MUCI positive cutaneous metastasis with transepidermal elimination from a breast carcinoma.

Breast cancer is the most common cause of cutaneous metastases from internal malignancies. Generally, the neoplastic cells are located in the dermis or hypodermis, while a finding of transepidermal elimination on cutaneous metastases is exceptional. In this report we present a patient with perforating cutaneous metastases from breast cancer with mucin 1 expression. Cutaneous, bone, lung, and hepatic lesions were detected two years after the diagnosis of the primary tumor.

Introduction

Cutaneous metastases are defined as dermal or hypodermal neoplastic tissue that has no contiguity with the primary tumor. Skin metastases from internal neoplasms are an uncommon clinical finding with an overall incidence of 5.3% and the most common cause is breast cancer with an incidence of 23.9%.1

In general, skin metastases of breast cancer affect the dermis and histologically appear as malignant ductal epithelial cells in sheets, cords, glands, or are arranged in a diffuse infiltrate.2 The finding of transepidermal elimination on cutaneous metastases is exceptional and has only been reported in a few cases.3,4 Mehregan classified transepidermal elimination into three types, and the elimination of dermal tumor nests corresponds to type 3 which involves an active interaction between epidermis and dermal connective tissue.5 Although transepidermal elimination is the histological feature of the classical perforating disorders, it is also described in other cutaneous conditions and in tumors such as melanocytic nevus,6 eccrine poroma,7 malignant melanoma,8 pilomatricoma,9 and metastatic carcinoma.3,4 In this report we present a case of perforating cutaneous metastasis from breast cancer with mucin 1 (MUCI) expression.

Case report

In February 2010, a 48-year-old Argentine woman had undergone tumorectomy in her left breast with diagnosis of an invasive ductal carcinoma with low nuclear and histological differentiation grades; estrogen (ER) and progesterone (PR) receptors were negative and Her2/neu was positive. In September 2011, a mastectomy with immediate breast reconstruction was performed due to local tumor recurrence and the patient received systemic chemotherapy. In March 2012, she consulted because multiple skin nodules had appeared 3 months before. Lung, bone, and hepatic metastases were also detected.

Physical examination revealed an erythematous nodule that was 4 cm in diameter, polylobulated, and with ulcerated surface on the chest region. Multiple erythematous painful nodules from 5 mm to 2 cm were distributed on her chest and over the reconstructed breast (Figure 1).

Figure 1

An ulcerated metastatic nodule on the chest region is observed.

Note: Other metastatic lesions over the chest and reconstructed breast are also present.

A skin biopsy of one of the small lesions revealed skin metastasis from breast carcinoma (ER-PR-Her2/neu+). Histopathologically, tumor cell nests were seen in the dermis. By immunohistochemistry, MUCI expression was studied and a strong reaction was found with a mixed pattern at the plasma membrane and in the cytoplasm (Figure 2). Some epidermal cells at the Malpighi stratum also showed cytoplasmic positive staining. Tumor cells in the papillary dermis appeared to penetrate through the epidermis, suggesting transepidermal elimination. The epidermis showed no signals of ulceration (Figure 3), and in some malignant cells, a MUCI moderate reaction was found.

Figure 2

Microphotograph of immunoperoxidase staining of a metastatic cutaneous lesion of the patient.

Notes: Neoplastic cells in the dermis show a strong reaction with anti-mucin 1 monoclonal antibody (HMFG1 monoclonal antibody) with a mixed pattern.

Figure 3

Breast cancer cutaneous metastasis.

Notes: Tumoral malignant cell nests passing through the epidermis are observed. Mucin 1 expression is found at the epidermal borders and at the tumor cells. The pattern of expression is cytoplasmic.

Discussion

Cutaneous metastases from breast carcinoma usually appear months to years after the diagnosis and treatment of the primary malignancy.10,11 The most common localizations are in the chest wall and abdomen, but they can also be found in the scalp and extremities.10 The clinical presentations vary over a wide range of different patterns. Nodules are the most common manifestation (80%), followed by telangiectatic carcinoma (11%), erysipeloid carcinoma (3%), “en cuirasse” carcinoma (3%), alopecia neoplastica (2%), and a zosteriform type (0.8%).12 A diagnosis of cutaneous metastases is based on the clinical manifestations and the histopathologic study of the lesions. Histopathologically, cutaneous metastatic nodules show malignant cells in the dermis arranged in nests surrounded with desmoplastic stroma.2 In our patient, clinically, the skin lesions were nodules, but histologically, tumor cells were not restricted to dermal nests since they also showed perforation and transepidermal elimination.

Altered structures of the dermis and foreign material like neoplastic cells or external substances can be removed from the dermis by different mechanisms. Mehregan5 classified transepidermal elimination into three types which differ in the mechanism of removal. In type 1, nonmotile cells or small particles, which produce minimal or no dermal reaction, can be caught between keratinocytes and carried to the epidermis surface during corneocyte differentiation. In type 2, motile cells or microorganisms actively migrate into the epidermis and are subsequently eliminated with normal desquamation similar to type 1. Type 1 and type 2 are passive processes and have been termed “transmigration.” Type 3 involves epithelial–dermal interaction with active elimination of the foreign material through the epidermis.

The phenomenon of transepidermal elimination occurs in certain dermatoses in which altered structures of the dermis and foreign substances induce an inflammatory response causing the release of collagenases, elastases, and proteases. This inflammatory response generates alteration of the matrix with necrosis and perforation, and can also stimulate pseudoepitheliomatous hyperplasia of the epidermis and subsequent formation of transepidermal perforating canals with elimination of the dermal material.4,5

In a case reported by Ohnishi et al,3 breast cancer cutaneous metastases with transepidermal elimination presented with epidermotropism of neoplastic cells and pagetoid spread, features that our patient did not show. On the other hand, Abbas et al4 published a case of perforating cutaneous metastasis from an ovarian carcinoma which showed malignant cells in the dermis and hypodermis with areas of transepidermal elimination without epidermotropism. Immunohistochemical staining of the tumor cells was positive for MUCI, as we report in our case.

Almost all breast cancer cells express MUCI13–16 although benign breast neoplasms and normal breast cells express this mucin as well.17,18 It is considered that MUCI nonapical expression, as well as its overexpression, are the hallmarks of MUCI reactivity in breast cancer cells.19

Although contradictory results have been found between MUCI expression and survival in breast cancer patients, more than 70% of studies on tumor samples have found that the presence of any MUCI in the majority of tumor cells is associated with an improved prognosis.20 In relation to subcellular localization of MUCI, it has been observed that patients with tumors with the lineal (membrane) pattern have better survival.21 –23 Rahn et al20 reported that aberrantly localized MUCI in the tumor cell cytoplasm or nonapical membrane is associated with a worse prognosis. In a previous report, we found a significant decrease of MUCI apical expression frequency according to histological as well as nuclear grade increment. In this sense, it is known that histological grade is an accurate predictor of tumor behavior.24 The presence of apical membrane staining would indicate that MUCI targeting pathways are intact, and it has been associated with better prognosis that is possibly related to functional differentiation of the tumor.24 Rahn et al20 also found a significantly lower mean nuclear grade in tumors with high MUCI expression (50%). Coincidentally, in the primary tumor of our patient, a high nonapical MUCI expression along with low nuclear and differentiation grades was observed.

MUCI may alter the interaction between tumor cells and their environment, changing the composition. It has been observed that MUCI cytoplasmic tail interacts with β-catenin through a similar motif to that found in E-cadherin and inhibits the formation of an E-cadherin-β-catenin complex, reducing cell–cell adhesion.19

Similar to Abbas et al,4 it is possible that in our case, the contributing factors to transepidermal elimination could be related to a tumor–dermis interaction in which the epidermis does not seem to be implicated. The physical effect by the expanding tumor and the inflammatory response are factors to be considered. Also, the possibility of a vascular compromise resulting in necrosis and ulceration of the epidermis as well as MUCI expression may play a role.