Breast carcinoma with chondroid differentiation: a clinicopathologic study of 21 triple negative (ER-, PR-, Her2/neu-) cases.

A total of 21 metaplastic breast carcinomas (MCs) with chondroid differentiation were evaluated to better establish the clinicopathological features of this variant. The tumors exhibited mainly invasive carcinoma admixed with areas of cartilaginous matrix production. An associated ductal intraepithelial neoplasia component grade 2 or 3 was observed in 43% of cases. Immunohistochemical analysis revealed a triple negative (ER-, PR-, and Her2/neu-) immunoprofile and no expression of the androgen receptor. EGFR-positivity was found in 88% of evaluated cases, consistent with the proposed basaloid phenotype for all MC. Compared with previous studies that reviewed MC with osseus and cartilaginous elements, the incidence of axillary lymph node metastasis was significantly higher in our study and 60% of positive nodes exhibited chondroid differentiation. Available follow-up data (n = 10) revealed aggressive behavior of this MC variant with frequent metastasis, including visceral involvement and local chest wall recurrence despite chemotherapy and radiation. Three patients subsequently died of metastatic disease.

Histologic alterations in endometrial hyperplasia and well-differentiated carcinoma treated with progestins.

The treatment of complex atypical hyperplasia (CAH) and well-differentiated endometrioid carcinoma (WDC) by progestin therapy has been shown to be a safe alternative to hysterectomy. Accurate assessment for regressive changes induced by the progestins is critical to successful treatment. However, there are few studies detailing the histopathologic changes associated with progestin therapy. A total of 44 patients with CAH or WDC, treated with oral progestins or a progesterone or levonorgestrel-releasing intrauterine device, were followed by endometrial biopsy and/or curettage at 3 to 6 month intervals for a maximum of 25 months. The pretreatment and posttreatment endometrial samples were evaluated for response to treatment and for the histologic features of gland-to-stroma ratio, architectural abnormalities [back-to-back glands and confluency (cribriform and/or papillary patterns)], glandular cellularity, mitotic activity, cytologic atypia, and cytoplasmic changes. Histologic changes seen in progestin-treated endometria included a decreased gland-to-stroma ratio, decreased glandular cellularity, decreased to absent mitotic activity, loss of cytologic atypia, and a variety of cytoplasmic changes including mucinous, secretory, squamous, and eosinophilic metaplasia. Architectural changes tended to resolve later in the course of treatment. Some architectural abnormalities, specifically cribriform and papillary patterns, were induced by progestins mimicking progression. Twelve (67%) of 18 women with CAH had complete resolution, 2 (11%) regressed to complex hyperplasia without atypia, and 4 (22%) demonstrated persistent disease over a median follow-up period of 11 months. Eleven (42%) of 26 women with WDC had complete resolution and 15 (58%) had persistent disease over a median follow-up period of 12 months. Three instances of disease progression occurred, presumably only after discontinuing progestin treatment. Only persistent architectural abnormalities and/or cytologic atypia in the 7 to 9-month biopsies were predictive of treatment failure, with a trend for cytologic atypia to be the most powerful predictor. These findings indicate that progestin therapy should be continued for no less than 6 months to accurately assess treatment response. A modified classification for progestin-treated lesions of the endometrium is proposed.

p16 expression in primary ovarian mucinous and endometrioid tumors and metastatic adenocarcinomas in the ovary: utility for identification of metastatic HPV-related endocervical adenocarcinomas.

Distinction of primary ovarian epithelial tumors from metastatic adenocarcinomas is challenging for tumors exhibiting mucinous, endometrioid, or mixed endometrioid/mucinous differentiation. Metastatic carcinomas with these types of differentiation can be derived from several sites, including the gastrointestinal tract and the uterus. Most endocervical adenocarcinomas exhibit mucinous and/or endometrioid differentiation; they infrequently metastasize to the ovaries but may simulate primary ovarian tumors [both atypical proliferative (borderline) and carcinoma]. Most are high-risk human papillomavirus (HPV)-related and demonstrate diffuse p16 over-expression due to complex molecular mechanisms by which high-risk HPV transforming proteins interact with cell cycle regulatory proteins. The performance of this expression pattern for identifying metastatic endocervical adenocarcinomas in the ovaries among primary ovarian tumors and other metastatic adenocarcinomas having mucinous and/or endometrioid/endometrioidlike differentiation has not been evaluated. Immunohistochemical expression of p16 was assessed in 195 tumors, including 98 primary ovarian tumors (51 mucinous, 47 endometrioid, and 4 mixed mucinous-endometrioid tumors), 93 metastatic adenocarcinomas of known primary sites (colorectum: 34, endocervix: 19, pancreaticobiliary tract: 17, appendix: 7, stomach: 5), 11 metastatic adenocarcinomas of unknown origin (7 established as noncervical), and 4 adenocarcinomas of uncertain (primary ovarian vs. metastatic) origin. The HPV status of the endocervical adenocarcinomas was determined by in situ hybridization and polymerase chain reaction (when in situ hybridization was negative). Expression was assessed based on the percentage of moderately to strongly positive cells, estimated to the nearest 10%. Mean and median expression values for HPV-positive endocervical adenocarcinomas (99%, 100%; range 90% to 100%) were substantially higher than those for primary ovarian mucinous (5%, 0%; range 0% to 70%) and endometrioid (20%, 10%; range 0% to 100%) tumors, HPV-unrelated endocervical adenocarcinomas (0%, 0%; range 0% to 60%), metastatic adenocarcinomas of unknown origin (11%, 0%; range 0% to 30%), and adenocarcinomas of uncertain (primary ovarian vs. metastatic) origin (40%, 35%; range 0% to 90%); only the 15 HPV-positive endocervical adenocarcinomas and 6 other tumors had values of 80% or greater. Diffuse (>75% positive tumor cells) moderate to strong p16 expression is a sensitive (100%) and specific (97%) marker for identifying HPV-related endocervical adenocarcinomas metastatic to the ovary among the primary ovarian tumors and metastatic adenocarcinomas from other sites that are in the differential diagnosis of ovarian tumors having mucinous and/or endometrioid/endometrioidlike differentiation. p16 is useful as part of a panel of immunohistochemical markers for distinguishing primary ovarian tumors from metastases and, when diffusely positive, can suggest the cervix as a potential primary site for metastatic adenocarcinomas of unknown origin.

Immunohistochemical expression of CDX2 in primary ovarian mucinous tumors and metastatic mucinous carcinomas involving the ovary: comparison with CK20 and correlation with coordinate expression of CK7.

Recent studies have demonstrated conflicting results regarding the value of CDX2 for distinguishing primary ovarian mucinous tumors from metastatic mucinous carcinomas in the ovary. Utility of coordinate expression of cytokeratins 7 and 20 is restricted to distinction of ovarian mucinous tumors from lower gastrointestinal tract metastases and data comparing coordinate expression of all three markers is limited. Immunohistochemical studies were performed to compare expression of CDX2 and cytokeratin 20, both markers of intestinal differentiation, in conjunction with coordinate expression of cytokeratin 7, in 90 mucinous tumors involving the ovary: 42 primary ovarian mucinous tumors (31 atypical proliferative (borderline) mucinous tumors (gastrointestinal type), 11 mucinous carcinomas) and 48 metastatic mucinous carcinomas of upper (pancreaticobiliary tract: 14; stomach: five) and lower (colon and rectum: 25; appendix: four) gastrointestinal tract origin. Primary ovarian tumors expressed CDX2 (40%) less frequently than cytokeratin 20 (83%) (P<0.0001). CDX2 expression in primary ovarian tumors (40%) was lower than CDX2 expression in metastatic carcinomas of both upper (74%; P=0.016) and lower gastrointestinal tract origin (90%; P<0.0001). Cytokeratin 20 expression was similar in primary ovarian tumors (83%) and metastases of upper (89%; P=0.071) and lower gastrointestinal tract origin (93%; P=0.29). Thus, as a single marker CDX2 offers some advantage over cytokeratin 20 because it is less frequently positive in primary ovarian tumors. In the almost universally cytokeratin 7-positive primary ovarian tumors and metastases of upper gastrointestinal tract origin, CDX2 coordinate expression was less common in primary ovarian tumors (36%) than in metastases of upper gastrointestinal tract origin (63%) (P=0.022) whereas cytokeratin 20 coordinate expression was identical in both tumor types (79%). In the almost universally cytokeratin 7-negative metastases of lower gastrointestinal tract origin, coordinate expression of CDX2 (83%) and cytokeratin 20 (86%) were equivalent (P=1.00). CDX2 was comparable to cytokeratin 20 in distinguishing metastases of lower gastrointestinal tract origin (usually cytokeratin 7-negative and CDX2/cytokeratin 20 positive) from primary ovarian tumors and metastases of upper gastrointestinal tract origin (usually cytokeratin 7-positive and CDX2/cytokeratin 20 variable). CDX2 provided some advantage over cytokeratin 20 for distinguishing primary ovarian mucinous tumors from metastases of upper but not lower gastrointestinal tract origin; however, the advantage in the former was limited due to the occurrence of shared coordinate expression profiles in both tumor types. Cytokeratin 7 provides the predominant discriminatory value among these markers yet is limited to distinction of primary ovarian tumors from metastases of lower gastrointestinal tract origin.

Cytokeratins 7 and 20 in primary and secondary mucinous tumors of the ovary: analysis of coordinate immunohistochemical expression profiles and staining distribution in 179 cases.

Coordinate expression profiles for cytokeratins 7 and 20 (CK7 and CK20) are useful for distinguishing certain types of adenocarcinomas but use for distinction of primary and secondary mucinous tumors in the ovary is limited due to the existence of a number of tumor types exhibiting overlapping CK7/CK20 immunoprofiles; the use of staining distribution patterns in the distinction of tumors with shared profiles has not been evaluated in detail. We report analysis of both coordinate expression profiles and staining distribution in 179 rigorously classified mucinous tumors in the ovary, including 53 primary tumors [35 atypical proliferative (borderline) mucinous tumors of gastrointestinal type and 18 invasive mucinous carcinomas] and 126 secondary tumors [28 colorectal adenocarcinomas, 54 appendiceal tumors (23 adenocarcinomas, 31 low-grade adenomatous mucinous tumors associated with pseudomyxoma peritonei), 14 pancreatic adenocarcinomas, 8 endocervical adenocarcinomas, 5 gastric adenocarcinomas, 4 gallbladder/biliary tract adenocarcinomas, and 13 adenocarcinomas of unknown primary sites). A CK7+/CK20+ immunoprofile was the most common profile in primary ovarian tumors (74%), upper gastrointestinal tract tumors (78%), and endocervical tumors (88%) but was occasionally observed in lower intestinal tract tumors (colorectal: 11%; appendiceal: 13% of low-grade tumors, 35% of carcinomas). A CK7-/CK20+ immunoprofile was the most common profile in lower intestinal tract tumors (79%) and was uncommon in upper gastrointestinal tract tumors (9%), rarely seen in primary ovarian tumors (4%), and not seen in endocervical tumors. A CK7+/CK20- profile was observed in some primary ovarian (23%), upper gastrointestinal tract (13%), and endocervical tumors (13%) but not in lower intestinal tract tumors. For CK7+ tumors, staining distribution was very frequently diffuse (>50% of tumors cells positive) in primary ovarian, upper gastrointestinal tract, and endocervical tumors, whereas staining distribution was often focal (<50% of tumors cells positive) when present in colorectal and appendiceal carcinomas but not in low-grade appendiceal tumors. For CK20+ tumors, staining distribution was variable but often focal in primary ovarian tumors and nonlower intestinal tract tumors, whereas the pattern was almost always diffuse in lower intestinal tract tumors. Immunohistochemical staining distribution can supplement CK7/CK20 coordinate expression profiles to distinguish subsets of primary ovarian and metastatic lower intestinal tract mucinous tumors having overlapping immunoprofiles but neither coordinate expression profiles nor staining distribution distinguishes primary ovarian tumors from the nonlower intestinal tract metastases.

Ovarian atypical proliferative (borderline) mucinous tumors: gastrointestinal and seromucinous (endocervical-like) types are immunophenotypically distinctive.

Ovarian atypical proliferative (borderline) mucinous tumors of gastrointestinal and seromucinous types are considered subtypes within the mucinous tumor category despite the presence of distinctive clinicopathologic features that seromucinous tumors share with pure serous tumors. Immunophenotypic differences have not been extensively investigated. Immunohistochemical studies were performed to compare the expression patterns of cytokeratins 7 and 20 (CK7, CK 20), estrogen and progesterone receptors (ER, PR), CA-125, mesothelin, and WT-1 in 28 tumors of gastrointestinal type and 12 tumors of seromucinous type. Both gastrointestinal and seromucinous type tumors had a high frequency of CK7 expression (93% and 100%, respectively). The gastrointestinal type tumors were characterized by frequent expression of CK20 (86%) and CDX2 (39%), infrequent expression of CA-125 (11%) and mesothelin (7%), and lack of expression of ER, PR, and WT-1. In contrast, the seromucinous type tumors were characterized by frequent expression of ER (100%), PR (67%), CA-125 (92%), and mesothelin (83%), infrequent expression of WT-1 (8%), and lack of expression of CK20 and CDX2. The gastrointestinal and seromucinous types of atypical proliferative mucinous tumors are immunophenotypically distinctive tumors. The former are characterized by expression of markers of gastrointestinal-type differentiation (CK20 and CDX2), whereas the latter are characterized by expression of "müllerian-type" markers (ER, PR, CA-125, and mesothelin). Expression of the latter markers in the seromucinous tumors, which also are expressed in pure serous tumors, and lack of expression of gastrointestinal-type markers, combined with the clinicopathologic features these tumors share with pure serous tumors, support the concept that this subtype is more closely related to serous than gastrointestinal type mucinous tumors and justify the designation "seromucinous."

Immunohistochemistry for estrogen and progesterone receptors in the distinction of primary and metastatic mucinous tumors in the ovary: an analysis of 124 cases.

Estrogen (ER) and progesterone receptor (PR) expression in primary ovarian mucinous tumors and the utility of these markers for distinguishing metastatic mucinous carcinomas in the ovary from primary ovarian mucinous tumors have not been extensively investigated. Immunohistochemical studies were performed on 124 mucinous tumors, including 52 primary ovarian tumors (30 atypical proliferative (borderline) mucinous tumors of gastrointestinal type, 11 atypical proliferative (borderline) mucinous tumors of seromucinous (endocervical-like) type, and 11 invasive mucinous carcinomas of usual (gastrointestinal) type) and 72 metastatic mucinous carcinomas in the ovary (primary sites: colorectum (24), pancreas (13), endocervix (eight), stomach (four), gallbladder/bile duct (four), appendix (four), and unknown (15)). All atypical proliferative mucinous tumors of gastrointestinal type, primary ovarian mucinous carcinomas, and metastatic mucinous carcinomas were negative for ER and PR with the exception of three metastatic endocervical adenocarcinomas which exhibited only weak expression of ER without PR. All atypical proliferative mucinous tumors of seromucinous type expressed ER to some degree and seven had some expression of PR. Immunohistochemical assessment of hormone receptor expression is of no value in distinguishing the common types of primary ovarian mucinous tumors (atypical proliferative mucinous tumors of gastrointestinal type and mucinous carcinomas of usual type) from the vast majority of mucinous carcinomas metastatic to the ovary. The above observations on hormone receptor expression in primary ovarian mucinous tumors support the concept that atypical proliferative (borderline) mucinous tumors of gastrointestinal and seromucinous (endocervical-like) types are distinctive tumors.

The relationship of glands to thick-wall blood vessels as a marker of invasion in endocervical adenocarcinoma.

The recognition of early invasion in endocervical adenocarcinomas can be difficult. We evaluated the proximity of endocervical glands and their pattern of infiltration in relation to thick-wall blood vessels as potential markers of invasion in a series of invasive endocervical adenocarcinomas removed by cone biopsy or hysterectomy. Routinely stained slides were examined from 50 invasive endocervical adenocarcinomas (37 of usual type and 13 of minimal deviation type), 26 noninvasive lesions (14 cases of adenocarcinoma in situ, 7 cases of hyperplasia, 4 cases of tunnel clusters, 1 adenomyoma), and 20 normal cervices, including 7 with deep nabothian cysts. The range of vessel wall thickness using an ocular micrometer was recorded in each specimen. A blood vessel with a wall > or =36-microm thick was defined as thick-walled. Both the blood vessel wall thickness and distance to the closest gland was recorded for each case. The median distance from a thick-wall blood vessel to a gland in the invasive tumors was 30 microm compared with 168 microm in the noninvasive group. In both groups, the measured blood vessel wall had a median thickness of 42 microm. The pattern of infiltration of glands around the thick-wall vessels was classified as "circumferential," in which multiple glands circumferentially enveloped the vessel, or "molded," in which single or multiple distorted glands were molded around the vessel. The circumferential and molded patterns were identified in 35 (70%) and 10 (20%) of 50 invasive adenocarcinomas, respectively. Of the 26 lesions in the noninvasive group, only 3 (6%) had a circumferential pattern and none had a molded pattern. Importantly, none of the cases in the noninvasive group showed either pattern in the presence of glandular atypia. In conclusion, close proximity of glands to thick-wall blood vessels (distance from the closest gland to a thick-wall vessel less than or equal to the thickness of the vessel wall) seems to be a useful feature in the diagnosis of invasive endocervical adenocarcinoma. This feature, in combination with certain glandular growth patterns and cytologic atypia, can be highly suggestive, if not diagnostic, of invasive carcinoma.

Tubulolobular carcinoma of the breast: an analysis of 27 cases of a tumor with a hybrid morphology and immunoprofile.

Tubulolobular carcinoma (TLC) is a rare subtype of mammary carcinoma that has eluded precise classification, exhibiting features of both ductal and lobular differentiation. The clinicopathologic features of 27 cases of TLC were analyzed by both hematoxylin and eosin and immunohistochemical stains for E-cadherin and 34betaE12 (high molecular weight cytokeratin). Five cases of both pure tubular and classic lobular carcinoma were included as controls. Patients with TLC ranged in age from 43 to 79 years (median, 60 years). Tumor characteristics were as follows: size, 0.5 cm to 2.5 cm (median, 1.4 cm); bilaterality, 1 of 27 (4%); and multifocality, 5 of 27 (19%). Twenty-two of the 27 cases (81%) contained an in situ component: 8 (36%) lobular (LIN); 4 (18%) ductal (DIN); and 10 (46%) mixed. All 27 cases were intensely positive (3+) for E-cadherin, a feature of ductal differentiation, while 25 of 27 (93%) cases showed variable positivity for 34betaE12 (1 to 3+), a feature far more common in tumors with lobular differentiation. Clinical follow-up was available on 25 of 27 (93%) patients. Three of 24 (13%) patients developed axillary lymph node metastases and 1 of 25 (4%) patients developed a local recurrence over a follow-up period of 2 to 91 months (median, 39 months). In conclusion, TLCs are a distinct subtype of mammary carcinoma with overlapping morphologic features that are mirrored by a hybrid immunohistochemical profile. The uniform 3+ expression of E-cadherin in TLC supports the ductal differentiation of these tumors, despite a dominant lobular growth pattern. The prognosis of these tumors appears to be excellent, especially in those cases that are unilateral and less than 2 cm in size.

Immunohistochemical staining for Ki-67 and p53 helps distinguish endometrial Arias-Stella reaction from high-grade carcinoma, including clear cell carcinoma.

The distinction of the Arias-Stella reaction from clear cell carcinoma of the endometrium is usually straightforward; however, this differential diagnosis can be difficult when the Arias-Stella reaction occurs outside the setting of pregnancy or in older patients. The differential diagnosis also is problematic when serous or clear cell carcinoma focally arises within an endometrial polyp, as part of "endometrial intra-epithelial carcinoma" (EIC), or in younger patients. The goal of this study was to determine whether immunohistochemical staining can distinguish the Arias-Stella reaction from endometrial high-grade carcinoma, particularly clear cell carcinoma. Cases of endometrial Arias-Stella reaction (n = 27), clear cell carcinoma (n = 11), serous carcinoma (n = 7), and EIC (n = 4) were assessed by immunohistochemical staining with antibodies for Ki-67, p53, estrogen receptor (ER), and progesterone receptor (PR). Composite immunohistochemical scores based on the percentage and intensity of stained cells were calculated, as was the overall positivity (percentage positive cases), using a cutoff value of >/=5% stained cells and at least weak intensity. Appropriate statistical tests were performed. Ki-67 and p53 immunostaining was significantly less in Arias-Stella reaction than in clear cell carcinoma (p < 0.0001 for both) or serous carcinoma/EIC (p < 0.0001 for both), measured by the composite immunohistochemical scores or overall positivity. ER showed a significant difference only between Arias-Stella reaction and clear cell carcinoma; PR showed a significant difference only between Arias-Stella reaction and serous carcinoma/EIC. When clinical or histologic features cannot facilitate the differential diagnosis, immunohistochemical staining for Ki-67 and p53 may help distinguish endometrial Arias-Stella reaction from clear cell carcinoma and other types of high-grade carcinoma.