Secretory carcinoma of the breast, commonly exhibits the features of low grade, triple negative breast carcinoma- A Case report with updated review of literature

ABSTRACT

Secretory carcinoma of the breast (SBC) is a rare breast neoplasm. Most of the patients present at an early stage with a relatively indolent clinical course. Lymph node and distant metastasis are also very infrequent. The histomorphological features of the secretory breast carcinoma are quite characteristic. Predominantly three histological patterns, solid, microcystic, and tubular, have been noted with copious amounts of intra and extracellular secretory material. Most commonly, no positivity for estrogen receptor (ER), progesterone receptor (PR) and ERBB2(HER2/neu) is observed in SBCs. As SBC can occasionally be hormone receptor-positive, they should not be categorized in the triple-negative breast carcinoma (TNBC) group in general. A very characteristic genetic translocation t (12;15) has been noted in this rare tumor, resulting in a fusion between ETV6 and NTRK3 proteins. We present a case of a 60-year-old lady who presented with right breast lump of 1-month duration and was managed by lumpectomy and sentinel lymph node dissection. Axillary dissection was not performed because the sentinel lymph node biopsy was negative. Postoperative radiotherapy was given to the right breast with a boost to the tumor bed. No adjuvant chemotherapy was given No recurrence has been noted even after a year of the completion of treatment

Keywords
Breast neoplasm; Secretory component; Sentinel lymph node biopsy; Translocation, genetic

INTRODUCTION

Secretory carcinoma of the breast (SBC) is a rare breast neoplasm. The overall incidence is less than 0.15% and was first described historically by Mc Divitt and Stewart¹ in the year 1966, and they named it as juvenile breast carcinoma owing to the increased number of cases in the pediatric age group. However, it has been renamed after recognizing that this tumor may occur in a wide age range and also because of its characteristic histomorphological findings.^1,2

Most of the patients present at an early stage with a relatively indolent clinical course. Lymph node metastasis is seen in 30% of individuals, and distant metastasis is also not frequent.^2,3 The histomorphological features of the SBCs are quite characteristic and can be easily distinguishable from invasive duct carcinomas. Predominantly three histological patterns, (i) solid, (ii) microcystic, and (iii) tubular, have been noted with copious amounts of intra and extracellular secretory material. Cellular atypia is usually minimal.⁴ Hormone receptor status is also very much characteristic in SBC. Most frequently, they do not show positivity for estrogen receptor (ER), progesterone receptor (PR) and ERBB2(HER2/neu). Therefore, SBCs very frequently show features of triple-negative breast carcinoma (TNBC). They also express cytokeratin 5/6, 14, 17, and c-Kit (CD117), which are also seen in the basal-like breast carcinomas (BLBC).⁵ Typically, 75–80% of the tumors classified as TNBCs belong to the basal-like breast cancer group, and they behave more aggressively and cause rapid vascular invasion.⁶ Transcriptomic analysis of breast malignancy revealed some distinctive genetic signatures, which is the basis for the intrinsic molecular subtyping of breast cancer. BLBC is one of the subtypes. It is defined by the expression of genes characteristic of the basally located epithelial layer of the mammary gland.⁷ BLBCs also uniformly lack molecular targets, which determine the responsiveness of highly effective targeted therapy.^7,8 BLBCs share some features with SBCs in terms of expression of cytokeratin 5/6, 14, 17, and c-Kit (CD117).⁵ A recent study also highlights the heterogeneity within the TNBC group, both morphologically and prognostically. They also encompass certain tumors with a far better prognosis than the other members of this group.⁹ A very characteristic genetic translocation t (12;15) has been noted in this rare tumor, resulting in a fusion between E26 transformation-specific translocation variant 6 (ETV6) and neurotrophic receptor tyrosine kinase 3 (NTRK3) which creates a fusion protein ETV6-NTRK3 resulting in activation of two oncogenic effector pathways.¹⁰

We present a case of a 60-year-old lady who presented with right breast lump of 6 months duration and was managed by lumpectomy and sentinel lymph node dissection and adjuvant radiotherapy. The radiological, histomorphological, and molecular features of SBC are also discussed.

CASE REPORT

A 60-year-old lady presented in the surgical outpatient clinic with the chief complaint of a palpable right breast lump over the last month. She had a fine needle aspiration cytology done at a local place, which showed malignancy. On examination, the mass appeared non-tender, firm, mobile, and was located in the central quadrant (Figure 1A). The lesion measured approximately 3x3 cm. No axillary lymph node was palpable at that time. The mammography showed a well-defined, sub-areolar, 3x2 cm radio-opaque lesion with no evidence of microcalcification. Two Giemsa stained aspiration smears undertaken during the consultation were also examined simultaneously. The smears were very cellular, with cells showing minimal nuclear atypia and arranged in cohesive clusters and sheets in a fluid background. No myoepithelial cells were detected. Based on those findings, the retro areolar mass was diagnosed as a malignant epithelial tumor (Figure 11C).

Figure 1
Mammography and photomicrographs of the aspiration smears. A – Well defined, sub-areolar, radio-opaque lesion within the breast; B – Cohesive clusters of tumor cells (Giemsa, 100X); C – Mildly pleomorphic polygonal tumor cells with centrally placed nuclei in a fluid background (Giemsa, 400X).

The patient was counseled about the disease status and the need for surgical intervention. A plan of lumpectomy with sentinel lymph node dissection was decided. The sentinel lymph node biopsy was performed, and the tissue was sent to the department of histopathology for an intraoperative frozen section. Grossly, a total of seven lymph nodes was identified in the whole sentinel lymph node specimen, and none of them showed metastatic deposit under microscopic examination. As the sentinel lymph nodes were free from metastasis, no axillary dissection was performed, and only the lumpectomy specimen was sent for final histopathological evaluation.

Gross and microscopic features

The lumpectomy specimen measured 2.3x2.2 cm and was oriented with sutures. Adequate sections were taken and were examined under light microscopy. The tumor cells were arranged in tubules, micro cysts, and follicles. A focally solid growth pattern was also noted. Within the micro cysts, there were abundant, pink, eosinophilic secretions, which were intensely positive for Periodic acid Schiff (PAS) and also resistant to diastase. Intracytoplasmic vacuolation and eosinophilic secretions were also noted. Tumor cells were mitotically not very active, and nuclear pleomorphism was also not conspicuous (Figures 222C). All the resection margins were tumor-free (at least more than 10 mm away from the tumor). As a part of the routine evaluation of the breast specimen, hormone receptor study was also performed. Tumor cells were uniformly negative for estrogen (ER) and progesterone (PR) receptors. Evaluation for HER2/neu was done by immunostain and incomplete; faint membranous staining was noted in more than 10% of the tumor cells (Figures 2 D, 33B). Hence, the tumor was labeled as negative (score 1) and fluorescent in-situ hybridization (FISH) was not performed.¹¹ In addition to that, diffuse membranous and cytoplasmic positivity for cytokeratin 5/6 and S100-P were also documented in the index case (Figures 33D). Hence, we were dealing with a case of secretory breast carcinoma.

Figure 2
Photomicrography of the tumor. A – Microcystic and follicular arrangement of the tumor cells with eosinophilic extracellular secretion (H&E, 100X); B – Intracellular vacuolation and eosinophilic secretion (H&E, 200X); C – Magenta colored secretion for Periodic acid Schiff stain (H&E, 100X); D – No positivity for ER immunostain (200X).

Figure 3
Photomicrography of the tumor: A – No reactivity to PR (100X), B – negative reaction to HER2/neu (200X); C – Diffuse membranous and cytoplasmic positivity for cytokeratin 5/6 (400X); D – Diffuse membranous and cytoplasmic positivity for S100-P (400X).

The FISH study was also performed from the paraffin-embedded sections to confirm the diagnosis. Dual-color break-apart probes (SureFISH^®, Agilent, St.Clara, USA) were used for FISH evaluation of both ETV6 (12p13.2) and NTRK3 (15q25.3) gene. Fifty nuclei were counted, and red-green split signals were noted in 20 and 19 nuclei for ETV6 and NTRK3 gene, respectively (Table 1, Figure 44B). Therefore, the characteristic translocation was present in the index case. Subsequently, a diagnosis of secretory breast carcinoma was offered in this case. The patient has been kept in a close follow-up. No recurrence or metastasis was noted after a year of lumpectomy, which has been confirmed by a positron emission tomography (PET) scan.

Table 1
Result of ETV6 and NTRK3 translocation analysis.

ETV6 translocation	ETV6 (Orange/Green)	5’ ETV6 (Orange)	3’ ETV6 (Orange)	No. of cells
Signals in cell	1	1	1	20/50
NTRK3 translocation	NTRK3 (Orange/green)	5’NTRK3 (Orange)	3’ NTRK3 (Orange)	No. of cells
Signal/s in cell	1	1	1	19/50

Figure 4
Photomicrography of FISH analysis. A – FISH analysis by dual-color break apart ETV6 probe. One fusion signal (red/green/yellow; arrowed) and one split (rearrangement) signal in the nucleus (400X); B – FISH analysis by dual-color break apart NTRK3 probe. Two fusion signal (red/green/yellow; arrowed) and two splits (rearrangement) signal in the nucleus (100X).

DISCUSSION

SBC is a rare breast malignancy with an overall incidence of less than 0.15%. It was first reported as juvenile breast carcinoma.¹ Afterward, it was shown that this tumor affects all age groups and can be detected in both males and females.¹² According to Jacob et al.¹³ the mean age of SBC is 56 years.¹³ This tumor has an indolent clinical course, and according to Horowitz et al.² the 5-year and 10-year cause-specific survival are 94.4% and 91.4%, respectively.¹⁴ The location of the tumor varies according to the age group. Adult patients present with upper outer quadrant mass, whereas in the young population, this is most commonly seen in the subareolar region. In the present case also, the tumor was located in the subareolar region which can be explained by the smaller relative size of the breast mound in younger patients deep to the nipple-areola complex.^15-17

Mammographic findings of SBC closely mimic a fibroadenoma as this carcinoma appears as a solitary, discrete lesion with a well-delineated margin. Since this carcinoma is more common in young girls, mammography always has diagnostic limitations because of the denser and glandular elements in the young breast. Ultrasonography of SBC also mimics a fibroadenoma. Mostly a well-circumscribed, hypo to isoechoic mass with micro lobulation is noted on ultrasound. Therefore, radiological findings of SBC overlap with other benign fibro-epithelial lesions of the breast. In the present case, the mammography also showed a well-defined, sub-areolar, radio-opaque lesion with no evidence of micro calcification.⁵

As mentioned previously, the SBCs are frequently non-reactive for hormone receptor analysis (ER, PR, HER2/neu) with strong and diffuse cytoplasmic positivity for S-100. Therefore, SBC commonly behaves as TNBC. Perineural and lymphovascular invasions are also extremely rare in SBC. Strong and diffuse cytoplasmic positivity for S-100 is a very common finding.¹⁸

The Characteristic genetic translocation (ETV6-NTRK3) of SBCs creates a fusion gene that codes a chimeric tyrosine kinase, which subsequently activates Ras-Mek1 and PI3K-Akt pathways, resulting in increased transforming and mitogenic activity of the fibroblasts and ductal epithelial cells. The chimeric protein also contributes to the expression of mammary growth factor protein in SBC, which is the key protein causing secretory changes, and its expression in SBCs is also very unique.^19,20

The NTRK gene fusion involving NTRK1, NTRK2, or NTRK3 is present in several tumors, like; congenital mesoblastic nephroma, infantile fibrosarcoma, mammary analog secretory carcinoma and many other tumors of different organs which make them susceptible to tyrosine kinase inhibitors (TKI).²¹ Larotrectinib and entrectinib are the first generations of TKIs. The efficacy of the larotrectinib was studied in three clinical trials. According to the published data of 55 patients, where one breast cancer patient was included, it showed an 80% overall response rate. Whereas the partial and complete response was 62% and 13%, respectively.²² Entrectonib was also tried on tumors harboring NTRK fusions. However, no breast tumor patient was included.²³ Both the drugs were well tolerated with mild side effects. Therefore, they can be used in TRK-fusion positive cancers. So far, two types of resistance to first-generation TKIs are known. One is on target, and the other one is off-target resistance. Next-generation TKIs can overcome the resistance to first degree TKIs.^21,22

The incidence of lymph node metastasis is seen in 30% of patients, and a negative sentinel lymph node biopsy is usually associated with a better prognosis. If the size of the tumor is less than 2 cm, then, the chance of metastasis is also low.²⁴ Horowitz et al.² reviewed the SEER database of 83 patients of SBC. According to that, 80% of the younger cohort (<30 years) were treated with a simple mastectomy, and only one patient received adjuvant radiation. Whereas 48.7% of the elderly patients (>30 years) were treated with lumpectomy, and 56% of the same cohort received radiation. Radiation therapy increases long term survival in SBC, just like other invasive breast malignancies.²⁵ In our case, the affected individual is a 60-year-old lady treated with breast conservation surgery and radiotherapy. As SBC is a slowly progressing tumor with the very infrequent possibility of metastasis, response to chemotherapy is low.²⁵ Herz et al.²⁶ in his case study also showed non-responsiveness of SBCs to the adjuvant chemotherapy. Therefore, adjuvant chemotherapy was not considered for our patient. She is disease-free at 1 year of follow up.

CONCLUSION

Secretory breast carcinoma is an uncommon, triple-negative breast tumor with a favorable clinical course. Radiologically, this tumor closely mimics fibroadenoma and other benign breast lesions. The morphology and genetic translocation of this tumor are also quite characteristic. There are no consensus guideline recommendations for the treatment of SBCs. Due to the indolent and slow‐growing nature of this tumor, most recurrences are seen between 10‐20 years after the initial presentation. Therefore, all the patients irrespective of their age demand long term follow-up.

• How to cite: Banerjee N, Banerjee D, Choudhary N. Secretory carcinoma of the breast, commonly exhibits the features of low grade, triple negative breast carcinoma- a case report with updated review of literature. Autops Case Rep [Internet]. 2021; 11 :e2020227. https://doi.org/10.4322/acr.2020.227
• This study was carried out at the Department of Oncopathology. NH superspeciality Hospital. Howrah, West Bengal, India.
• Ethics statement: The authors retain informed consent signed by the patient’s next of kin authorizing the data publication.
• Financial support: none.

REFERENCES

• ¹
  McDivitt RW, Stewart FW. Breast carcinoma in children. JAMA. 1966;195(5):388-90. http://dx.doi.org/10.1001/jama.1966.03100050096033 PMid:4285563.
  » http://dx.doi.org/10.1001/jama.1966.03100050096033
• ²
  Horowitz DP, Sharma CS, Connolly E, Gidea-Addeo D, Deutsch I. Secretory carcinoma of the breast: results from the survival, epidemiology and end results database. Breast. 2012;21(3):350-3. http://dx.doi.org/10.1016/j.breast.2012.02.013 PMid:22494666.
  » http://dx.doi.org/10.1016/j.breast.2012.02.013
• ³
  Li D, Xiao X, Yang W, et al. Secretory breast carcinoma: a clinicopathological and immunophenotypic study of 15 cases with a review of the literature. Mod Pathol. 2012;25(4):567-75. http://dx.doi.org/10.1038/modpathol.2011.190 PMid:22157932.
  » http://dx.doi.org/10.1038/modpathol.2011.190
• ⁴
  Laé M, Fréneaux P, Sastre-Garau X, Chouchane O, Sigal-Zafrani B, Vincent-Salomon A. Secretory breast carcinomas with ETV6-NTRK3 fusion gene belong to the basal-like carcinoma spectrum. Mod Pathol. 2009;22(2):291-8. http://dx.doi.org/10.1038/modpathol.2008.184 PMid:19011601.
  » http://dx.doi.org/10.1038/modpathol.2008.184
• ⁵
  Vasudev P, Onuma K. Secretory breast carcinoma: unique, triple-negative carcinoma with a favorable prognosis and characteristic molecular expression. Arch Pathol Lab Med. 2011;135(12):1606-10. http://dx.doi.org/10.5858/arpa.2010-0351-RS PMid:22129193.
  » http://dx.doi.org/10.5858/arpa.2010-0351-RS
• ⁶
  Kozioł M, Püsküllüoglu M, Zygulska A. PARP inhibitors and their role in the therapy of triple-negative metastatic breast cancer. Przegl Lek. 2012;69(6):256-70. PMid:23094440.
• ⁷
  Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747-52. http://dx.doi.org/10.1038/35021093 PMid:10963602.
  » http://dx.doi.org/10.1038/35021093
• ⁸
  Yehiely F, Moyano JV, Evans JR, Nielsen TO, Cryns VL. Deconstructing the molecular portrait of basal-like breast cancer. Trends Mol Med. 2006;12(11):537-44. http://dx.doi.org/10.1016/j.molmed.2006.09.004 PMid:17011236.
  » http://dx.doi.org/10.1016/j.molmed.2006.09.004
• ⁹
  Pareja F, Geyer FC, Marchiò C, Burke KA, Weigelt B, Reis-Filho JS. Triple-negative breast cancer: the importance of molecular and histologic subtyping, and recognition of low-grade variants. NPJ Breast Cancer. 2016;2(1):1603. http://dx.doi.org/10.1038/npjbcancer.2016.36 PMid:28721389.
  » http://dx.doi.org/10.1038/npjbcancer.2016.36
• ¹⁰
  Tognon C, Knezevich SR, Huntsman D, et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2(5):367-76. http://dx.doi.org/10.1016/S1535-6108(02)00180-0 PMid:12450792.
  » http://dx.doi.org/10.1016/S1535-6108(02)00180-0
• ¹¹
  Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997-4013. http://dx.doi.org/10.1200/JCO.2013.50.9984 PMid:24101045.
  » http://dx.doi.org/10.1200/JCO.2013.50.9984
• ¹²
  Lijuan L, Nan W, Fangxuan L, Lingmei L, Lijuan W, Juntian L. Clinicopathologic and molecular characteristics of 44 patients with pure secretory breast carcinoma. Cancer Biol Med. 2019;16(1):139-46. http://dx.doi.org/10.20892/j.issn.2095-3941.2018.0035 PMid:31119054.
  » http://dx.doi.org/10.20892/j.issn.2095-3941.2018.0035
• ¹³
  Jacob JD, Hodge C, Franko J, Pezzi CM, Goldman CD, Klimberg VS. Rare breast cancer: 246 invasive secretory carcinomas from the National Cancer Data Base. J Surg Oncol. 2016;113(7):721-5. http://dx.doi.org/10.1002/jso.24241 PMid:27040042.
  » http://dx.doi.org/10.1002/jso.24241
• ¹⁴
  Amott DH, Masters R, Moore S. Secretory carcinoma of the breast. Breast J. 2006;12(2):183. http://dx.doi.org/10.1111/j.1075-122X.2006.00233.x PMid:16509851.
  » http://dx.doi.org/10.1111/j.1075-122X.2006.00233.x
• ¹⁵
  Rosen PP, Cranor ML. Secretory carcinoma of the breast. Arch Pathol Lab Med. 1991;115(2):141-4. PMid:1992979.
• ¹⁶
  Soyer T, Yaman Bajin İ, Orhan D, et al. Secretory breast carcinoma in a 6-year-old girl: mastectomy with sentinel lymph node dissection. Pediatr Surg Int. 2015;31(7):677-81. http://dx.doi.org/10.1007/s00383-015-3721-0 PMid:25994562.
  » http://dx.doi.org/10.1007/s00383-015-3721-0
• ¹⁷
  Garlick JW, Olson KA, Downs-Kelly E, Bucher BT, Matsen CB. Secretory breast carcinoma in an 8-year-old girl: A case report and literature review. Breast J. 2018;24(6):1055-61. http://dx.doi.org/10.1111/tbj.13126 PMid:30251458.
  » http://dx.doi.org/10.1111/tbj.13126
• ¹⁸
  Din NU, Idrees R, Fatima S, Kayani N. Secretory carcinoma of breast: clinicopathologic study of 8 cases. Ann Diagn Pathol. 2013;17(1):54-7. http://dx.doi.org/10.1016/j.anndiagpath.2012.06.001 PMid:22832018.
  » http://dx.doi.org/10.1016/j.anndiagpath.2012.06.001
• ¹⁹
  Tognon C, Gamett M, Kenward E, Kay R, Morrison K, Sorensen PH. The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3- kinase-Akt signaling for fibroblast transformation. Cancer Res. 2001;61(24):8909-16. PMid:11751416.
• ²⁰
  Strauss BL, Bratthauer GL, Tavassoli FA. STAT 5a expression in the breast is maintained in secretory carcinoma, in contrast to other histologic types. Hum Pathol. 2006;37(5):586-92. http://dx.doi.org/10.1016/j.humpath.2006.01.009 PMid:16647957.
  » http://dx.doi.org/10.1016/j.humpath.2006.01.009
• ²¹
  Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731-47. http://dx.doi.org/10.1038/s41571-018-0113-0 PMid:30333516.
  » http://dx.doi.org/10.1038/s41571-018-0113-0
• ²²
  Drilon A, Laetsch TW, Kummar S, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018;378(8):731-9. http://dx.doi.org/10.1056/NEJMoa1714448 PMid:29466156.
  » http://dx.doi.org/10.1056/NEJMoa1714448
• ²³
  Drilon A, Siena S, Ou SI, et al. Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7(4):400-9. http://dx.doi.org/10.1158/2159-8290.CD-16-1237 PMid:28183697.
  » http://dx.doi.org/10.1158/2159-8290.CD-16-1237
• ²⁴
  Vasudev P, Onuma K. Secretory breast carcinoma: unique, triple-negative carcinoma with a favorable prognosis and characteristic molecular expression. Arch Pathol Lab Med. 2011;135(12):1606-10. http://dx.doi.org/10.5858/arpa.2010-0351-RS PMid:22129193.
  » http://dx.doi.org/10.5858/arpa.2010-0351-RS
• ²⁵
  Lee SG, Jung SP, Lee HY, et al. Secretory breast carcinoma: A report of three cases and a review of the literature. Oncol Lett. 2014;8(2):683-6. http://dx.doi.org/10.3892/ol.2014.2213 PMid:25009650.
  » http://dx.doi.org/10.3892/ol.2014.2213
• ²⁶
  Herz H, Cooke B, Goldstein D. Metastatic secretory breast cancer. Non-responsiveness to chemotherapy: case report and review of the literature. Ann Oncol. 2000;11(10):1343-7. http://dx.doi.org/10.1023/A:1008387800525 PMid:11106125.
  » http://dx.doi.org/10.1023/A:1008387800525

Publication Dates

• Publication in this collection
  14 Dec 2020
• Date of issue
  2021

History

• Received
  30 May 2020
• Accepted
  12 Aug 2020