpression between CCC and EC/EC-CC, with Napsin A being a more specific marker for CCC than HNF1&bgr;. Overall, the immunoprofile of EC-CC is more comparable to that of EC than CCC. The use of a panel of immunostains can help distinguish EC-CC from CCC.

Alpha-fetoprotein (AFP)-producing ovarian tumor in an elderly woman

Apart from typical yolk sac tumors, ovarian tumors with elevated alfa-fetoprotein (AFP) are uncommon and the differential diagnosis needs to consider the hepatoid pattern of a yolk sac tumor, hepatocellular carcinoma metastatic to the ovary, hepatoid carcinoma, and other epithelial ovarian tumors. We report here an AFP-producing ovarian tumor with uncertain pathological diagnosis, which was extremely responsive to chemotherapy. A 59-year-old Japanese woman presented with lower abdominal distension and was found to have a left ovarian mass on pelvic examination and magnetic resonance imaging (MRI) scan. Laboratory tests showed serum AFP, 73 687 ng/ml; carbohydrate antigen 125 (CA125), 1599 U/ml; and carcinoembryonic antigen (CEA), 13.9 ng/ml. Total hysterectomy with bilateral salpingo-oophorectomy, partial omentectomy, and low anterior resection of the rectum was performed, without any residual macroscopic tumor. Microscopically, the tumor was characterized by a hepatoid carcinomatous component composed of solid sheets of large eosinophilic cells with pleomorphic nuclei. The pathological stage was pT2N0M0. Tumor cells were diffusely immunoreactive for AFP and cytokeratin (CAM5.2), but monoclonal CEA and CA19-9 were focally positive in the cytoplasm, while CA125 was negative. The patient was treated postoperatively with three cycles of chemotherapy consisting of bleomycin, etoposide, and cisplatin; with this regimen, serum AFP decreased to 16 ng/ml from 12 600 ng/ml just before the initiation of chemotherapy. The patient received secondary cytoreductive surgery of systemic lymphadenectomy, which revealed no evidence of residual tumor.

Napsin A is frequently expressed in clear cell carcinoma of the ovary and endometrium

Napsin A is a reliable marker for pulmonary adenocarcinoma and is expressed in a subset of ovarian clear cell carcinomas (O-CCCs), endometrial (EM) CCCs, and endometrioid carcinomas (EC). We investigated napsin A levels in O-CCC and EM-CCC and compared these with levels in other nonmucinous ovarian carcinomas and EM-EC, respectively. Napsin A, thyroid transcription factor (TTF)-1, paired box (PAX) 8, and cancer antigen (CA) 125 expression was evaluated in 111 ovarian and uterine carcinoma cases (22 O-CCC, 15 EM-CCC, 13 ovarian EC (O-EC), 39 high-grade serous carcinoma [HGSC], and 22 EM-EC) using immunohistochemistry. Napsin A immunoreactivity was observed in 21 (95.5%) of 22 O-CCC and 10 (66.7%) of 15 EM-CCC cases but was rare in O-EC and EM-EC (7.7% and 4.5%) and undetectable in HGSC cases. Thyroid transcription factor 1 was not expressed in O-CCC but was detected in 1 (6.7%) of 15 EM-CCC, 3 (23.1%) of 13 O-EC, 2 (5.1%) of 39 HGSC, and 1 (4.5%) of 22 EM-EC cases. All 111 cases examined were positive for PAX8, whereas 3 (20.0%) of 15 of EM-CCC and 1 (4.5%) of 22 EM-EC cases were negative for CA125. There were no napsin A/TTF-1 double-positive cases, except for 1 EM-CCC, in which cells had a focal expression pattern. All napsin A- and/or TTF-1-positive cases expressed PAX8 and CA125. In conclusion, napsin A is frequently expressed in O-CCC and EM-CCC, rarely in O-EC and EM-EC, and never in HGSC cases. These findings confirm the importance of using a panel of antibodies that includes napsin A, TTF-1, and PAX8 when evaluating metastatic carcinomas of unknown origin, particularly when gynecologic and pulmonary adenocarcinomas are included in the differential diagnosis.

Preoperative differential diagnosis of minimal deviation adenocarcinoma and lobular endocervical glandular hyperplasia of the uterine cervix: a multicenter study of clinicopathology and magnetic resonance imaging findings.

Objective: To clarify the preoperative differential diagnosis and management of minimal deviation adenocarcinoma (MDA) and lobular endocervical glandular hyperplasia (LEGH), a multicenter study was performed. Methods: A total of 112 patients who underwent conization or a hysterectomy for suspected MDA were collected from 24 hospitals. The pathological diagnosis in each case was determined by a central pathological review board. The diagnostic significance of clinicopathologic findings including results of magnetic resonance imaging (MRI), Papanicolaou (Pap) smears, and testing for gastric mucin was analyzed. Results: The central pathological review identified 37 cases of Nabothian cyst or tunnel cluster, 54 cases of LEGH, 6 cases of MDA, 11 cases of adenocarcinoma, and 4 cases of benign disease. Lobular endocervical glandular hyperplasia was often associated with adenocarcinoma in situ, MDA, and mucinous adenocarcinoma. Three MDA patients had a recurrence, whereas none of LEGH patients had a recurrence irrespective of the type of surgery. On MRI, LEGH appeared as a characteristic multicystic lesion with an inner solid component, whereas MDA showed a predominantly solid pattern. A Pap smear or gastric mucin alone had limited diagnostic power. However, a combination of these findings is useful; that is, a cystic structure with inner solid components on MRI associated with mild glandular atypia and gastric mucin strongly suggested LEGH (24/26, 92%). A solid structure with atypical glandular cells was indicative of MDA or adenocarcinoma (5/5, 100%). Conclusions: The combination of MRI, Pap smears, and gastric mucin will improve the accuracy of the preoperative diagnosis of MDA and LEGH. Patients suspected of having LEGH may need to be treated with less aggressive methods. Abbreviations: MDA - Minimal deviation adenocarcinoma, LEGH - Lobular endocervical glandular hyperplasia, NC - Nabothian cyst, TC - Tunnel cluster, NILM - Negative for intraepithelial lesion, AGCs - Atypical glandular cells, AIS - Adenocarcinoma in situ, CPR - Central pathological review, Pap - Papanicolaou, MRI - Magnetic resonance imaging