Cancer of the Skin

Before mammary analog of secretory carcinoma was noted in salivary glands  and shown to carry the ETV6-NTRK3 rearrangement (Skalova 2010), a breast like secretory carcinoma was noted in skin adrexal (appendages) in absence of evidence of ectopic breast tissue (Brandt 2009).

An overview of cutaneous  adrexal glands

An adrexal structure is an appendage. Ovaries are an appendage of the uterus. Skin is composed of keratinocytes, melanocytes and Langerhan immune cells. Sweat and sebaceous glands are considered appendages o those barrier cells.

  • Sebaceous glands secrete oily substances.
  • Apocrine cells in sweat glands secrete material into the lumen by pinching off pieces of membrane.
  • Eccrine (also merocrine) cells in  sweat glands secrete substances by exocytosis.

All three glands have been shown to be sites of malignant transformation, e.g. apocrine gland  carcinomas.

Pictures showing Sebaceous glands, Apocrine cells in sweat glands and Eccrine (also merocrine) cells in sweat glands.

Figure 1 glands of the skin

One of the central premises of ETV6-NTRK3 driven secretory cancers is that that the expression of the kinase domain of TrkC is driven by the active promoter of the TEL transcription factor. The other premise is that the N-terminus of TEL drives dimerization of the TrkC kinase domain in the absence of ligand. Protein Atlas is a nice source of high resolution immunohistochemistry images of antibodies the parent company sells.

Low and high resolution image of TEL expression in normal skin of 53 year old female.

Figure 2. TEL (ETV6 gene product) expression in skin. a. an example of a sebaceous gland b. low magnification image of TEL in normal skin of a 53 year old female c. higher magnification of what appears to be TEL in the nuclei of a sebaceous gland.

IHC low and high resolution image of normal skin from an 86 year old male.

Figure 3 Low and high resolution image of normal skin from an 86 year old male.

More IHC Low and high resolution image of normal skin from an 56 year old female.

Figure 4 More images of TEL in the normal skin of a 56 year old female

Protein Altas lists the TEL expression in keratinocytes as being moderate and melanocytes and Langerhan cells as low.  Glands are not acknowledged. In summary, TEL expression is strong in adrexal glands of the skin but not keratinocytes themselves.    

Two cases of ETV6 rearrangements found in adrexal glands of the of the axilla (arm pit)

In September of 2016 Huang ad coworkers published a report of a 22 year old female with a cutaneous neoplasm in the axilla. The histology of this tumor resembled secretory carinoma of the breast and salivary glands. The ETV6-NTRK3 fusion gene transcript was amplified by  reverse transcriptase PCR and sequenced.

In November of  2016 Michael Chang and coworkers reported a case of a 57 year old male with an apparently slow growing cutaneous “nodule” with the following characteristics:

  • 6 cm, in the dermis and superficial subcutis
  • gray-tan
  • lobulated areas with cystic components
  • aggregation of tubular and microcystic structures
  • fibrotic, hyalinized stroma
  • ‘colloid-like’ eosinophilic secretions
  • eosinophilic to vacuolated cytoplasm
  • nuclei with occasional single nucleoli

The Chang group used ETV6 break point FISH that proved positive for an ETV6 gene break. They may have been prompted by

    • a few recent publications of cutaneous tumors that resembled MASC but stopped short of proving the ETV6-NTRK3 gene fusion
  • a preliminary abstract from the Bishop group

The Bishop group expands on an abstract

Bishop and coworkers (2017) followed up on an abstract by presenting six cases of cutaneous MASC.  Four of these six tumors involved skin of the arm pits, a rich source of apocrine glands.  One involved skin of the cheek, a rich source of sebaceous glands. The  image in figure 5 maps the distribution of various glands in the skin.  While the neck is missing in this image, many would consider the ventral (back) of the neck a rich source of sweat glands.

Diagram showing secretory glands in human skin with an inset table showing clinical characteristics of cutaneous MASCs.

Figure 5 secretory glands in human skin and secretory carcinoma of the skin patients, Bishop 2017 Table 1

These adrexal gland associated tumors had their epicenter in the superficial dermis. The images in Figure 6 are from Figure 1 of Bishop (2017). The images shown are  representative of the six cases. Some zoom in images are shown suggesting the adrexal glands might be sebaceous.

IHC images of images representative of the six carcinoma cases. The bottom lower slides are zoomed images of upper images.

Figure 6   Top panels from Fig 1 Bishop 2017.  A. One of six cutaneous secretory carcinomas  B. associated with adrexal structures Bottom panels are zoomed in  from top panel B

Bishop and coworkers (2017) proceeded with three common immunohistochemical markers of MASC (S100, mammaglobin, and Stat5a) as well as ETV6 break apart FISH

IHC images with markers of MASC (S100, mammaglobin, and Stat5a) as well as ETV6 break apart FISH.

Figure 7 demonstration of  MASC like features in adrexal glands of the skin

Stat5a is a transcription factor. S100 is observed in the nucleus in salivary gland MASC as well.  Even though these tumors did not appear to arise from ectopic breast tissue, staining for mammaglobin is very intense. The levels were manipulated to elucidate differences in staining. Some mammaglobin appears to be in the secretions.

Zoomed IHC images from Fig 5 and Fig 6 showing oval nuclei, nuclear S100 and mammaglobin respectively.

Figure 8. Zoom ins on images in Figure 5, oval nuclei and Figure 6 nuclear S100, and membrane and secreted mammaglobin

Important Information

In the salivary gland, acinic cell carcinoma is often reclassified as MASC, now known as secretory carcinoma. We have reviewed acinic cell carcinoma and other salivary gland carcinomas that are often reclassified as secretory carcinoma. We can only speculate that a similar trend may follow cutaneous glandular carcinomas. An oncologist can visit Trk tests if a patient is suspected of having a cutaneous secretory carcinoma. A patient may learn about secretory sweat gland treatment options at the same site describing secretory cancer treatment options for the salivary glands. If you are a patient or physician and would like to watch an entertaining  TRK inhibitor video, follow this link.

References

Bishop JA, Taube JM, Su A, Binder SW, Kazakov DV, Michal M, Westra WH. (2017) Secretory Carcinoma of the Skin Harboring ETV6 Gene Fusions: A Cutaneous Analogue to Secretory Carcinomas of the Breast and Salivary Glands. Am J Surg Pathol. 41(1):62-66. PubMed

Brandt SM, Swistel AJ, Rosen PP. (2009) Secretory carcinoma in the axilla: probable origin from axillary skin appendage glands in a young girl. Am J Surg Pathol. 2009 Jun;33(6):950-3. PubMed

Chang MD, Arthur AK, García JJ, Sukov WR, Shon W. (2016) ETV6 rearrangement in a case of mammary analogue secretory carcinoma of the skin. J Cutan Pathol. 43(11):1045-1049. PubMed

Huang S, Liu Y, Su J, Liu J, Guo X, Mei F, Zheng J, Liao S. (2016) “Secretory” Carcinoma of the Skin Mimicking Secretory Carcinoma of the Breast: Case Report and Literature Review. Am J Dermatopathol. 38(9):698-703. PubMed