Secretory Carcinoma of the Breast, a review

Secretory Carcinoma of the breast, a review after nine years

In 2011 Pooja Vasudev and Kazuya Onuma of McMaster University published a nice review of secretory breast cancer. The following post follows the review and adds some additional images from a case study of Arce and coworkers  (2005)  to make it easier to understand. Unlike the six year old female in which secretory carcinoma of the breast was discovered, this cancer was found in a 52 year old male. 

Clinical Features

age

In keeping with its discovery in a pediatric patient, secretory carcinoma occurs in both children and adults. An age range of 3-83 years with a median range of 25 years in females.  Secretory breast cancer is also seen in young males.

growth

Like other secretory carcinomas, those of the breast tend to be  slow-growing, and painless. The secretory breast tumor may or not be palpable and mobile. To be mobile suggests that it is not attached to surrounding tissue.

location

The most common location of secretory carcinoma of the breast appears to be the upper-outer quadrant with rare occurrence in the ectopic breast tissue of the axilla (arm pit). This comment is of interest in that the axilla is a common location for secretory carcinoma of the skin.

Hormonal involvement

When secretory carcinoma of the breast occurs in prepubertal males, it tends to present as a sub areolar mass and limited nipple discharge. The authors mentioned “characteristic hypersecretion” and the suggestion of possible  “hormonal pathogenesis” without the documentation of a hormonal abnormality. Nevertheless, in male patients, secretory carcinoma may develop in gynecomastia.

Sonography Features

The authors presented an ultrasound image of a secretory carcinoma. The tumor was termed hypoechoic meaning that it reflected the sound waves less than the surrounding tissue. A fluid filled  simple cyst reflects sound waves even less (Fig. 1).  Unlike their thyroid gland counterparts, breast secretory carcinomas tend to lack calcium deposits.   Calcium deposits in infiltrating ductal carcinoma may also show up in ultrasound. (Fig. 1).

Ultrasound image of a secretory carcinoma showing simple breast cyst, infiltrating ductal carcinoma and secretory carcinoma.

Figure 1 Contrasting image of different types of ultrasound images of breast lesions

Ultrasound images of secretory carcinoma of the breast may also resemble

  • fibroadenoma with a well-circumscribed, hypoechoic to isoechoic mass, sometimes with micro lobulations
  • medullary carcinoma
  • papillary carcinoma
  • mucinous carcinomas

Figure 2 shows some examples of these lesions.

Ultrasound images of secretory carcinoma of the breast may also resemble, fibroadenoma, medullary carcinoma, intracystic papillary carcinoma and mucinous carcinoma.

Figure 2 Common breast cancers that may appear similar to secretory carcinoma in ultrasound

Macroscopic Features

  • solitary, discrete, firm mass
  • variable “nodularity”
  • well defined margins, though can be infiltrative
  • cut surface  gray, white, yellow, or tan
  • maximum size range 0.5 – 16 cm, typical size range 1.5 – 3.0 cm.
  • Tumors tend to be larger in adults.

Arce and coworkers (2005) published a case of a 52 year old male who presented with a slow growing secretory carcinoma that was surgically removed a month before they saw him. The original tumor measured 5×7 cm. Residual tumor is shown in Figure 3, panel 1a from Arce 2005. The patient underwent a traditional cytotoxic chemotherapy with adjuvant 5-fluorouracil, adriamycin and cyclophosphamide. After 18 months the patient presented with metastases (Figure 3, Arce 2005 panel 3a).

Fig 1a shows an excised residual tumor and Fig 3a, shows ulcerated metastases at surgical scar and arm pit of patient.

Figure 3. Images from Arce (2005) that illustrate content in the Vasudev,& Onuma review. 1a An excised residual secretory carcinoma 3a Two metastases occurred at the surgical scar, one of which is ulcerated. Three more tumors metastasized to the arm pit

Microscopic Features

  • Microcystic, ductal, and solid patterns are observed. TRK kinases control  lobular growth of glands.
  • Hyalinized fibrous material is frequently observed centrally.
  • Peripheral papillary architecture is sometimes observed.
  • Tumor cells are polygonal, with vacuolated pale-pink or
    amphophilic cytoplasm.  This is a common feature of MASC.
  • Nuclei are small, round, and cytologically bland, with minimal atypia. In other secretory carcinomas, nuclei are said to be oval with atypical, single nucleoli.  (See Fig 3. arrows)
  • Mitotic activity is low.
  • Eosinophilic cytoplasm is also typical of MASC. Secretory carcinoma of the breast may resemble apocrine carcinoma, which can be a site of secretory carcinoma of the skin.
  • Eosinophilic, diastase-resistant, and positive periodic acid–Schiff (PAS-D) secretions are seen. These features are also present in  MASC. These secretions show variable reactivity to mucin stains. This topic is toughed upon in the history of MASC.
  • Comedonecrosis may be also found.
H&E and PAS-D stains pictures showing features of secretory carcinoma.

Figure 3 Some features of secretory carcinoma of the breast revealed by H&E and PAS-D staining. Right panels from Arce 2005.  Left and center panels from Vasudev and Onuma 2011

Immunohistochemical Features

  • Secretory Carcinoma of the breast is usually triple negative for the following:  ERBB2 (formerly HER2/neu) and the estrogen and progesterone receptors.
  • As in MASC, staining tends to be positive for cytokeratins 5/6, 14, and 17.
  • The basal cell receptor tyrosine kinase markers c-Kit (CD117) and epidermal growth factor receptor (EGFR) may be positive.
  • The intermediate filament protein vimentin  belongs in the spectrum of ‘‘basal-like carcinomas’’ markers that can be positive.
  • Like other secretory carcinomas, those of the breast are S100 positive.
  • Information on expression of α-lactalbumin in other secretory carcinomas is lacking.
  •  E-Cadherin was described as a marker for secretory carcinoma of the breast as would be expected for  any subtype of ductal carcinoma.

Molecular Diagnosis Then and Now

Arce and coworkers used a technique called fluorescence in situ hyridization (FISH) to detect chromosome rearrangements that bring the 5′ end of the ETV6 gene (red) and the 3′ end of the NTRK3 gene(green). In the early days of MASC, ETV6 break apart FISH probes, good H&E stains, and a battery of immunohistochemistry markers comprised an excellent battery of diagnostic tools. The pathologist looked for a separation of the green and red signals in ETV6 break apart FISH. A yellow signals an intact ETV6 gene. The caveat in use of ETV6 break apart FISH is that the ETV6 is often involved in other gene fusions, not just NTRK3. Arce and coworkers used a break apart FISH assay to detect the ETV6-NTRK3 gene fusion.

Arce and coworkers used a break apart FISH assay to detect the ETV6-NTRK3 gene fusion.

Figure 4. FISH results from Arce 2005

One of the problems with FISH is that it requires the use of a microscope with means to excite and detect the green and red fluorescent probes. Others have proposed using a well orchestrated series of IHC probes to detect MASC in smaller clinical laboratories.

A simpler 2-step  method uses (1) IHC with a pan-receptor tyrosine kinase antibody selects for tumors over expressing RTK. A second set of antibodies against kinase domains of protein products of cancer driving gene fusions. (2) Once the kinase domain has been identified, PCR is used to amplify kinase fusion protein transcripts followed by next generation sequencing.

TRKC, the actionable target of secretory carcinomas

The reason the oncologist may care about knowing the genomic alteration that drives the cancer is that the kinase domain of TrkC may be an “actionable target.” Specific inhibition of what drives the cancer is more targeted than the 5-fluorouracil, adriamycin and cyclophosphamide given to Arce and coworkers’ patient back in 2005. For more information, consult TRK tests. These tests are part of an open clinical trial testing a TRK treatment. Additional information on the Trk Phase I clinical trial results are also available on line. A patient friendly video on entrectinib and its inhibition of TRK fusions is available on line.

References

Arce C, Cortes-Padilla D, Huntsman DG, Miller MA, Dueñnas-Gonzalez A, Alvarado A, Pérez V, Gallardo-Rincón D, Lara-Medina F. (2005) Secretory carcinoma of the breast containing the ETV6-NTRK3 fusion gene in a male: case report and review of the literature. World J Surg Oncol. 3:35. PubMed

Vasudev P, Onuma K. (2011) Secretory breast carcinoma: unique, triple-negative carcinoma with a favorable prognosis and characteristic molecular expression. Arch Pathol Lab Med.135(12):1606-10. PubMed