Fattaneh A. Tavassoli

The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting{

NIH sponsored a meeting of medical and veterinary pathologists with mammary gland expertise in Annapolis in March 1999. Rapid development of mouse mammary models has accentuated the need for definitions of the mammary lesions in genetically engineered mice (GEM) and to assess their usefulness as models of human breast disease. The panel of nine pathologists independently reviewed material representing over 90% of the published systems. The GEM tumors were found to have: (1) phenotypes similar to those of non-GEM; (2) signature phenotypes specific to the transgene; and (3) some morphological similarities to the human disease. The current mouse mammary and human breast tumor classifications describe the majority of GEM lesions but unique morphologic lesions are found in many GEM. Since little information is available on the natural history of GEM lesions, a simple morphologic nomenclature is proposed that allows direct comparisons between models. Future progress requires rigorous application of guidelines covering pathologic examination of the mammary gland and the whole animal. Since the phenotype of the lesions is an essential component of their molecular pathology, funding agencies should adopt policies ensuring careful morphological evaluation of any funded research involving animal models. A pathologist should be part of each research team.

Interobserver Reproducibility in the Diagnosis of Ductal Proliferative Breast Lesions Using Standardized Criteria

Although the categorization of proliferative breast lesions provides valuable information regarding subsequent risk of breast cancer, the ability of pathologists to classify such lesions in a reproducible fashion has not been adequately evaluated. To assess further interobserver reproducibility in the categorization of proliferative breast lesions, six pathologists each reviewed 24 proliferative ductal lesions and classified them as either usual hyperplasia (H), atypical hyperplasia (AH), or carcinoma in situ (CIS). Before evaluation of the study slides, all the participants were instructed to use the diagnostic criteria of Page and co-workers and were provided with both a written summary of these criteria and a set of teaching slides with representative examples of each type of lesion. Complete agreement among all six pathologists was seen in 14 cases (58%); five or more agreed in 17 cases (71%); and four or more arrived at the same diagnosis in 22 cases (92%). No pathologist consistently rendered more “benign” or “malignant” diagnoses than any other. After assigning numerical values for each diagnostic category (H = 1, AH = 2, CIS = 3), the scores for the group of 24 cases did not differ significantly by pathologist (p = 0.68; average score range, 1.7–2.0). Our results indicate that with the use of standardized criteria, interobserver concordance in the diagnosis of proliferative ductal breast lesions can be obtained in the majority of cases.

A comparison of the results of long‐term follow‐up for atypical intraductal hyperplasia and intraductal hyperplasia of the breast

Follow‐up information was obtained on 199 women with breast biopsy specimens containing intraductal epithelial proliferation. The proliferations were divided into regular or ordinary intraductal hyperplasia (IDH) (117 cases) and atypical intraductal hyperplasia (AIDH) (82 cases). The average length of followup was 14 years for the patients with IDH and 12.4 years for the patients with AIDH. Of the 117 patients with ordinary IDH, carcinoma subsequently developed in six (5%); three of these were invasive carcinomas (2.6%). All three invasive carcinomas were in the ipsilateral breast, but of the three intraductal carcinomas (IDCa), two were in the contralateral breast. Of the 82 patients with AIDH, invasive carcinoma subsequently developed in eight (9.8%); six of these were located in the ipsilateral breast and two in the contralateral breast. One of these six patients died of disseminated carcinoma. The average interval to the subsequent carcinoma (intraductal and invasive carcinoma) was about the same in the two groups (8.3 years for AIDH and 8.8 years for IDH lacking atypia). When considering only subsequent invasive carcinomas, the interval was 8.3 years for the AIDH and 14.3 years for the IDH lacking atypia. Of the 14 patients with IDH and a family history of breast carcinoma, invasive carcinoma subsequently developed in one (7%) as compared with two (2%) of the 91 with a negative family history. Among patients with AIDH, invasive carcinoma subsequently developed in two of the 13 (15%) of those with a family history of breast carcinoma as compared with one of 57 (1.8%) of the women with a negative family history. The presence of atypia in epithelial hyperplasia is a significant factor in increasing the likelihood of the development of subsequent invasive carcinoma (P = 0.03; two‐tailed test). Of women with AIDH, invasive carcinoma subsequently developed in 17% of those with sclerosing adenosis (SA) as compared with 4.2% of those without it. Therefore, SA may be a contributing factor to increased risk. A positive family history also appears to increase the likelihood of the subsequent development of invasive carcinoma, particularly in patients with AIDH.

Myoepithelial lesions of the breast. Myoepitheliosis, adenomyoepithelioma, and myoepithelial carcinoma.

The clinical and pathologic features of 31 breast lesions composed of a prominent proliferation of myoepithelial cells either admixed with epithelial cells or in pure form were studied. The lesions were divided into three categories: myoepitheliosis, adenomyoepithelioma, and malignant myoepithelioma (myoepithelial carcinoma); the latter is the only lesion composed purely of myoepihelial cells. Three multifocal, microscopic lesions located in the peripheral duct system were designated as myoepitheliosis. Twenty-seven solitary, grossly palpable, predominantly centrally located lesions qualified as adenomyoepithelioma. These were further subdivided into spindlecell, tubular, and lobulated variants. Two lesions in the latter group had a carcinoma arising within them. Only one case, which was characterized by a solitary mass composed of an infiltrative spindle cell proliferation, qualified as malignant myoepithelioma (myoepithelial carcinoma). Two patients with adenomyoepithelioma developed recurrences; one tumor was of the tubular type, the other of the lobulated type. Both of these tumors had irregular margins. One of these patients had two recurrences and is currently well 8.5 years after the initial excision. The second patient developed a recurrence 8 months after initial excision; the recurrence presented as multiple nodules. One of the patients with myoepithelial carcinoma arising in an adenomyoepithelioma also developed a recurrence within 2.3 years. Her initial tumor was located in the axillary tail of the breast, and she had axillary node metastasis at the time of presentation. All remaining patients with follow-up are well without evidence of recurrence up to 17.3 years after the initial diagnosis (average follow-up. 6.1 years); one patient died of unrelated causes.

Multicystic mesothelioma. An analysis of pathologic findings and biologic behavior in 37 cases.

We report the clinicopathologic findings of 37 cases of multicystic mesothelioma. The tumor, which occurs most frequently in young to middle-aged women, affects chiefly the pelvic peritoneum—particularly the cul de sac, uterus, and rectum. It grows along the serosa as multiple, translucent, fluid-filled cysts. Occasionally, it manifests as a solitary or free-floating mass. The tumor is made up of mesothelial-lined cysts embedded in a delicate fibrovascular stroma. The mesothelial cells may be flattened or cuboidal. Adenomatoid change or squamous metaplasia of the mesothelium occurs in one-third of cases. In a significant percentage of cases, the stroma shows marked inflammatory changes that make it difficult to recognize the underlying neoplastic nature. Follow-up information in 25 patients showed that 21 patients were alive, two had died of tumor, and two died of other causes. One of the two patients who died of their tumors was an infant whose tumor showed transition to conventional mesothelioma; the other was a man who had refused therapy. The extent of tumor at the time of diagnosis did not predict survival. The low incidence of previous surgery, the lack of prior abdominal infections, and the documentation of disease-related mortality all support a neoplastic, rather than a reactive, basis for this lesion.

Secretory carcinoma of the breast.

Nineteen examples of a very rare type of carcinoma of the breast have been studied. The carcinoma is unusual in that it has exaggerated secretory features previously reported only (with one exception) in juveniles. But not all the patients in our series were juveniles; they ranged in age from 9 to 69 years (median age, 25 years). Six were 30 years of age or older. Eighteen patients were female and 1 was a 9‐year‐old boy. Treatment varied from local excision of the tumor to radical mastectomy. Four of the 11 patients who had axillary node dissection had metastatic deposits showing the same secretory features as the primary neoplasm. One of these 4 patients, a 25‐year‐old woman, died within ten months with disseminated tumor. Because this distinctive pattern of carcinoma is not limited to children and adolescents, we propose that it be called “secretory carcinoma.” Since, of the 19 patients, 4 (21%) had axillary node metastases and 1 (5%) died with disseminated tumor, an extended simple mastectomy is recommended as the inital treatment for patients more than 20 years of age.

CD10 expression in epithelial tissues and tumors of the gynecologic tract: a useful marker in the diagnosis of mesonephric, trophoblastic, and clear cell tumors.

We tested 417 cases of formalin-fixed, paraffin-embedded normal or hyperplastic gynecologic tissues as well as neoplasms involving the gynecologic tract with a monoclonal antibody against CD10 (clone 56C6), with special emphasis on epithelial and epithelial-like structures and tumors. CD10 was always expressed in mesonephric remnants (mesonephric remnants of the uterine cervix, epoophoron, rete ovarii) and tumors (mesonephric adenocarcinoma of the uterine cervix, tumors of wolffian origin of the broad ligament and ovary). CD10 was also positive in the syncytiotrophoblast, cytotrophoblast, and intermediate trophoblast of normal gestations, partial and complete moles, choriocarcinoma, and placental site trophoblastic tumors. Finally, CD10 was positive in several metastatic neoplasms to the gynecologic tract (100% in metastatic renal clear cell and intestinal carcinomas and melanomas). In contrast, CD10 was almost invariably negative in müllerian epithelia of the female genital tract and in their corresponding tumors, with the exception of focal expression found in squamous epithelia and tumors with squamous differentiation. Thus, the expression of CD10 may be useful in the establishing the diagnosis of mesonephric and trophoblastic tumors and in the differential diagnosis between gynecologic clear cell carcinoma (always negative) and metastatic clear cell carcinoma of renal origin.

Use of monoclonal antibody against human inhibin as a marker for sex cord-stromal tumors of the ovary.

Inhibin is a glycoprotein hormone produced by normal ovarian granulosa cells and testicular sertoli cells. In the ovary, it inhibits the secretion of follicle-stimulating hormone. Patients with granulosa cell tumors (GCT) have elevated serum levels of inhibin and this finding has been used to detect recurrent tumor. This study attempts to determine whether inhibin antibody (IAB) can preferentially mark GCT and Sertoli-cell or Sertoli-Leydig cell tumors (SCT) in paraffin-embedded tissues and facilitate distinction of GCT from small cell carcinoma of hypercalcemic type (SCC), SCT from Sertoliform endometrioid carcinoma (SEC), and primitive gonadal-stromal tumors from a variety of poorly differentiated neoplasms. Applying microwave-enhanced immunohistochemistry, a total of 126 paraffin-embedded and microwave-enhanced archival ovarian tumors and tissues were studied by using monoclonal IAB. The tumors included 32 adult GCT, 7 juvenile GCT, 4 metastatic GCT, 8 SCT, 7 SCC, 6 primitive gonadal stromal tumors (PGST), 5 fibrothecomas, 6 lipid cell tumors (LCT), 5 extrauterine endometrial stromal sarcomas (ESS), 5 hemangiopericytomas (HPC), 1 metastatic malignant melanoma, 1 metastatic malignant lymphoma, and 27 epithelial tumors including 8 SEC, 5 mucinous tumors, and 4 Brenner tumors. Seven pregnancy luteomas (nodular theca lutein hyperplasia of pregnancy), 3 corpora lutea and 2 ovarian follicles were also studied. The intensity of immunostaining was scored from one to three and the percentage of the immunoreactive tumor cells was determined and expressed in 10% increments. Among 32 adult GCT, 31 (97%) tumors reacted positively with IAB. The percent of positive cells ranged from 30% to 100% (average 80%). Similarly, all four metastatic GCT, 7 juvenile GCT and 4 of 5 fibrothecomas were immunoreactive with monoclonal IAB. Seven of 8 (88%) SCT, 5 of 6 (83%) PGST, all 6 LCT, 7 pregnancy luteomas, 3 corpora lutea and the 2 ovarian follicles were also positive with IAB. The most intense positivity was observed in luteinized stromal cells regardless of tumor type. No immunoreactivity was observed in any of the 7 SCC, 5 ESS, 5 HPC, 1 metastatic malignant melanoma, 1 metastatic malignant lymphoma and the epithelial component of all 27 epithelial tumors including 8 SEC. Among the mucinous tumors of the ovary, however, 3 tumors with luteinized stromal cells showed immunoreactivity in these cells, but no positivity was seen in the mucinous epithelium. We conclude that IAB is an excellent marker for sex cord differentiation in ovarian tumors. It can be used effectively in the diagnosis of GCT and its distinction from epithelial neoplasms particularly SCC. The IAB may also be helpful in differentiating LCT from epithelial malignancies. However, it cannot be used to distinguish GCT from SCT.

Association of mucinous tumors of the ovary and appendix. A clinicopathologic study of 25 cases.

Twenty-five patients with mucinous tumors of the ovary and appendix were studied. The average age of the patients was 52 years, and the ovarian and appendiceal tumors were discovered synchronously in all but two cases. The majority had either a pelvic mass or abdominal or pelvic pain. A high frequency of bilateral ovarian tumors (11/25), and right-sided predominance for the unilateral ovarian tumors (nine right, five left) were found. Four patients had ovarian mucinous carcinomas, 10 had mucinous tumors of low malignant potential, 10 had mucinous cystadenomas, and one had a mucinous cyst. Pseudomyxoma ovarii was present in 22 cases. Twenty-two of 24 appendices were grossly abnormal. There were six appendiceal mucinous adenocarcinomas, 10 mucinous tumors of uncertain malignant potential, seven mucinous cystadenomas, one hyperplastic polyp, and one mucocele. Twelve patients had ovarian and appendiceal tumors of similar malignant potential, nine had appendiceal tumors with more aggressive morphologic features than the corresponding ovarian tumor, and four had ovarian tumors with more aggressive morphologic features than the appendiceal tumor. Eighteen patients had peritoneal involvement by mucinous epithelium admixed with mucus (nine localized, nine diffuse). Immunoperoxidase reactions for four epithelial antigens in 15 cases showed complete concordance between ovarian and appendiceal lesions in only five cases and were not helpful in determining the site of origin of the peritoneal tumor. Our findings suggest an independent origin of the ovarian and appendiceal tumors in most cases and do not favor an origin in a single site. Furthermore, it is proposed that the peritoneal lesions may arise de novo as part of a multifocal neoplastic process.

Minimal uterine serous carcinoma: a clinicopathological study of 40 cases

The term ‘minimal uterine serous carcinoma’ has been proposed to include serous carcinomas with invasion limited to the endometrium (superficial serous carcinoma), and those without stromal invasion (intraepithelial serous carcinoma or endometrial intraepithelial carcinoma). Both lesions display similar cytological and immunohistochemical profiles of a typical invasive serous carcinoma with a high nuclear grade and an overexpression of mutant p53 protein. We studied the clinicopathologic features of 40 cases of minimal uterine serous carcinoma. All patients were postmenopausal and underwent hysterectomy and surgical staging procedures. There were nine cases of intraepithelial serous carcinoma and 31 cases of superficial serous carcinoma. Five intraepithelial serous carcinomas and 16 superficial serous carcinomas exclusively involved an endometrial polyp. A total of 18 minimal uterine serous carcinomas also involved, in addition to a polyp, the endometrium proper in the form of intraepithelial serous carcinoma (13 cases) and superficial serous carcinoma (five cases). Overall, minimal uterine serous carcinomas were found to involve an endometrial polyp in 88% of the cases (35/40) and were confined to the polyp in 53% (21/40). Extrauterine tumors were present in 45% of the cases (18/40). In all, 22 patients with tumor limited to their uteri demonstrated an overall survival of 94% (2–73 months of follow-up). Eight of 18 patients with extrauterine tumors died of their malignancy (1.5–62 months of follow-up). In conclusion, a significant majority of minimal uterine serous carcinomas involve an endometrial polyp. Complete surgical staging is important to predict the prognosis. When the lesion is confined to an endometrial polyp and/or the endometrium proper, the clinical outcome is excellent.