Tumor attributes predicting cutaneous metastatic destiny: a report of two interesting cases.

Cutaneous metastases are the result of complex interaction between the tumor cells ("seed") and the host environment ("soil"). Metastases to the skin can be an early sign of internal malignancy or represent recurrence of the primary tumor and portends a poorer prognosis. Invasion and metastasis are the hallmarks of on cogenesis. Skin is the largest organ in the body, but the incidence of metastases is low. With advances in molecular biology, factors responsible for the initiation and perpetuation of metastatic tumor cells at distant sites are being elucidated. The concept of "pre-metastatic niche" and interaction between various chemokines has given a new outlook in understanding the organ specificity of metastatic tumor cells. We present two cases of cutaneous metastases with interesting clinical findings correlating with its biologic subtypes.

What was known?

Cutaneous metastases to the skin is rare with the multitude of clinical presentations reported so far

Tumors are known to spread via the blood, lymphatics, perineural and direct contiguity

Little is known about the factors that determine the metastatic destiny to the skin.

Introduction

Cutaneous metastases are relatively rare of all malignant metastatic disease with recorded frequency of 0.7-9% with a median of 5%.[12] Metastasis to the skin usually occurs as a secondary phenomenon to the known primary tumor. Metastatic cascade occurs through four discrete steps: Invasion, intravasation, survival in circulation and extravasation. Metastatic process is initiated by overcoming the selection pressure of tumor microenvironment by expression of transcription genes mediated through hypoxia inducible factor. Invasive migration of tumor cells occurs through acquisition of phenotypic switch from E-cadherin (epithelial marker) to N-cadherin (mesenchymal marker). Epithelial mesenchymal transition favors cell matrix interaction and the reverse mesenchymal to epithelial transition favors metastatic outgrowth.[3] Tissue trophism of disseminated tumor cells can be explained by the biological subtypes, protein expression of the tumor and the corresponding molecular alterations in the target organ. Though the skin is the largest organ, the incidence of cutaneous metastasis is a rare occurrence. Skin as a metastatic destiny to various tumors is challenging to explain. Nevertheless, there may be unique factors secreted by the primary tumor that prepares the “pre-metastatic niche” in the skin for its arrival and growth. Metastatic dormancy is a unique feature of breast and prostate carcinoma even after clearance of the primary tumor. Prometastatic (p38 MAPK) and antimetastatic (RAS-MEK-ERK) mechanisms maintains the cellular quiescence at G0/G1 phase for a longer period.

Cutaneous metastases have varied presentations mimicking many other skin disorders. Immunohistochemical analysis assists to uncover the veil of mystery regarding its origin. We, hereby, discuss two patients with cutaneous metastases from the most common (breast) and the least common site (prostate) with interesting clinical features in correlation with its biologic subtypes.

Case Reports

Case 1

A 55-year-old female was referred to us with complaints of asymptomatic nodule over the right side of forehead for 3 months duration. She has been diagnosed with mixed duct/lobular carcinoma breast and operated for the same 10 years ago followed by 6 cycles of chemotherapy with carboplatin and paclitaxel. Since then, she had been disease free and now has developed metastases of the long bones, vertebrae and the liver. Dermatological examination showed a single erythematous, non-tender, firm to hard nodule with hyperpigmentation and scaling on the surface, located on the right temporal region [Figure 1]. Regional lymph nodes were not palpable. Excisional skin biopsy showed poorly differentiated carcinoma with sheets of atypical cells with moderate eosinophilic cytoplasm and pleomorphic vesicular nucleus in the dermis consistent with metastatic deposits [Figure 2]. Immunohistochemistry confirmed the origin to be from the breast (estrogen receptor [ER] +; progesterone receptor [PR] +; gross cystic disease fluid protein [GCDFP] 15+; TIF, life cycle assessment S100 - negative) [Figure 3].

Figure 1

Solitary nodule on the temporal region

Figure 2

Poorly differentiated carcinoma with sheets of atypical cells with moderate eosinophilic cytoplasm (H and E, ×100) and pleomorphic vesicular nucleus in the dermis consistent with metastatic deposits (H and E, ×400)

Figure 3

Immunohistochemistry consistent with breast metastasis

Case 2

A 75-year-old male with adenocarcinoma prostate who was treated 5 years ago was now referred to us with multiple skin nodules over the left thigh of 6 months duration. On examination, he had multiple hard nodules along with an ill-defined erythematous indurated plaque of size 8 × 6 cm over the right thigh [Figure 4]. The nodule along with the sclerodermatous skin was excised and subjected to histopathological examination, which showed infiltration of malignant cells in the dermis with tumor cells arranged in nests and cords in a desmoplastic stroma [Figure 5]. Immunohistochemistry panel confirmed the metastasis from prostate (cytokeratin+; prostate specific antigen+; PSAP + ER−) [Figure 6].

Figure 4

Multiple nodules with surrounding sclerotic skin

Figure 5

Histology showing infiltration of malignant cells in the dermis with tumor cells (H and E,×100) arranged in nests and cords in a desmoplastic stroma (H and E,×400)

Figure 6

Immunohistochemistry consistent with prostate metastasis

Discussion

Cutaneous metastases may precede the internal malignancy (“precocious” mets) or occur simultaneously with the primary tumor (“synchronous” mets). Stephen Paget put forward the “seed and soil theory” wherein the tumor cells (“seed”) have high affinity for the chemokine milieu of the tissue (“soil”).[4] Recent evidence explains the organ specificity of metastatic tumor cells by the formation of “pre-metastatic niche” since the inception of the primary tumor. Pre-metastatic niche is formed when the hematopoietic progenitor cells are recruited by the secreted growth factors of the primary tumor. VEGFR1, c-kit, CD133, CD134 expression increases angiogenesis at pre-metastatic sites.[5] Specific chemokines like CCR10 is expressed in melanoma cells, which interact with CCL27 in the normal keratinocytes favors skin metastases. CXCR4 expressed by the breast cancer cells is attracted to the secondary metastatic organ expressing its ligand CXCL12, which is absent in skin. Little is known about the chemokines and genes expressed by the visceral malignancies that metastasize to the skin.

Cutaneous deposits from the breast are common with the multitude of clinical presentations. Anterior chest is the most common site, in addition, head, neck and extremities are also potential sites of metastases of breast carcinoma.[67] In our first patient with carcinoma breast, the metastasis of the skin and skeletal system occurred concurrently a decade after she was operated. Metachronous metastases occurs with an interval of more than 5 years in about 7% of cases.[3] Circulating tumor cells are found to be detected as long as 22 years after mastectomy. In our case, the lesion was located in the right temporal region, which is distant from the vicinity of the primary tumor. Lobular carcinoma with ER/PR positivity has a higher propensity to metastasize to distant sites. High vascularity of head and neck region may provide a favorable angiogenic environment to the growing tumor. Several proteins have been identified in breast tumor, which determine the first site of metastasis. Absence of E-cadherin and SNAI2 is associated with first metastasis in the skin or subcutaneous tissue.[8] Many E-cadherin negative tumors have lobular morphology. Breast cancer patients with mutations of BRCA1 and BRCA2 have high-risk of developing second new primary carcinomas of ovary, fallopian tubes and peritoneum. Positivity for Estrogen, progesterone and HER2 receptors, GCDFP concordant with primary is highly suggestive of cutaneous metastatic breast primary rather than the occurrence of new second malignancy.

Cutaneous and subcutaneous deposits from cancer prostate is a rare (<1%) occurrence in the late stage of the disease with poor prognosis.[7] They occur as papules, nodules, pyoderma such as lesions and extramammary Paget's disease. In the above described patient with adenocarcinoma prostrate, multiple hard nodules were located in the thigh region along with indurated plaques.[910] Sclerodermatous lesions are rare and occur in cancers with desmoplastic stroma as in our patient.[11]

In our second case, the ER positivity was found to be negative. Estrogen action is mediated through the two receptors (ER alpha and beta [ER a and b]), which are expressed distinctly with transcriptional differences in various tissues. ER a is found in endothelium, breast, ovary and hypothalamus while ER b is documented in kidney, brain, skeleton, prostate and endothelial cells. Prostate tissue is found to express ER b in the epithelial cells and ER a in the stromal and basal cells.[1213] There are reports of intense ER staining in malignant prostate according to the grade of adenocarcinoma.[14] However, the ER expression in normal and malignant prostate is still unclear. Further studies are necessary to elucidate the proclivity of ER positive tumors homing to the skin.

Cutaneous metastasis is rare in clinical practice. Skin lesions in patients with known primary irrespective of disease free interval even at distant sites should raise a high suspicion of metastasis. Rarely, skin lesions can be the early sign of recurrence of the primary tumor emphasizing the importance to recognize them early for prompt treatment and better survival. Research into the biological subtypes, gene expression and chemokines involved in predicting the metastatic destination will guide us to formulate targeted drug therapies. With increasing incidence of various carcinomas world-wide, the unique clinical behavior of most tumors metastasizing to the skin remains enigmatic and continues to surprise the clinicians.

What is new?

Factors determining the metastatic destiny to the skin can be explained by the concept of pre-metastatic niche and chemokines expressed in the metastatic sites

Predilection of estrogen receptor positive tumors metastasizing to the skin requires further studies in large no of cases

The knowledge of molecular biology and tumor behavior would help us find the target molecule for drug therapy.