Accurately assessing her-2/neu status in needle core biopsies of breast cancer patients in the era of neoadjuvant therapy: emerging questions and considerations addressed.

BACKGROUND: Emerging data show that patients with operable, HER-2/neu overexpressed/amplified breast carcinomas have significantly better responses (more frequently obtaining pathologic complete response and greater percent disease-free survival) when treated with trastuzumab (Herceptin) simultaneously with neoadjuvant chemotherapy than with chemotherapy alone. With the increasing use of neoadjuvant therapies, clinicians require information on biomarkers including HER-2/neu status at the time of needle core biopsy. Concordance rates between fluorescence in situ hybridization (FISH)-determined HER-2/neu status on needle core biopsies and on subsequent excisional biopsies of the same tumor have not been well studied. Moreover, the practice of automatically performing ("reflexing") 2+ immunohistochemical (IHC) staining needle core biopsies for FISH analysis on the same sample needs to be validated. In this study, we set out to (1) determine the accuracy of HER-2/neu status as determined by FISH on needle core biopsy material compared with FISH on the subsequent excisional biopsy of the same tumor with special consideration of IHC 2+staining cases and (2) determine the constancy of HER-2/neu status in pre-neoadjuvant and post-neoadjuvant chemotherapy-treated tumor in the form of needle core biopsy and excisional biopsy samples, respectively. DESIGN: 100 patients whose needle core biopsies and subsequent excisional biopsy samples were pathologically evaluated at our institution were studied. For each patient, unstained sections from both specimens were prepared and used for IHC or FISH. IHC was carried out using the HercepTest kit (DAKO, Carpinteria, CA). Parallel unstained slides were used to carry out FISH (dual probe, Vysis). Statistical analyses were carried out on the resulting data generated after interpretation. RESULTS: The concordance rate between FISH results determined on the needle core biopsy and subsequent excisional biopsy of the same tumor was 86% (kappa=0.56, P=2x10). If equivocal FISH cases (> or =1.8 to < or =2.2 amplification ratio) in a needle core biopsy or excisional biopsy specimen or both, were excluded, the concordance rate increased to 95% (kappa coefficient=0.86, P=2x10). Fourteen of 100 (14%) cases showed 2+ IHC staining in the needle core biopsy specimen with good concordance of FISH-determined HER-2/neu status between the needle core biopsy and excisional biopsy specimens (79% agreement and kappa=0.512, P=0.05). Nine, 3, and 2 cases of the 14 cases were amplified, equivocal, and negative on the excisional biopsy specimens, respectively. Of the 15 patients who received neoadjuvant chemotherapy, 93% and 87% had no change in HER-2/neu status as determined by IHC or FISH, respectively, in the excisional biopsy specimen when compared with that determined on the prior core biopsy sample. CONCLUSIONS: Excellent overall concordance was achieved between FISH-determined HER-2/neu status on the needle core biopsy and that determined on the subsequent excisional biopsy of the same tumor. These results suggest that intratumoral heterogeneity of HER-2/neu assessed by FISH is not a significant confounding factor when analyzing smaller sized samples. Furthermore, 79% of 2+IHC staining needle core biopsy cases showed concordant FISH results in the needle core biopsy and subsequent excisional biopsy specimens. Our results show good concordance, however, larger cohorts need to be studied to verify this finding. HER-2/neu status remains unchanged in the majority of cases when comparing pre-neoadjuvant and post-neoadjuvant chemotherapy-treated specimens.

Secretory carcinoma in the axilla: probable origin from axillary skin appendage glands in a young girl.

Invasive carcinoma in the axilla may arise from skin appendage glands or ectopic breast tissue or it may be a metastasis. Carcinomas of the skin adnexal glands and breast can be difficult to distinguish from each other as they often display the same patterns of growth. Tubular, cribriform, papillary, apocrine, mucinous, and adenoid cystic are histologic types of carcinoma seen in the breast and skin appendage glands. To our knowledge, secretory carcinoma, the most common form of mammary carcinoma in children, has not yet been described as a morphologic pattern of skin adnexal carcinoma, although we cannot exclude the possibility that such a case was reported with a different diagnosis. We report a case of a young girl with secretory carcinoma that seems to have arisen from skin appendage glands in the skin of the axilla in the absence of demonstrable ectopic breast tissue.

Molecular evidence for progression of microglandular adenosis (MGA) to invasive carcinoma.

Microglandular adenosis (MGA) is an uncommon, benign breast lesion that is characterized by a proliferation of small uniform, round glands lined by a single layer of epithelial cells around open lumina with haphazard infiltrative growth in fibrous and fatty breast tissue. Although MGA usually has an indolent course, there is morphologic evidence that MGA can be a precursor for the development of intraductal and invasive ductal carcinoma. To investigate the possibility of such a transition, we studied 17 cases of MGA or atypical MGA some of which had given rise to carcinoma in situ (CIS) and/or invasive ductal carcinoma using the reticulin stain, immunohistochemistry (S-100, p63, Ki-67, and p53), and a molecular approach involving microdissection and high-resolution comparative genomic hybridization and MYC chromogenic in situ hybridization. MGA and carcinomas arising from MGA were typically negative for p63 and positive for S-100 and Ki-67 and occasionally positive for p53. High-resolution comparative genomic hybridization identified recurrent gains and losses in MGA (2q+, 5q-, 8q+, and 14q-) and atypical MGA (1q+, 5q-, 8q+, 14q-, and 15q-). Some examples of MGA and carcinomas arising from MGA harbored few gross chromosomal abnormalities whereas others had considerable genetic instability with widespread aberrations affecting numerous chromosomal arms. Such widespread genetic changes, together with recurrent loss of 5q and gain of 8q were reminiscent of those reported specifically for basal-like, estrogen receptor-negative, and BRCA1-associated breast tumors. Concordant genetic alterations were identified between MGA, atypical MGA, and higher risk lesions (CIS and invasive ductal carcinoma) and in some cases there was an accumulation of genetic alterations as cases "progressed" from MGA to atypical MGA, CIS, and invasive ductal carcinoma. The molecular data suggests that MGA, atypical MGA, and carcinoma arising in MGA in a single case were clonally related. This result implicates MGA as a nonobligate precursor for the development of intraductal and invasive ductal carcinoma.

Sclerosing adenosis in sentinel axillary lymph nodes from a patient with invasive ductal carcinoma: an unusual variant of benign glandular inclusions.

Benign glandular inclusions in axillary lymph nodes are very rare events that have to be distinguished from metastatic carcinoma. We report an exceptional instance in which a patient with invasive ductal carcinoma had benign glandular inclusions in the form of sclerosing adenosis in 2 sentinel lymph nodes. The lymph nodes did not contain metastatic carcinoma. Immunohistochemical studies facilitated the correct diagnosis.

Bilateral presentation of fibroadenoma with digital fibroma-like inclusions in the male breast.

Fibroepithelial lesions are uncommon in the male breast. Most published reports describe phyllodes tumors. Fibroadenomas are very common in female breasts, but are exceedingly rare in the male breast. Gynecomastia and/or lobular differentiation have been known to coexist in both types of fibroepithelial lesions in men. We report an exceptional case of recurrent, bilateral fibroadenomas in a man under treatment for prostatic carcinoma. Intracytoplasmic inclusion bodies in stromal cells identical to those seen in infantile digital fibromatosis were identified in one fibroadenoma. To the best of our knowledge, this is the first reported case of bilaterally occurring fibroadenomas in the male breast, one of which also contained digital fibroma-like inclusions, a second unreported phenomenon.

Hemangiomas and angiosarcomas of the breast: diagnostic utility of cell cycle markers with emphasis on Ki-67.

CONTEXT: Vascular tumors comprise a minor subgroup of tumors arising in the breast and represent variants of hemangiomas and angiosarcomas. Diagnostic challenges may arise when differentiating hemangiomas from types I and II angiosarcomas. Ki-67 expression has been used as an adjunct to distinguish between benign and malignant lesions exhibiting histologic overlap at various anatomic sites. OBJECTIVE: To investigate the utility of Ki-67 and other cell cycle regulatory proteins (S-phase kinase-associated protein 2 [Skp2], p27, and cyclin D1) in the differential diagnosis of mammary vascular lesions. DESIGN: Thirty-four vascular tumors (21 hemangiomas and 13 angiosarcomas) of the breast were studied. The Ki-67 index and immunoreactivity for Skp2, p27, and cyclin D1 were determined in each case. Appropriate statistical methods were used. RESULTS: The mean value of Ki-67 index was statistically different when comparing hemangiomas and angiosarcomas (P < .001). Angiosarcomas were typically positive for Skp2, whereas hemangiomas were negative (P < .001). Sensitivity and specificity cutoffs for Ki-67 index to distinguish hemangiomas from angiosarcomas showed a candidate cutoff point of 175. The mean values of Ki-67 of low-grade angiosarcomas were significantly different from all hemangiomas (P < .001) and also different from the subset of atypical hemangiomas (P = .02). Sensitivity and specificity cutoffs for Ki-67 index to distinguish all hemangiomas from low-grade angiosarcomas showed a candidate cutoff point between 150 and 175. Among angiosarcomas, positivity for Ki-67 was inversely related to that of p27 but not to Skp2 or cyclin D1. This was also true among hemangiomas. CONCLUSIONS: Ki-67 index can be used as a diagnostic tool to distinguish between benign and malignant vascular lesions of the breast. This can be particularly helpful in cases of histologic overlap such as low-grade angiosarcoma and hemangioma.

Nephrogenic systemic fibrosis mimicking inflammatory breast carcinoma.

Nephrogenic systemic fibrosis, previously known as nephrogenic fibrosing dermopathy, is a newly recognized systemic fibrosing disorder primarily affecting patients with chronic renal failure. Patients with skin involvement often develop papules and plaques with peau d'orange surface changes. The lower extremities and trunk are most commonly affected. The most important histologic differential diagnosis is with scleromyxedema. To our knowledge, we report the first case of nephrogenic systemic fibrosis involving the breasts of a 61-year-old woman with end-stage renal disease, clinically mimicking inflammatory breast carcinoma. We propose that nephrogenic systemic fibrosis be considered in the differential diagnosis as a rare possibility when cutaneous changes in the breast suggest inflammatory breast carcinoma in a patient with renal failure.

Aberrant E-cadherin staining patterns in invasive mammary carcinoma.

BACKGROUND: E-cadherin, a cell surface protein involved in cell adhesion, is present in normal breast epithelium, benign breast lesions, and in breast carcinoma. Alterations in the gene CDH1 on chromosome 16q22 are associated with changes in E-cadherin protein expression and function. Inactivation of E-cadherin in lobular carcinomas and certain diffuse gastric carcinomas may play a role in the dispersed, discohesive "single cell" growth patterns seen in these tumors. The molecular "signature" of mammary lobular carcinomas is the loss of E-cadherin protein expression as evidenced by immunohistochemistry, whereas ductal carcinomas are typically E-cadherin positive. PATIENTS AND METHODS: We report on E-cadherin immunostaining patterns in five cases of invasive mammary carcinoma. RESULTS: These were five exceptional instances in which the E-cadherin immunophenotype did not correspond to the apparent histologic classification of the lesion. These cases which are exceedingly rare in our experience are the subject of this report. CONCLUSION: Findings such as those illustrated in this study occur in virtually all biologic phenomena and they do not invalidate the very high degree of correlation between the expression of E-cadherin and the classification of breast carcinomas as ductal or lobular type on the basis of conventional histologic criteria.

Mammary presentation of adult-type "juvenile" xanthogranuloma.

Juvenile xanthogranuloma (JXG) is a benign histiocytic disorder of infants and childhood. Approximately 15% of cases occur in adults. Adult JXG characteristically affect patients in their 20s and 30s; however, about 5% of patients are older than 60 years. Adult JXGs rarely regress spontaneously, and reports of concomitant extracutaneous lesions are rare. Herein, we report an exceptional case of adult xanthogranuloma in a 74-year-old woman who presented with ipsilateral breast masses and also found to have prior cutaneous lesions. This is the first reported case of cutaneous and extracutaneous adult JXG where the latter manifested in the breast as a spindle cell xanthogranuloma. Histologically, the lesion was composed predominantly of spindle cells with associated multinucleated giant cells and a chronic inflammatory cell infiltrate. Spindle cells were immunoreactive for various histiocytic markers and negative for cytokeratins, S-100, CD34, factor XIIIa, and CD1a. In the breast, the morphologic features of JXG evoked several entities in the differential diagnosis, including spindle cell metaplastic carcinoma, inflammatory pseudotumor, fibromatosis, myofibroblastoma, and phyllodes tumor. With the aid of immunohistochemical stains and appropriate clinical history, the correct diagnosis of extracutaneous adult JXG manifesting as a spindle cell xanthogranuloma can be made.

Prepubertal gynecomastia with lobular differentiation.

We report the case of a 19-month-old African American boy with a unilateral breast mass that developed shortly after birth. A sonogram confirmed the presence of a "fatty" breast mass. Microscopy of the subcutaneous mastectomy specimen revealed florid gynecomastia with marked ductal hyperplasia and focal lobular differentiation. This exceptional example of prepubertal gynecomastia with lobular differentiation has been previously reported only four times in the literature. We report a fifth patient, as well as the youngest, with this unusual histologic finding.

Observations on the pathologic diagnosis of selected unusual lesions in needle core biopsies of breast.

Pathologic diagnoses rendered on needle core biopsies of mammary lesions are primary determinants of further intervention. Such biopsies are being performed for an ever-widening range of diseases in an attempt to reliably and efficiently render a diagnosis. This review is intended to provide practical guidance to pathologists in dealing with selected unusual lesions encountered in these biopsies. Herein we offer advice on avoiding common diagnostic errors and on considering the relevant differential diagnosis of mucocele-like lesions, spindle-cell metaplastic carcinoma, adenomyoepithelioma, pseudoangiomatous stromal hyperplasia (PASH), collagenous spherulosis, myofibroblastoma, vascular lesions, and lymphoid infiltrates in the breast.

Recurrent breast carcinoma arising in a transverse rectus abdominis myocutaneous flap.

Reconstruction after mastectomy for breast carcinoma with implants or myocutaneous flaps is a widely used surgical technique. Recurrence of breast carcinoma after these procedures is uncommon. Most recurrences occur in the skin or scar site of the mastectomy and are readily detectable by physical examination. There are rare reported cases of recurrent carcinoma occurring within the flaps that are usually diagnosed with the aid of imaging and subsequent pathologic examination. In most cases, these recurrences represent invasive or in situ ductal carcinoma. We report an additional 2 cases of breast carcinoma recurring within the myocutaneous flap, both of which exhibited uncommon histologic features not previously reported.

Carcinoma arising from preexisting pregnancy-like and cystic hypersecretory hyperplasia lesions of the breast: a clinicopathologic study of 9 patients.

The intimate histologic relationship of pregnancy-like hyperplasia (PLH) and cystic hypersecretory hyperplasia (CHH) has been previously reported. However, none of these published cases contained coexisting carcinoma. In this study, we describe 9 additional cases of this lesion, all of which also revealed ductal carcinoma in situ (DCIS) as well as invasive carcinoma in 1 case. Hematoxylin and eosin-stained slides were reviewed for all cases. All were women who ranged in age from 35 to 49 years (mean 42.0 years; median 42.5 years). Reasons for surgical biopsy were calcifications in 6, breast mass in 2, and nipple discharge in 1. One patient with a mass also experienced nipple discharge. Three women initially underwent needle core biopsy and 6 had an excisional biopsy. Six women ultimately had mastectomies. Histologically, 5 had CHH merging with coexisting PLH. Atypia was seen in one or both components. All 9 cases contained DCIS. Two cases showed micropapillary DCIS, one of which appeared to arise from atypical PLH, while 4 of the 7 cases containing cystic hypersecretory DCIS appeared to arise from coexisting atypical CHH. Well-differentiated invasive carcinoma was identified in 1 case adjacent to cystic hypersecretory DCIS. Subsequent sentinel lymph node biopsy in this case revealed micrometastatic disease. Clinical follow-up was obtained in 9 patients and ranged from 10 to 69 months. All patients were free of disease at the time of last follow-up. Careful clinical follow-up is recommended for lesions that display atypia in PLH, CHH, or a histologically combined lesion. If these lesions are found on a needle core biopsy specimen, an excisional biopsy is recommended. DCIS, usually micropapillary or cystic hypersecretory types, and rarely invasive carcinoma can arise in this setting. Affected patients are typically younger than those with more common types of breast carcinoma.

Secondary tumors in mammary adenolipomas: a report of 2 unusual cases.

Two unusual examples of secondary tumors arising in adenolipomas were diagnosed in a 16-year-old girl and a 27-year-old woman, each of whom presented with asymmetric enlargement of the right breast. In both instances, a significant secondary lesion was associated with the adenolipoma. In the first case, a cyst appeared to have arisen in a fibroadenoma within the adenolipoma, which had apparently undergone infarction during a recent pregnancy and postpartum period. There was micropapillary duct epithelial hyperplasia of the cyst lining epithelium. In the second case, an adenofibroma with atypical lobular hyperplasia was present within the adenolipoma.

Benign heterotopic epithelial inclusions in axillary lymph nodes. Histological and immunohistochemical patterns.

Benign heterotopic epithelial inclusions in axillary lymph nodes are an extremely rare condition that must be differentiated from metastatic carcinoma. We describe 2 histologically different examples of benign epithelial inclusions in nonsentinel axillary lymph nodes, each with an unusual clinical presentation.

Ten-year follow-up of mammary carcinoma arising in microglandular adenosis treated with breast conservation.

adenosis is a rare proliferative lesion of the breast that may mimic carcinoma grossly and histologically. Although the lesion in its simplest form is benign, it can give rise to carcinoma, which may be found at the time of diagnosis in a minority of cases. Limited follow-up data have indicated no predisposition to develop subsequent carcinoma in patients treated with excisional biopsy for microglandular adenosis when carcinoma was not initially present. Breast conservation has rarely been used in patients with carcinoma arising in microglandular adenosis. We report here the unique 10-year follow-up of a woman who underwent breast conservation treatment for carcinoma that arose in microglandular adenosis.

Practical considerations in the pathologic diagnosis of needle core biopsies of breast.

The success of needle core biopsy procedures and the validity of pathologic diagnoses made on material from the procedures are key determinants in planning the optimal management of a wide variety of breast diseases. The most common diagnostic problems encountered in these biopsy specimens include lobular and ductal proliferations, sclerosing and papillary lesions, cellular fibroepithelial tumors, and minimally invasive or microinvasive carcinoma. This review provides practical guidance to help narrow the differential diagnosis of lesions on needle core biopsies and offers guidelines for the pathologic reporting of these specimens.