Spectrum of Mucin-containing Lesions of the Breast: Multimodality Imaging Review with Pathologic Correlation.

Mucin-containing lesions of the breast encompass a wide range of benign and malignant processes. The spectrum of histologic findings includes incidental mucus-filled benign cysts or ducts, mucocele-like lesions (MLLs), mucin-producing ductal carcinoma in situ, and invasive mucinous carcinoma. MLL is characterized by the presence of mucin-containing cysts that are typically associated with extravasated stromal mucin. MLL is often benign but can be associated with epithelial atypia or malignancy. Mucinous carcinoma represents the malignant end of the spectrum of mucinous lesions of the breast. Evidence-based literature supports a conservative approach for benign MLLs without associated atypia or malignancy, reserving excision for those lesions exhibiting such pathologic features. The most common imaging finding for MLL is microcalcifications at mammography. No specific imaging feature is predictive of malignant outcome at surgical excision. Invasive mucinous carcinoma is a heterogeneous breast tumor subtype, as defined according to the World Health Organization criteria. Mucinous carcinomas are categorized into pure (>90% mucinous component) or mixed (10%-90% mucinous component) subtypes. Pure mucinous carcinomas are generally associated with excellent prognosis and survival, with a few exceptions. Mixed mucinous carcinomas do not have the same favorable prognosis and instead behave similarly to invasive breast carcinomas of no special type. Characteristic diagnostic imaging features can be identified for mucinous carcinoma based on its mucinous and nonmucinous contents. ©RSNA, 2023 Online supplemental material is available for this article. Quiz questions for this article are available through the Online Learning Center.

Atypical cystic hypersecretory lesions of the breast commonly harbour TP53 alterations.

AIMS: Cystic hypersecretory lesions are rare and include atypical cystic hypersecretory hyperplasia (A-CHH) and cystic hypersecretory carcinoma in situ (CHC-IS). Despite detailed morphological descriptions, little is known about the genetic landscape of these lesions. METHODS AND RESULTS: We identified four A-CHH and three CHC-IS from 2010 to 2022. Patients ranged from 39 to 65 (median 49) years. All lesions showed characteristic cystically dilated ducts with colloid-like secretions lined by enlarged cells with hyperchromatic nuclei and at least moderate cytological atypia. CHC-IS was remarkable for a greater degree of intraductal proliferation, typically with a micropapillary pattern. Four patients had concurrent ipsilateral invasive carcinoma. Next-generation sequencing (104 cancer-associated genes) was successful in four, showing variants in TP53 (3), KEAP1 (1) and MDM2 (1). p53 immunohistochemistry was concordant with molecular results with mutant-pattern staining in three TP53-mutants and wild-type in one. In three cases where sequencing failed, one showed mutant p53 staining, one was wild-type and one had no remaining lesion. The combined molecular and immunohistochemical results demonstrated p53 alterations in one A-CHH and three CHC-IS. CONCLUSION: Based on this limited cohort, atypical cystic hypersecretory lesions appear to commonly harbour TP53 alterations. To our knowledge, this is the first study to characterise molecular alterations in this rare subset of breast lesions.

Fibroepithelial tumours of the breast-a review.

Fibroepithelial tumours of the breast are biphasic neoplasms composed of both epithelial and stromal elements, including the common fibroadenoma and the infrequent phyllodes tumour. The admixture of epithelium and stroma in the fibroadenoma shows intra- and pericanalicular patterns, and may display a variety of histological changes. Fibroadenoma variants include the cellular, juvenile, myxoid and complex forms. The cellular fibroadenoma may be difficult to distinguish from the benign phyllodes tumour. Stromal mitotic activity can be increased in fibroadenomas in the young and pregnant patients. Phyllodes tumours, neoplasms with the potential for recurrence, show an exaggerated intracanalicular growth pattern with broad stromal fronded architecture and stromal hypercellularity. They are graded into benign, borderline and malignant forms based on histological assessment of stromal features of hypercellularity, atypia, mitotic activity, overgrowth and the nature of the tumour borders. Classification of phyllodes tumours is imperfect, compounded by tumour heterogeneity with overlapping microscopic features among the different grades, especially in the borderline category. Malignant phyllodes tumours can metastasise and cause death. Determining which phyllodes tumours may behave aggressively has been difficult. The discovery of MED12 mutations in the pathogenesis of fibroepithelial tumours, together with other gene abnormalities in the progression pathway, has allowed refinements in diagnosis and prognosis.

Lobular Carcinoma of the Breast Metastatic to the Ovary: A Clinicopathologic Study of 38 Cases.

We evaluated the clinicopathologic features of 38 cases of metastatic lobular (n=33) or predominantly lobular (n=5) carcinoma involving the ovary. The patients were from 39 to 91 years of age (mean: 53 y). In 2 cases, the breast primary and ovarian metastasis were diagnosed synchronously, and in 5, the breast primary was only discovered after the metastatic carcinoma in the ovary was found. In the majority of cases (79%), both ovaries were involved; the mean ovarian tumor size was 5.9 cm. The ovarian tumors demonstrated a range of architectural patterns including macronodular (71%), diffuse/solid growth (87%), single-cell infiltration (87%), cords (74%), and small nests/clusters (50%). Nine cases demonstrated focal signet ring cell morphology. The associated stromal reaction ranged from none to marked, with almost half of cases demonstrating a marked stromal response, largely prominent sclerosis. A variety of neoplasms, most typically sex cord-stromal tumors, lymphoma/leukemia, and desmoplastic small round cell tumor, may enter the differential. In addition to the obvious help afforded in most cases by the clinical history, a combination of judicious sampling, particularly to unearth the delicate cords or single-cell growth of lobular carcinoma, appropriate consideration of the cytologic features of the neoplastic cells, and immunohistochemistry can resolve the diverse issues in differential diagnosis that may arise.

Ovarian Metastases of Breast Cancers With Signet Ring Cells: A Report of 17 Cases Including 14 Krukenberg Tumors.

Krukenberg tumor, defined as metastatic adenocarcinoma to the ovary containing at least 10% signet ring cells, usually arises from the stomach but can also originate from other sites. We reviewed 17 metastatic breast carcinomas to the ovary with signet ring cells to potentially identify features indicative of mammary origin as opposed to other possible primary sites. The patients ranged from 41 to 76 (mean, 53.6) yr. Fourteen had a prior history of invasive breast carcinoma (invasive ductal carcinoma, 4; invasive lobular carcinoma, 3; adenocarcinoma not otherwise specified, 3; carcinoma with ductal and lobular features, 2; and unspecified carcinoma, 2) and metastases were identified 2 to 284 (mean, 79) mo after the original diagnosis. Three patients had no known history of invasive breast carcinoma: 1 was subsequently diagnosed with invasive lobular carcinoma, 1 had suspicious bilateral breast masses identified on imaging, and 1 was lost to follow-up. Bilateral ovarian metastases were present in 87%, and the tumors ranged from 3.8 to 19 (mean, 8) cm. Microscopically the ovarian architecture was effaced in 71% by discrete tumor lobules separated by striking edema. The tumors exhibited a variety of histologic patterns: nests were most common (88%), followed by cords (82%), diffuse sheets (82%), single cells (71%), small clusters (41%), glands (29%), and follicle-like cysts (12%). Signet ring cells comprised 2% to 70% (mean, 33%) of the tumors, with 14 cases meeting the criteria for Krukenberg tumor. Signet ring cells were most frequently observed within diffuse sheets (71%) and cords (65%). Tumor cells arranged in nests, cords, and diffuse sheets are typical of Krukenberg tumor of breast origin, and the patterns recapitulate those seen in primary breast carcinomas. Features characteristic of gastrointestinal origin, such as extracellular mucin, intestinal-type glands, dirty necrosis, microcysts, and goblet cell carcinoid-like foci, were absent. The overall morphologic picture in cases of ovarian spread of breast cancer with signet ring cells is usually strongly suggestive of mammary origin. The diagnosis can be further supported by the clinical history and immunohistochemical evaluation.

Computational pathology to discriminate benign from malignant intraductal proliferations of the breast.

The categorization of intraductal proliferative lesions of the breast based on routine light microscopic examination of histopathologic sections is in many cases challenging, even for experienced pathologists. The development of computational tools to aid pathologists in the characterization of these lesions would have great diagnostic and clinical value. As a first step to address this issue, we evaluated the ability of computational image analysis to accurately classify DCIS and UDH and to stratify nuclear grade within DCIS. Using 116 breast biopsies diagnosed as DCIS or UDH from the Massachusetts General Hospital (MGH), we developed a computational method to extract 392 features corresponding to the mean and standard deviation in nuclear size and shape, intensity, and texture across 8 color channels. We used L1-regularized logistic regression to build classification models to discriminate DCIS from UDH. The top-performing model contained 22 active features and achieved an AUC of 0.95 in cross-validation on the MGH data-set. We applied this model to an external validation set of 51 breast biopsies diagnosed as DCIS or UDH from the Beth Israel Deaconess Medical Center, and the model achieved an AUC of 0.86. The top-performing model contained active features from all color-spaces and from the three classes of features (morphology, intensity, and texture), suggesting the value of each for prediction. We built models to stratify grade within DCIS and obtained strong performance for stratifying low nuclear grade vs. high nuclear grade DCIS (AUC = 0.98 in cross-validation) with only moderate performance for discriminating low nuclear grade vs. intermediate nuclear grade and intermediate nuclear grade vs. high nuclear grade DCIS (AUC = 0.83 and 0.69, respectively). These data show that computational pathology models can robustly discriminate benign from malignant intraductal proliferative lesions of the breast and may aid pathologists in the diagnosis and classification of these lesions.

Metastases to and from the Breast.

Breast cancer is a common source of systemic metastatic disease. Distinguishing metastatic breast cancer from other types of malignancies can be diagnostically challenging but is important for correct treatment and prognosis. Nonmammary tumors can also metastasize to the breast, although this is a rare phenomenon. Differentiating a metastasis to the breast from a primary breast cancer can likewise be difficult. Knowledge of the clinical history and careful morphologic evaluation are the cornerstones of diagnosis. A panel of immunohistochemical stains tailored to the differential diagnosis at hand can provide helpful information in ambiguous cases.

PAX2 distinguishes benign mesonephric and mullerian glandular lesions of the cervix from endocervical adenocarcinoma, including minimal deviation adenocarcinoma.

Mesonephric remnants of the cervix are vestiges of the embryonic mesonephric system which typically regresses during female development. Uncommonly, hyperplasia of the mesonephric remnants may occur. The differential diagnosis of exuberant mesonephric hyperplasia includes minimal deviation adenocarcinoma of the cervix, a tumor with deceptively bland morphology for which no reliable diagnostic biomarkers currently exist. PAX2 encodes a transcription factor necessary in the development of the Wolffian duct system, and the protein is expressed in several tumors of mesonephric origin, including renal cell carcinoma, Wilm tumor, and nephrogenic adenoma. We hypothesized that PAX2 may also be expressed in mesonephric lesions of the cervix and may distinguish mesonephric hyperplasia from minimal deviation adenocarcinoma of the cervix. We demonstrated that PAX2 was strongly and diffusely expressed in mesonephric remnants (6 of 6) and in mesonephric hyperplasia (18 of 18); however, no expression was noted in mesonephric adenocarcinoma (0 of 1). PAX2 was expressed in normal endocervical glands (including tunnel clusters and Nabothian cysts) (86 of 86), lobular endocervical glandular hyperplasia (5 of 5), tubal/tuboendometrioid metaplasia (8 of 8), and cervical endometriosis (13 of 14). In contrast, only 2 cases of endocervical adenocarcinoma were positive for PAX2 [invasive adenocarcinoma of the minimal deviation type (0 of 5), usual type (1 of 22), and endometrioid type (1 of 1)]. Adjacent adenocarcinoma in situ, as well as cases of pure adenocarcinoma in situ (0 of 6), were also PAX2 negative. PAX2 expression in the 2 positive endocervical adenocarcinomas was patchy and weak. Most (11 of 15) stage II endometrial endometrioid adenocarcinomas lacked PAX2 expression but 1 of 10 grade 1 tumors and 3 of 5 grade 2 tumors did express PAX2. These results suggest that PAX2 immunoreactivity may be useful to (1) distinguish mesonephric hyperplasia from minimal deviation adenocarcinoma, (2) to distinguish lobular endocervical glandular hyperplasia from minimal deviation adenocarcinoma, and (3) to distinguish endocervical tubal metaplasia or cervical endometriosis from endocervical adenocarcinoma in situ. Overall, a strong, diffuse nuclear PAX2 expression pattern in a cervical glandular proliferation predicts a benign diagnosis (positive predictive value 90%, negative predictive value 98%; P<0.001); however, PAX2 should not be interpreted in isolation from the architectural and cytologic features of the lesion as it may be expressed in some stage II endometrial adenocarcinomas involving the cervix.

Breast hamartomas in adolescent females.

Breast hamartomas are uncommon lesions that have not been extensively characterized in the adolescent population. A search of patient records at our institution over a 17-year period identified seven cases of breast hamartomas in patients less than 18 years of age. We examine and report the clinical, radiographic, and pathologic characteristics of these cases. Breast hamartomas present as painless, palpable masses in the adolescent population. Ultrasonography reveals a well-defined, solid, oval mass, similar to the more common fibroadenoma. Two of the patients underwent core needle biopsy for diagnosis as the only intervention with the remainder undergoing surgical excision. None of the patients had any complications from surgery. There was one recurrence 9 months after initial excision. Histologically, the hamartomas consisted of densely packed, enlarged lobules set within a fibrous stroma. Breast hamartomas are rare in the adolescent population. The clinical and radiographic features are similar to the more common fibroadenoma, but the pathologic findings are diagnostic. Recurrence can occur if excision is incomplete. Increased recognition and accurate diagnosis will improve our understanding of the natural history of these lesions.

Primary ovarian carcinoid tumors may express CDX-2: a potential pitfall in distinction from metastatic intestinal carcinoid tumors involving the ovary.

Carcinoid tumors of the ovary are rare neoplasms that may be primary or metastatic. Clinicopathologic features such as unilaterality and early stage favor a primary ovarian neoplasm but in the absence of other teratomatous elements it may be difficult or impossible to determine whether an ovarian carcinoid is primary or metastatic. CDX-2 is a marker of intestinal differentiation that has been proposed as a marker of midgut origin for metastatic carcinoids. Its expression has not been tested in ovarian carcinoids. Additional markers of potential help in defining the origin of a carcinoid include cytokeratin (CK) 20, CK7, and thyroid transcription factor (TTF-1), none of which have been studied in ovarian carcinoids. We evaluated the diagnostic utility of CDX-2, CK20, CK7, and TTF-1 as well as conventional clinicopathologic features in determining the site of origin in 26 ovarian carcinoids (16 primary and 10 metastatic from midgut). Non-neoplastic premenopausal ovaries (n=10) served as controls. All primary ovarian carcinoids were unilateral whereas only 3/10 metastatic carcinoids were unilateral. Multinodular growth occurred in 6/10 metastatic carcinoids but not in any primary carcinoid. The average size of primary ovarian carcinoids was 3.4 cm (range: 0.2-13.5 cm) versus 10.2 cm for metastatic carcinoids (range: 4-32 cm). Of the primary ovarian carcinoids, 12/16 were 3 cm or smaller whereas all metastatic carcinoids were 4 cm or larger. Teratomatous elements were present in association with 10/16 primary ovarian carcinoids, whereas none were present in any metastatic carcinoid. The primary ovarian carcinoid types were insular (n=6), trabecular (n=3), strumal (n=6, of which 5 were trabecular pattern and 1 was insular pattern) or mucinous (n=1). CDX-2 was not expressed in any cells in normal ovaries. Among primary ovarian neoplasms, there was diffuse nuclear CDX-2 expression in 4/6 insular, 0/3 trabecular, 1/6 strumal (1/1 insular pattern and 0/5 trabecular pattern strumal carcinoids), and 1/1 mucinous carcinoids. All metastatic carcinoids, except for two of mucinous type, were insular. CDX-2 was diffusely and strongly expressed in all 8 metastatic insular carcinoids and in both metastatic mucinous carcinoids. None of the metastases was trabecular in type but 12 primary hindgut or foregut trabecular carcinoids were evaluated and all were negative for CDX-2. None of the ovarian carcinoids expressed TTF-1, CK7, or CK20, except for the primary and metastatic mucinous carcinoids, all of which were CK20-positive. These results demonstrate that CDX-2 cannot be used to determine if a carcinoid is primary in the ovary or metastatic from the intestine as insular and mucinous types of either origin express this marker. Trabecular carcinoids of either origin lack CDX-2 expression. CK20, CK7, or TTF-1 do not have diagnostic utility in this context. Conventional clinicopathologic features (unilaterality, lack of multinodular growth, early stage, presence of teratomatous elements, and size 3 cm or smaller) are the most helpful findings in suggesting a primary origin for an ovarian carcinoid tumor.

Use of Myoepithelial Cell Markers in the Differential Diagnosis of Benign, In situ, and Invasive Lesions of the Breast.

Immunohistochemical markers for myoepithelial cells are commonly used to distinguish invasive from noninvasive lesions in the breast. The approach takes advantage of the fact that conventional invasive carcinomas lack surrounding myoepithelial cells, whereas nearly all benign lesions and in situ carcinomas retain their myoepithelial cell layer. Although conceptually straightforward, the interpretation of myoepithelial cell markers can be complicated by misleading patterns of reactivity (such as stromal or tumor cell staining) or lack of reactivity (due to reduced numbers of myoepithelial cells or variable antigenicity). In this article, we discuss the advantages and disadvantages of commonly used myoepithelial cell markers, their general utility in distinguishing invasive from noninvasive processes, and pitfalls in their interpretation. We also examine whether the detection of myoepithelial cells is helpful in the evaluation of papillary lesions, another common application. Myoepithelial cell markers can be diagnostically useful in the distinction of many benign, in situ, and invasive lesions, but they must be interpreted in conjunction with careful morphologic analysis.

Carcinoma of extrahepatic bile ducts and gallbladder metastatic to the ovary: a report of 16 cases.

Information on ovarian metastasis of carcinoma of the extrahepatic bile ducts and gallbladder is limited. Sixteen examples are reported; 3 primary tumors were hilar cholangiocarcinomas, 5 common bile duct carcinomas, and 8 gallbladder carcinomas. The patients ranged from 21 to 87 years (mean, 59 years); 7 presented to gynecologists with nonspecific pelvic symptoms similar to primary ovarian neoplasms. The primary tumor was identified before the detection of the ovarian lesions in 5 cases, was simultaneously detected with the ovarian metastases in 9, and was diagnosed postoperatively in 2. All but one case had bilateral ovarian involvement. The thirty-one ovarian lesions included twenty-nine grossly abnormal ovaries that were enlarged (range, 3.0-16.5 cm, mean, 9.4 cm) and 2 ovaries with only microscopic involvement. The sectioned surface was solid in 9, solid-cystic in 15, and multicystic in 5. Microscopically, ovarian surface implants were seen in 66%, multinodular growth in 58%, and infiltrative stromal invasion in 81%. Mucinous epithelial differentiation was seen in 81%, sometimes with foci of benign-like or borderline-like epithelium simulating primary ovarian mucinous neoplasia. Cystadenoma and cystadenofibroma of nonmucinous type was even mimicked strikingly in some cases because of flattening of epithelium lining glands and cysts. Signet ring cells were present in sufficient quantity for a diagnosis of Krukenberg tumor in four tumors. Colloid-type carcinoma was observed at least focally in 3 tumors. Nonmucinous carcinomatous components included adenocarcinoma with high-grade endometrioid-like morphology in 2 cases, papillary adenocarcinoma simulating mixed müllerian epithelial adenocarcinoma in 1, and undifferentiated carcinoma in 2. Immunohistochemical studies in 8 cases showed a positive reaction for cytokeratin 7 in all and for cytokeratin 20 in 4 cases. The high rate of bilaterality, surface involvement, multinodular growth, and heterogeneity of patterns were the most helpful features for indicating a metastatic nature, with signet ring cells also being helpful in the minority of cases in which they were present. Although the diagnosis of a metastatic tumor to the ovary is possible in most of the cases based on standard diagnostic criteria, problems in the differential diagnosis may be posed by morphologic patterns that overlap strikingly with primary ovarian neoplasms, benign, borderline, and malignant, as discussed herein.

Flat epithelial atypia of the breast.

Flat epithelial atypia is a presumably neoplastic alteration of terminal duct-lobular units that is characterized by the replacement of the native luminal epithelium by ductal cells demonstrating low-grade cytologic atypia. The atypical cells maintain a "flat" pattern of growth without evidence of architectural atypicality. Morphologic, immunohistochemical, and molecular investigations support that flat epithelial atypia represents an early step in the evolution of low-grade ductal carcinomas. It is frequently seen in association with atypical ductal hyperplasia, low-grade ductal carcinoma in situ, invasive tubular carcinoma, and lobular neoplasia. The risk for subsequent breast carcinoma remains to be defined, but flat epithelial atypia likely represents a nonobligate precursor with an extended time course to progression. Certain benign alterations may superficially mimic its appearance; careful attention to cytologic and architectural characteristics can help one distinguish these unrelated entities from flat epithelial atypia.

Ovarian metastases of intestinal-type gastric carcinoma: A clinicopathologic study of 4 cases with contrasting features to those of the Krukenberg tumor.

Ovarian metastases of intestinal-type gastric adenocarcinomas are rare, and information on them is very limited compared with that on signet-ring cell carcinomas that result in the Krukenberg tumor. Four cases are reported herein. The patients averaged 55 years of age. In 3 patients, the ovarian metastases were identified several to 21 months after the diagnosis of the gastric primary, and the tumors were synchronous in the fourth. Two tumors were bilateral, 1 unilateral, and for 1, the laterality was unknown. The ovarian tumors were characteristically solid and cystic, with multinodular growth in 2. In 2 cases, the ovarian tumors had a pseudoendometrioid morphology with tubulo-glandular, cribriform, and papillary patterns; they also had focal trabecular and insular patterns. Prominent necrosis was present, including segmental and intraluminal "dirty" necrosis. In the other 2 cases, the ovarian tumors had a mucinous appearance, 1 being dominantly cystic with occasional goblet cells and the other with prominent foveolar-type cells. Nuclei ranged from deceptively bland to highly atypical. Surface implants were identified in 2 cases. Two ovarian tumors examined expressed cytokeratin 7 and 20 but not estrogen receptor. Three patients with follow-up information all died within 1 year of the ovarian metastases. Although information is limited, our results suggest that metastatic spread to the ovary by intestinal-type gastric adenocarcinoma is usually seen in patients older than those with Krukenberg tumors, with a known history of gastric carcinoma, and with concomitant widespread disease. Involvement of the ovary by intestinal-type gastric carcinoma produces a microscopic picture distinctly different from that of a Krukenberg tumor. These metastatic intestinal-type tumors may be confused with metastases from other gastrointestinal sites that are more frequently the cause of pseudoendometrioid or mucinous metastases, and like such tumors may be confused with primary ovarian endometrioid and mucinous neoplasms.

Solid papillary ductal carcinoma in situ versus usual ductal hyperplasia in the breast: a potentially difficult distinction resolved by cytokeratin 5/6.

The solid papillary variant of ductal carcinoma in situ is an uncommon entity, which usually presents in the seventh or eighth decade and may be associated with invasive mucinous carcinoma. Solid papillary ductal carcinoma in situ (SP-DCIS) shares many morphological features with usual ductal hyperplasia (UDH) involving a papilloma: papillary architecture, solid growth, cellular streaming, and low-grade nuclear features. These similarities can make the distinction between these 2 entities challenging. Recent studies have demonstrated that immunohistochemical staining for cytokeratin 5/6 can distinguish UDH from conventional forms of ductal carcinoma in situ. Most of the epithelial cells of UDH express cytokeratin 5/6, but the tumor cells of ductal carcinoma in situ do not. We tested the hypothesis that the results of staining for cytokeratin 5/6 can distinguish UDH from the solid papillary variant of ductal carcinoma in situ. Immunohistochemical staining of 14 cases of SP-DCIS and 9 cases of UDH (4 involving papillomas) was performed using cytokeratin 5/6 antibody clone D5/16 B4. Strong cytoplasmic or membrane staining was considered positive. The hyperplastic cells in all cases of UDH showed strong staining for cytokeratin 5/6. The percentage of positive cells ranged from 50% to 80%. None of the SP-DCIS tumor cells stained for cytokeratin 5/6; however, many cases did show staining of occasional entrapped, benign epithelial, and myoepithelial cells. We conclude that the absence of strong cytokeratin 5/6 expression by SP-DCIS distinguishes it from its morphological mimic, UDH. Pathologists must guard against misinterpreting SP-DCIS as UDH in those cases in which the carcinoma cells engulf cytokeratin 5/6-expressing residual, native epithelial cells.