Breast Carcinoma with Melanotic Features

Sometimes breast cancer tumors are found to contain elements of melanocytes within them. This is somewhat unusual because melanocytes are cells found primarily in the skin, and are responsible for the production of the 'dark pigment' melanin (the darker skin color from a 'tan'). When they are found within the same lesion as carcinoma cells (carcinoma is derived from epithelial cells), the tumor might be referred to as 'heterogenous' breast cancer. So, essentially a breast carcinoma with melanotic features is a combination of ductal carcinoma and melanoma.

 

 

Heterogenous breast malignancies are very rare, and there is always some interpretation involved as to whether or not the heterogenous (foreign or not typically 'local') elements were part of the breast cancer to begin with (primary), or whether they arrived at the site due to metastasis from a cancer somewhere else. Another possibility is that the presence of melanotic features within breast carcinoma (evidence of melanocytes) indicates that the breast cancer is highly aggressive and has begun to metastize. That was the working hypothesis among breast cancer specialists until fairly recently. New evidence now suggests that melanocytes are actually native to certain kinds of malignant breast carcinoma cells, and do not indicate anything out of the ordinary or 'extra-aggressiveness' of the cancer. In fact, melanocytic elements are now generally thought to be a completely benign and incidental feature of the primary breast carcinoma.

What is 'melanoma'?

Melanoma is a malignant tumor of melanocytes, so essentially a melanoma is a skin cancer tumor. Melanocytes typically comprise between 5% to 10% of the cells in the basal layer of the epidermis, and there are usually between 1000 and 2000 melanocytes per square millimeter of skin. In addition to the skin, melanocytes are are also found in the bowel and the eye. Melanoma is actually one of the less common types of skin cancer, but causes the majority of skin cancer related deaths.(about 75%). One might occassionaly see the term 'nevi' or nevus, ('nevi' is plural), and these refer to 'moles'. A malignant melanoma is typically something which evolves from one of these nevi. Now, it is quite common to develop nevi on the skin of the breast, and some breast nevi cells have been known to have quite atypical features. However, atpyical features of breast nevi have not been shown to correspond to any suspicious biolical behavior and pose no increased risk for melanoma on the breast.

Malignant skin melanomas frequently mestastize to the breast, but a primary breast carcinoma with melanotic features is something completely different.

An important distinction must be made between primary breast carcinoma with melanotic features (the main subject of this page) and breast cancers which develop as a result of metastasis from a primary cancer somewhere else. It is estimated that between 2.7-5.1 % of breast malignancies are due to metastasis, and almost 80% of metastatic breast cancers are from skin cancers. The most likely cancers to metastize to the breast are malignant melanoma, and lung cancer.

Metastastic tumors are slightly more likely in younger women

A metastatic breast tumor will usually appear as a painless, solitary, well circumscribed mass in a breast regions rich in glandular tissue. Most of the time, metastatic breast tumors will occur in the upper outer quadrant, which has the most abundtant glandular tissue and also the best blood supply. Younger women are a little bit more likely to develop a metastatic breast cancer tumor because they have increased vascularity compared to older women. A metastatic breast tumor will tend to appear mammographically as a discrete round shadow without spiculation, quite similar in appearance to cinrcumscribed primary breast caricnomas such as papillary and mucinous breast carcinoma. Unforunately, with a metastitic breast carcinoma, most patients do succumb to the illness within one year, with an average survival time of about 11 months.

There are rare instance of malignant melanoma primary to the breast

Malignant skin melanomas characteristically disseminate widely, and metastize to the breast only infrequently (about 3%-5% of the time.) A primary melanoma of the breast is even rarer, but they can arise in the in the glandular tissue of the breast. Sometimes one may find a primary malignant melanoma of the breast arising in the skin of the breast, but without actually developing a cutaneous lesion.

 

 

Cause of melanocytic proliferation in breast tumors a matter of speculation only

No one knows exactly why melanotic pigmentation sometimes occurs within breast carcinomas. Generally, melanocytic colonization and pigmentation in breast tumors occurs if the dermal-epidermal junction is involved by the tumor. ( The breast cancer tumor is developing right at the 'edge' of the skin). Perhaps the melanocytes 'migrate' into the breast tumor from the skin. Other theories suggest that the increased proliferation of melanycytes characteristic of breast carcinoma with melanotic features is actually somehow induced by elements already present within the tumor itself.

 

Melanocyte Growth Factor (MeGF) in breast cancer cells might stimulate the proliferation of melanocytes in breast tumors

Breast cancer cells have sometimes been known to present with transforming growth factors and epidermal growth factor receptors. It is believed that these factors are capable of inducing the proliferation of both normal and neoplastic cells in breast carcinomas. In recent lab experiments, melanocytes have also been shown to proliferate when exposed to an enriched culture medium containing melanocyte growth factor (MeGF, a type of hormone). So, it is hypothesized that it might be the presence of tranforming growth factor in breast cancer cells which would stimulate the growth and heterogenous presence of melanotic features in some breast carcinomas.

 

 

Melanocytic elements within breast carcinoma are observed microscopically, through specific stains.

Microscopically, breast cancer tumors with melanotic features might show abundant deposits of melanin pigment in macrophages and groups of melanocytes among the breast cancer cells. Pigmentation is usually only observed microscopically, but occassionally breast cancer melanosis may be observed clinically. In that situation, one must be careful not to assume that the lesion is a clinically malignant melanoma . Different elements of heterogenous breast cancers such as breast carcinoma with melanotic features will test positive for different stains. The 'carcinoma' element in breast carcinoma with melanotic features might typically test positive for epithelial membrane antigen and CA19-9, while the melanoma component might test positive for for HMB45 and vimentin, and other stains.

New research suggests that melanocytic elements of breast carcinomas might even evolve from genetic alterations of the same clone cells.

Among recent genetic discoveries in the area of breast cancer is the realization that breast cancer cells are not bound by the same 'programmed' cell differentiation course as is the case for normal cells. That might seem to be an obvious conclusion, but, it has been traditionally and somewhat logically believed that if malignant breast cancer cells derive from either mature or immature epithelial cells, then all neoplastic cancer cells which develop would still be within the epithelial cell line. If a non-epithelial cancer cell develops at the same site, it was assumed that it must have migrated to the area from somewhere else, or was perhaps growing adjacent all along. New evidence, however, suggests that some breast cancer cells are not bound to follow the same cell-line, but may in fact differentiate in different cell lines, for example, as melanocytes. This might be a reasonable explanation for a heterogenous breast tumor such as breast cancer with melanotic features. Furthermore, if this is in fact the case, it presents a significant realization that melanocytic elements within breast carcinomas are no more aggressive and worrysome than breast carcinomas without melanocytic features. (Since they are native to the site and have not metastized to the area, the cancer 'staging' is reduced somewhat from the traditional view of heterogenous breast carcinomas with melanoma.)

MDA-MD-435 breast cancer cells prove melanocytic differentiation of primary breast cancer cells is possible, even common.

Recent reports in the area of breast cancer genetics have demonstrated a a wide spectrum of expression of melanocyte-related genes within histologically confirmed breast cancer tumors. In fact, it would appear that aberrant co-expression of multi-lineage markers is actually quite common in breast cancer. By analyzing tumor cells for certain 'molecular signatures' via gene-expression-profiling, one can determine the tissue origin of a given breast cancer cell line. The same genetic alterations with loss of heterozygosity has been noted in both the melanoma and invasive-ductal elements of breast tumors, suggesting that they might have arisen from the same clone-source via multiple genetic alterations during the early stages of breast cancer development (ductal carcinoma in situ).

MDA-MD-435 was discovered in 1976

MDA-MB-435, which is a member of the NCI-DTP panel of 60 human tumor cell lines, has been used for many years as a model of metastatic human breast cancer. (It was discovered in 1976). It has now been shown that the pattern of gene expression for MDA-MB-435 more closely resembled that of melanoma cell lines than traditional breast carcinoma lines. Through analysis, MDA-MB-435 cells have been shown to express melanocyte proteins tyrosinase and melan-A, and RXRG, TYR, ACP5, and DCP, and all of these genes are commonly derived from a melanoma cell line. It has been concluded that the presence of this genetic profile within a common breast cancer cell could not be the result of metastasis, but is actually the product of cell differentiation native to the primary breast cancer. Follow-up studies about the potnetial genetic origins of cancer cells in heterogenous breast cancer tumors have reinforced the notion of abherrant genetic mutation into other cell lines.

 

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