Development and validation of a model predictive of occult nipple involvement in women undergoing mastectomy.

BACKGROUND: This prospective study aimed to build a predictive model using preoperative information to aid selection for nipple-sparing mastectomy. METHODS: Two hundred consecutive skin-sparing mastectomy specimens without overt nipple involvement were evaluated. Demographic, preoperative pathology and imaging information was collected. Nipple specimens (2 x 2 x 2 cm) were sectioned at 3-mm intervals. Haematoxylin and eosin-stained slides were examined by a breast pathologist for involvement by tumour. Logistic regression analyses of 65 therapeutic procedures identified factors associated with occult involvement and created a predictive model. This was tested on specimens from a further 65 therapeutic procedures. RESULTS: Occult nipple involvement was noted in 32 (24.6 per cent) of 130 mastectomy specimens. In the training set, imaging diameter of the lesion and its distance from the nipple predicted nipple involvement on univariable analysis (P = 0.011 and P = 0.014 respectively). The multivariable logistic regression model was validated in the test set. The areas under the receiver-operating characteristic curve were 0.824 and 0.709 for the training and test sets respectively. CONCLUSION: Three-quarters of women undergoing mastectomy did not have occult nipple involvement. A clinical tool including tumour size and distance from the nipple has been developed to improve patient selection for nipple-sparing mastectomy.

Morphological observations regarding the origins of atypical cystic lobules (low-grade clinging carcinoma of flat type).

This study seeks to define the morphological pathogenesis of a form of cystic transformation of lobules referred to as atypical cystic lobule or low-grade clinging carcinoma of flat type. We collected 25 examples that seem to represent the early stages in the formation of atypical cystic lobules and made a careful study of their morphology. Our observations indicate that this lesion arises from pre-existing, structurally normal terminal duct-lobular units and that it seems to develop by the direct transformation of indigenous luminal cells. The transformed cells first become evident in the small duct or terminal ductule, where they appear as slightly enlarged columnar cells containing atypical nuclei. In more advanced examples, these alterations affect all luminal cells of the terminal duct-lobular unit, but the cells of the terminal ductule continue to show more pronounced changes than the cells lining the acini. The atypical cells within the lobule do not seem to displace the normal acinar cells. Instead, the cells form a continuum, making it impossible to define the point at which atypical cells and normal cells meet. Within the small duct, however, the atypical epithelium comes to an abrupt halt as the duct courses towards the nipple. Considering these observations, we ascribe the formation of atypical cystic lobules to the accumulation of atypical cells in pre-existing terminal duct-lobular units.

Atypical cystic lobules in patients with lobular neoplasia.

We analyzed the frequency and anatomic distribution of atypical cystic lobules (ACLs) in patients whose index biopsy specimen contained lobular neoplasia (LN). Thirty of 54 patients (56%) had ACLs in their index biopsy specimen. Five of the patients whose index biopsy lacked ACLs underwent an additional biopsy, and 4 of these patients had ACLs in an additional specimen, bringing the total number of patients having both ACLs and LN to 34 of 54 (62.9%). ACLs involved both breasts with equal frequency and neither the extent of the involvement nor the anatomic location of the LN paralleled the distribution of the ACLs. The presence of ACLs in patients with LN might explain its increased risk for the development of ductal carcinomas and their bilateral distribution. Int J Surg Pathol 9(3):201-206, 2001

Solid low-grade in situ carcinoma of the breast: role of associated lesions and E-cadherin in differential diagnosis.

Low-grade solid in situ carcinomas of the breast are difficult to classify. The authors investigated 12 cases of in situ carcinomas with equivocal features and correlated their histologic attributes with those of the associated invasive carcinomas as well as with E-cadherin expression in both in situ and invasive disease. E-cadherin-positive in situ lesions were invariably associated with invasive carcinomas of the ductal type. In situ carcinomas that were E-cadherin negative were associated with invasive carcinomas of the lobular type in five of six cases. In all cases, the invasive carcinomas showed the same pattern of E-cadherin reactivity as the in situ lesions. Sharply defined cellular membranes, necrosis, and occasional microacini were seen in both E-cadherin-positive and negative in situ carcinomas, whereas intracytoplasmic lumina and a noncohesive appearance were seen only in E-cadherin-negative lesions.

Mammographic appearance of ductal carcinoma in situ does not reliably predict histologic subtype.

Histologic subtypes of ductal carcinoma in situ (DCIS) have been correlated with disease prognosis. There are conflicting reports on whether the grade of DCIS can be predicted by the morphology of calcifications seen on mammography. We undertook this study to determine whether the grade of DCIS can be reliably and accurately determined by mammography prior to excisional biopsy. Ninety consecutive cases of DCIS from 1993 to 1996 were identified, of which 75 cases had mammograms available for review. Any lesion with invasion was excluded. The mammogram showed only a mass in 10 of 75 cases, a mass and calcifications in 3 of 75 cases, and calcifications alone in 62 of 75 cases. Three board-certified radiologists with special expertise in mammography reviewed and categorized the mammographic findings as well, intermediate or poorly differentiated DCIS without knowledge of the histologic diagnosis. Histologic grading was performed without knowledge of the mammographic finding. Receiver operating curves (ROCs) were computed for each of the radiologists. For microcalcifications, the ROC comparisons of the radiologists' opinions of tumor grade and random chance were not significantly different. In those cases with available magnification views, the grade assessment did not change significantly. If only a mass was present on mammography, well-differentiated DCIS was the predominant histologic subtype. A histologic grade of DCIS cannot accurately be determined prospectively based on the mammographic appearance of microcalcifications. However, if only a mass is present, this is more likely to represent well-differentiated DCIS.

Collagenous spherulosis: an ultrastructural study.

Ultrastructural findings are described in two cases of collagenous spherulosis associated with intraductal hyperplasia and sclerosing adenosis. The spherules showed a variable composition of basement membrane, banded collagen, and mineral deposition. Some spherules were connected to the periacinal stroma by a thin pedicle. The authors propose that spherules represent a peculiar form of stromal invagination that could be seen in a variety of breast lesions, rather than a form of intraductal hyperplasia.

Endocrine mucin-producing sweat gland carcinoma: a cutaneous neoplasm analogous to solid papillary carcinoma of breast.

We describe two cases of a distinctive in situ and invasive cutaneous adnexal neoplasm occurring in the eyelid. Mucinous carcinoma represented the invasive portion of the tumor in one case, whereas the other infiltrated in small solid nests. The in situ component is identical to the recently described solid papillary carcinoma of the breast (endocrine ductal carcinoma in situ). Both tumors produced intra- and extracellular mucin, exhibited endocrine differentiation by immunohistochemistry and ultrastructural analysis, and were positive for estrogen and progesterone receptors.

Metaplastic carcinoma of the breast with melanocytic differentiation.

We report the clinical and pathologic findings of a metaplastic carcinoma of the breast that exhibited melanocytic differentiation. The tumor possessed both in situ and invasive components. Lower grade regions of the infiltrating carcinoma had features of tubular, mucinous, and matrix-producing carcinomas. In the higher grade areas, conventional poorly differentiated ductal carcinoma merged with an anaplastic neoplasm that looked like malignant melanoma. The nonpigmented cells stained for keratin but lacked HMB-45 and S-100 proteins, whereas the cells containing melanin showed the opposite characteristics. Electron microscopic examination disclosed melanosomes in the neoplastic cells. We believe that these observations convincingly establish both the origin of the tumor from the mammary epithelium and the synthesis of melanin by the tumor cells. We propose the diagnosis of metaplastic carcinoma with melanocytic differentiation for this neoplasm and suggest that the phenomenon of melanocytic metaplasia might underlie the formation of primary melanomas of the breast.

Solid papillary carcinoma of breast: an ultrastructural study.

Solid papillary carcinoma of the breast is a subset of papillary carcinoma, which occurs in older women and usually has a favorable prognosis. It is primarily intraductal but also is often associated with invasive carcinoma, especially mucinous carcinoma. Intracellular and extracellular mucin is also found in the in situ stage, in most tumors. In addition to forming solid papillary masses, the cells palisade around vessels in pseudorosettes and show minimal nuclear atypia. Some cells show neuroendocrine differentiation, based on argyophilia with Grimelius staining. Four examples of this neoplasm were studied electron microscopically. Myoepithelial cells were not found. Neoplastic cells had an ultrastructure that was generally similar to that of other types of mammary carcinoma. There were extracellular microlumens, but intracellular lumens and pseudolumens were few or absent. Secretory activity varied among cells, and those cells appearing active had a variety of granule types, including typical flocculent and "bull's-eye" mucinous granules, small dense-core granules, and large serous-like granules. Some of the dense-core granules were interpreted as neuroendocrine in nature, based on their abluminal or juxtavascular location, whereas others that were apical and subluminal were probably mucinous in type. The large serous-appearing granules were subluminal in some cells and diffuse in others and may also have represented a variant of mucinous granules. The results support earlier opinions that accurate interpretation of specific granular function at the electron microscopic level depends on cytochemical studies using uranaffin as a marker of neuroendocrine activity. Although mucinous granules are identified by their lack of staining with uranaffin, the nature of the serous-appearing granules would still not be answered by this method; that is, a negative reaction would not define whether the granules are truly serous, or simply another form of mucin. Regardless of limitations of this type, correlation and extrapolation of histochemical (Grimelius and Alcian blue) and immunohistochemical (chromogranin and synaptophysin) results with subcellular structure are still very useful in establishing cell type.

High risk of breast carcinoma after irradiation of young women with Hodgkin's disease.

BACKGROUND: Treatment-associated second neoplasms have emerged as a major threat to the continued survival of patients cured of Hodgkin's disease. In this study, the authors investigated the risk of breast carcinoma in an irradiated Hodgkin's disease population. METHODS: One hundred and eleven women younger than 60 years presenting between 1964 and 1984 with Stage I and II Hodgkin's disease who received mantle irradiation were retrospectively analyzed and compared with an age specific population. Median follow-up was 18 years (range, 10-30 years), and the median age at initiation of therapy was 24 years. Kaplan-Meier actuarial risks, relative risks (RRs) (the ratio of the observed to the expected cases) with 95% confidence intervals (CIs), and the log rank test for trends were calculated. RESULTS: Fourteen women developed breast carcinoma: 8 of 33 patients younger than 20 years at the time of irradiation, 5 of 48 patients age 20 to 29 years, and 1 of 30 patients age 30 years or older. Actuarial calculation predicted a 34.0% (CI, 14.2-53.8) risk of breast carcinoma at 25 years after therapy for the youngest group, 22.3% (CI, 4.1-40.5) for the group of intermediate age, and 3.5% (CI, 0-10.1) for the oldest group. The RR of breast carcinoma was 56 (CI, 23.3-107) for those 19 years or younger at the time of treatment, 7.0 (CI, 2.3-16.4) for those age 20-29 years, and 0.9 (CI, 0-5.3) for those 30 years and older. Excluding 1 patient who was age 38 years at the time of irradiation, the remaining 13 breast carcinomas were tightly clustered in women irradiated between the ages of 14 through 25, and were detected in years 11 through 25 after treatment, with 7 occurring in years 15 through 18. CONCLUSIONS: Women younger than 30 years, particularly those younger than 20 years, who have received mantle irradiation for Hodgkin's disease require meticulous follow-up for breast carcinoma. The high incidence of breast carcinoma in this patient population should be considered when making treatment decisions in young women with early stage Hodgkin's disease.

Cyclin D1 (PRAD1) alternative transcript b: full-length cDNA cloning and expression in breast cancers.

The cyclin D1/PRAD1 protooncogene is a key regulator of the G1 phase of the cell cycle and has been incriminated in the pathogenesis of a variety of primary human tumors. Recently, part of a novel alternatively spliced cyclin D1 transcript, called transcript b, has been identified. This variant transcript showed a failure of splicing at the 3' end of exon 4 and as a result, the expected protein product is altered at its C-terminus. Because of similar transcript sizes, previous Northern analyses would not have been expected to distinguish the two variants, and the relative levels of the two cyclin D1 transcripts in human tumors is unknown. To elucidate the role of cyclin D1 transcript b, we have isolated cDNA clones of this variant transcript from human breast cancer cell lines and report the sequence of the entire coding region of the cDNA. The protein predicted from the cDNA sequence consists of 274 amino acid residues and lacks a PEST sequence in its C-terminus. Examination of the levels of the two alternative cyclin D1 transcripts in primary breast cancers and breast cancer cell lines by Northern blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) assays showed that the variant transcript b is indeed expressed in primary breast cancers and breast cancer cell lines, but the level of transcript b is dramatically lower than that of the originally reported transcript a of the cyclin D1 gene. In breast cancers, oncogenic overexpression of cyclin D1 mRNA appears to consist overwhelmingly of transcript a, and the role of transcript b, if any, in oncogenesis remains to be established. Science Ireland Ltd.

Spindle cell endocrine carcinoma of the mammary gland.

We report the pathological characteristics of a variant of mammary endocrine tumour, predominantly formed from cytologically bland spindle cells. This neoplasm grows as a red, well defined mass lacking the usual macroscopical characteristics of breast cancer. Within smoothly contoured aggregates arranged in an insular pattern, delicate capillaries and collagen bundles support the neoplastic epithelial cells. Most of the tumour cells possess a slender spindle shape and form a solid or fenestrated sheet, but a few appear cuboidal and create glands. Immunohistochemical studies demonstrate that the spindle cells and the glandular cells constitute a single population. Both types of cells stain for neuroendocrine markers (chromogranin, synaptophysin, and CD 57), carcinoembryonic antigen, keratin 8/18, S-100 protein, and receptors for oestrogen and progesterone. Many of the tumour cells possess argyrophilic granules, and electron microscopy may reveal dense core granules.

Smooth-muscle tumors of the vulva. A clinicopathological study of 25 cases and review of the literature.

The clinical and pathological features of 25 smooth-muscle tumors of the vulva were analyzed. The patients ranged in age from 17 to 67 (mean, 37.6) years; two were pregnant. Twenty-three tumors were 1.5 to 16 (mean, 5.2) cm in greatest dimension; the size of two tumors was unknown. Microscopic examination showed that 16 tumors were circumscribed, six had focally infiltrative margins, and the margins could not be evaluated in three tumors. Fourteen tumors were composed mainly of spindle cells; two of these tumors had prominent myxoid stroma. Seven tumors were predominantly epithelioid and had a prominent hyalinized or myxoid stroma; often the cells had a plexiform pattern. Four tumors contained an approximately equal number of epithelioid and spindle cells. Ten tumors had mild, nine moderate, and six severe cytologic atypia. Mitotic figures ranged from 0 to 10 (average, 1.8) per 10 high-power fields (hpf). Immunohistochemically, all the tumors stained for one or more muscle markers. Thirteen of 17 tumors were positive for estrogen receptors, and 16 of 18 were positive for progesterone receptors. Follow-up information ranging from 1 month to 19 years (average, 5 years) was available in 19 cases. Four tumors recurred locally, and one patient with recurrent tumor died of metastases 7 months after the initial operation. We propose an expanded criteria to distinguish between leiomyomas and leiomyosarcomas of the vulva. Tumors that manifest three or all of the four following features should be considered sarcomas: > or = 5 cm in greatest dimension, infiltrative margins, > or = 5 mitotic figures per 10 hpf, and moderate to severe cytologic atypia. Those that have only one of these characteristics should be diagnosed as leiomyoma, and those that exhibit only two of these features should be considered benign but atypical leiomyomas. The sarcomas should be excised with widely negative margins; the leiomyomas and the atypical leiomyomas should be excised conservatively, with long-term, careful follow-up.

Involvement of collagenous spherulosis by lobular carcinoma in situ. Potential confusion with cribriform ductal carcinoma in situ.

We describe five cases in which the cells of lobular carcinoma in situ seemed to form round, regular lumens similar to the cribriform spaces of ductal carcinoma in situ. After careful inspection, we concluded that the spaces indicate the presence of collagenous spherulosis and that this unusual pattern arises through the confluence of lobular neoplasia and spherulosis. We base this conclusion on three lines of evidence. First, attenuated myoepithelial cells, rather than carcinoma cells, form the spaces in question. Immunohistochemical staining for smooth-muscle actin and keratin 8/18 established the myoepithelial nature of these flattened cells because they express the former protein but lack the latter. These results also differentiate the myoepithelial cells from those of conventional in situ carcinomas, which do not contain smooth-muscle actin but virtually always possess keratin 8/18. Second, the material within the spaces looks like the deposits that characterize collagenous spherulosis. They consist of densely eosinophilic protein or radiating, fibrillar ground substances, and they differ in appearance from the disorganized, flocculent mucin and the cellular debris found in some in situ ductal carcinomas. Finally, the neoplastic cells display a loosely cohesive growth pattern that is more in keeping with the properties of lobular neoplasia than ductal carcinoma. Considered together, these three points should distinguish involvement of collagenous spherulosis by lobular neoplasia from cribriform ductal carcinoma in situ. Pathologists must remain alert to this form of mimicry because classification of in situ carcinoma of the breast carries important clinical implications.

Solid papillary carcinoma of the breast. A form of intraductal carcinoma with endocrine differentiation frequently associated with mucinous carcinoma.

We report 20 examples of a distinctive form of intraductal papillary carcinoma frequently associated with both mucinous carcinoma and infiltrating ductal carcinoma, not otherwise specified. All the patients were in the seventh decade of life or older. The clinical presentation and macroscopic appearance suggested a benign lesion in most cases. The tumors grew in a solid papillary pattern and displayed low-grade cytological features as well as intracellular and extracellular mucin. Endocrine differentiation was demonstrated by the Grimelius stain in 11 of 17 cases and by the chromogranin immunohistochemical technique in eight of 14 cases. Lymph node metastases were not observed, but pulmonary metastasis occurred in one case. All the tumors were positive for estrogen receptors. We postulate that these lesions are the preinvasive counterpart of mucinous carcinomas with endocrine differentiation.

Cyclin D1 (PRAD1) protein expression in breast cancer: approximately one-third of infiltrating mammary carcinomas show overexpression of the cyclin D1 oncogene.

Amplification of chromosome 11q13 has been observed in 10-20% of breast carcinomas and numerous other tumors, including squamous cell carcinomas of the head, neck, and esophagus; transitional cell carcinomas of the urinary bladder; and epithelial ovarian tumors. Cyclin D1/PRAD1 is a likely "driver" gene for this amplicon because of its role in cell cycle control and because it has been specifically implicated as an oncogene in parathyroid adenomas and B-cell lymphomas with 11q13 translocation breakpoints. We examined cyclin D1 protein expression in 48 consecutive cases of infiltrating mammary carcinoma using an affinity-purified polyclonal antisera to cyclin D1 and a microwave/citrate buffer antigen retrieval system. Staining data were correlated with clinicopathological features, protein detection by immunoblots, and 11q13 DNA amplification. Definite nuclear staining was seen in 17/48 (35%) tumors (16 infiltrating ductal carcinomas, predominantly grade 2/3, and one infiltrating lobular carcinoma). There was no nuclear staining of normal breast epithelium, fat cells, or admixed lymphocytes. Tumors with overexpression of cyclin D1 were estrogen receptor-positive (P < .005) and usually progesterone receptor-positive (P < .005) but otherwise were similar to other negative cases in the study group. Correlation between Western blot and immunostaining data was excellent (P < .01). Five of the 22 cases studied showed 11q13 DNA amplification as well as increased levels of cyclin D1 protein by Western blot and immunostaining. Four cases with increased cyclin D1 protein by both western blots and immunohistochemistry did not have detectable 11q13 amplification. Nuclear cyclin D1 protein can be detected in approximately one-third of infiltrating breast carcinomas using an immunohistochemical technique on formalin-fixed, paraffin-embedded tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Progesterone receptor detection in paraffin sections of human breast cancers by an immunoperoxidase technique incorporating microwave heating.

We sought to establish an easily interpretable and highly sensitive immunohistochemical method for detecting progesterone receptor protein in formalin-fixed, paraffin-embedded samples of breast carcinomas. Beginning with a conventional immunoperoxidase staining procedure, we incorporated microwave heating to compensate for the effects of conventional fixation and processing and then applied the method to 90 samples of primary breast carcinomas. We used the results of hormone binding assays as true values to establish the sensitivity, specificity, positive predictive value, and negative predictive value of the staining method. Our technique yielded good preservation of morphological detail and low nonspecific staining of background tissue. Comparisons of the results of staining and biochemical assays revealed that this progesterone receptor immunostaining procedure shows high sensitivity and acceptable specificity. We believe its performance characteristics make reliable study of small specimens and archival material possible.

Carcinomas of the breast with endocrine differentiation: a review.

The occurrence of endocrine differentiation in some mammary carcinomas seems well-established, but pathologists continue to debate its significance. Contemporary thinking suggests that endocrine tumours of the breast do not constitute a single clinicopathological entity with a consistent histogenesis but rather that endocrine differentiation represents a pathway of neoplastic development available to a range of breast cancers. This pattern of differentiation occurs in tumours with vastly different morphological appearances, such as: ductal carcinoma in situ, mucinous carcinoma, a variant of lobular carcinoma, and low grade invasive ductal carcinoma. Although such tumours share some characteristics with intestinal endocrine neoplasms, the typical pattern of intestinal carcinoid virtually never occurs in mammary lesions. Conventional microscopy permits the diagnosis in most cases. Specialized techniques (histochemistry, immunohistochemistry, and electron microscopy) can serve as the basis for diagnosis in the absence of the appropriate morphological features. Although the system of nomenclature proposed by the World Health Organization for use with endocrine tumours in other organs can be used for endocrine tumours of the breast, only a minority of lesions will fit the established criteria. Most lesions are classifiable in the conventional categories of mammary carcinomas. No special prognostic significance is attached to these tumours at the present time.