Flat epithelial atypia (DIN 1a, atypical columnar change): an underdiagnosed entity very frequently coexisting with lobular neoplasia.

AIMS: Flat epithelial atypia of the breast [FEA; synonyms: ductal intraepithelial neoplasia (DIN) 1a, atypical columnar change] is increasingly recognized by pathologists and shows distinct genetic alterations. The aim of this study was to determine its biological significance as an incidental finding in breast biopsy specimens. METHODS AND RESULTS: On the assumption that both FEA and lobular neoplasia (LN) derive from progenitor cells in the terminal ductal-lobular unit, we investigated the association between FEA and LN semiquantitatively in 111 excisional breast biopsy specimens which contained LN, but did not contain ductal carcinoma in situ (DCIS) or invasive carcinoma. Ninety-six cases (86.5%) revealed coexistence of LN and FEA (P < 0001). The distribution of LN was focal in 41 cases (37%), multifocal in 50 (45%) and extensive in 20 (18%) cases. FEA was identified as focal, multifocal and extensive in 29 (26%), 42 (38%) and 25 (23%) cases, respectively. Distribution patterns of LN and FEA showed no statistically significant correlation. CONCLUSIONS: Due to the striking association between LN and FEA in our material, one may speculate that these two lesions are biologically related and that FEA is an early but non-obligate precursor lesion similar to LN. Based on this assumption, regular clinical and mammographic follow-up of patients with FEA would be prudent.

Mammary and extramammary Paget's disease: an immunohistochemical study of 83 cases.

AIM: Mammary Paget's disease (MPD) and extramammary Paget's disease (EMPD) are rare neoplasms. The aim of this study was, by the use of immunohistochemistry, to derive further information about the cell(s) of origin, find a diagnostically useful immunohistochemical panel and investigate candidates for possible targeted therapy. MATERIAL AND RESULTS: Sixty MPD and 23 EMPD cases were studied using antibodies to cytokeratin (CK) 34betaE12, CK8/18, CK7, CK5/6, CK20, gross cyctic disease fluid protein (GCDFP)-15, MUC1-8, epidermal growth factor receptor (EGFR) (HER1), HER3 and HER4. In all MPD cases CK7 and MUC1 were positive. CK8/18 was positive in 59/60 cases. GCDFP-15, MUC2, MUC3, MUC4, MUC7, MUC8 were positive in 29/60, 3/60, 35/47, 4/40, 3/43 and 2/45 cases, respectively. In all EMPD cases CK8/18 and CK7 were positive. MUC1, GCDFP-15, MUC5AC, MUC3, MUC8 and CK20 were positive in 22/23, 19/23, 8/19, 3/19, 1/19 and 3/23 cases, respectively. With the remaining antibodies no immunoreactivity was observed. CONCLUSION: MUC1 and low-molecular-weight CKs in conjunction with immunonegativity for high-molecular-weight CKs are the most diagnostically useful markers. MPD is caused by the epidermotropic spread of underlying tumour cells, whereas EMPD probably arises from intraepithelial cells of sweat gland origin. Targeted therapy with antibodies against EGFR (HER1), HER3 or HER4 is unlikely to prove of clinical value.

Remarkably high frequency of EGFR expression in breast carcinomas with squamous differentiation.

The human epidermal growth factor receptor (EGFR) is reportedly overexpressed in 15-20% of breast carcinomas. EGFR overexpression is associated with reduced survival and is inversely correlated with expression of estrogen receptor (ER). This study assessed EGFR expression in breast carcinomas with squamous differentiation. The immunohistochemical (IHC) expression of EGFR was evaluated in 39 breast carcinomas with squamous differentiation (30 pure squamous, 6 adenosquamous, 3 carcinosarcomas) by use of the pharmDx assay (clone 2-18C9, DakoCytomation). Cases were considered positive if at least 10% of the cells showed 1+ positivity in the squamous component. Squamous differentiation was confirmed with IHC for CK5-6 (clone D5/16B4, DakoCytomation). ER, PR, and HER2 status as well as clinical information regarding treatment and outcome were correlated. As a control, a tissue microarray comprising 280 lymph node positive breast carcinomas was evaluated with the same EGFR assay. The 39 patients ranged in age from 33 to 77 years (mean 52). The tumors measured 1.3-30 cm (mean 4.8). Sentinel or full axillary lymph node dissection was performed in 28 patients. Fourteen patients had positive lymph nodes. At the time of initial diagnosis, 3 patients had distant metastasis. Follow-up was available for 16 patients (mean 45 months). Disease-free survival at 3 years was 70%. Among the 39 tumors 87% (34) were positive for EGFR (p<0.0001). Sixty-nine percent (27 of 39) showed >50% 2+ EGFR staining. EGFR-positive tumor cells (showing squamous morphology) were also found in 1 bone, 1 lung, and 8 of 11 lymph node metastases available for evaluation. All 11 lymph nodes showed squamous differentiation. All but 1 of the EGFR+ tumors examined were ER and PR negative. Six EGFR-positive tumors were HER2 positive. No statistically significant differences in HER2 status, size, lymph node status and disease-free survival were observed between EGFR+ and EGFR- cases, but the number of EGFR-negative tumors was quite small. Nine of 280 (3%) of lymph node-positive invasive carcinomas on the tissue microarray were EGFR+; review of the initial diagnostic slides failed to reveal squamous features in all but 1 of the 9 EGFR+ tumors. Breast carcinomas with squamous differentiation are a distinct subgroup of breast tumors with a very high frequency of EGFR positivity. Breast carcinomas of this type would be ideal candidates for a trial with EGFR inhibitors.

Metaplastic breast carcinomas are negative for Her-2 but frequently express EGFR (Her-1): potential relevance to adjuvant treatment with EGFR tyrosine kinase inhibitors?

BACKGROUND: Metaplastic carcinomas (MCs) of the breast rarely express steroid receptors and Her-2, which minimises the options for adjuvant treatment in patients with advanced disease. AIMS: To investigate the possible eligibility of patients with MCs for epidermal growth factor receptor (EGFR) targeted treatment. METHODS: Immunohistochemical assessment of the expression of steroid receptors and four members of the EGFR/Her family (EGFR/Her-1-4) in 20 MCs (eight with heterologous elements, seven spindle cell MCs, four carcinosarcomas, and one matrix producing carcinoma). Fourteen of the 20 MCs were positive for EGFR (Her-1). Among these cases, 1+, 2+, and 3+ reactivity were seen in two, four, and eight cases, respectively. Her-2 was only present in one MC with 1+ reactivity. Her-3 (1+ reactivity), Her-4 (2+ reactivity), and the androgen receptor (2+ reactivity) were also expressed by one tumour. Oestrogen and progesterone receptors (3+ reactivity each) were detected in the epithelial component only of two carcinosarcoma-type MCs. CONCLUSIONS: MCs express EGFR considerably more frequently than the types of breast carcinomas that have been investigated previously. Although molecular analyses for possible genetic alterations in the EGFR might be required, these results suggest that women suffering from this aggressive form of breast carcinoma might benefit from treatment with protein kinase inhibitors, such as gefitinib.

Malignant transformation within benign adnexal skin tumours.

AIMS: To report five malignant trichogenic tumours arising in longstanding, previously benign adnexal neoplasms through malignant transformation. Malignant trichogenic adnexal tumours are extremely rare neoplasms. METHODS AND RESULTS: The patients were between 55 years and 79 years of age. Three of the tumours were located on the arms, two on the face. Three of our patients had a history of chronic lymphocytic leukaemia, one patient had a history of colonic adenocarcinoma. The duration of the tumour nodules was reported as between 20 and 40 years before sudden changes occurred. These changes included rapid growth, pain, itching, ulceration and bleeding. Histologically, all tumours were well circumscribed and encapsulated. There was a residual benign tumour component and morphological signs such as bone formation, dystrophic calcification and sclerosis suggesting long duration of the lesions. All patients except for one, who refused further clinical investigation due to her advanced age of 79 years, had an underlying systemic malignancy. CONCLUSIONS: The growth stimulus in these benign adnexal neoplasms resulting in malignant transformation may be attributed to the acquisition of additional genetic events or to immunosuppression due to an underlying neoplastic disease. Therefore, patients with systemic diseases or malignancy should be carefully examined and followed for sudden changes in pre-existing benign cutaneous tumours.