Mammary secretory carcinoma

In a review study of 190 individuals diagnosed with MSC, patient ages ranged from 2 to 96 years (median age: 56 years); 5% of cases were aged less than 21 years; the male to female ratio was 1 to 30; the tumors were in the left, right, and both breasts in 103, 85 and 2 cases, respectively; and the tumors were usually located on a breast's left, outer quadrant.[1] (In younger patients, these tumors more often occur beneath the areola, i.e. pigmented region around the breast's nipple.[14]) In a subgroup of 99 patients on which there was sufficient information, average tumor sizes were 2.3 centimeters (cm.) with 29.3% of these patients evidencing lymph node metastases.[1] This study did not have patients who presented with metastasis to tissues beyond their sentinel lymph nodes. In a review study of 44 individuals with MSC, 41 patients were female and 3 were male; patient ages ranged between 4 and 76 years (median age: 48 years) with 4 patients being adolescents; patient tumor sizes ranged from 1.5 to 10 cm. (mean size: 3.5 cm.) (Individual cases of MSC have had tumor sizes as large as 16 cm.[4]) and 15 patients presented with lymph node metastases. While none of these patients presented with metastasis beyond sentinel lymph nodes, follow up studies over an average of 93.4 months identified 4 patients with metastases to the bone, 1 patient with metastases to the liver, and 1 patient with unspecified distant metastases. Five of these patients died of their disease.[15]

In a review study 12 female and 2 male patients 8 to 81 years (mean age: 48 years), 8 patients presented with a palpable mass, 4 presented with a mass detected on screening mammography, and 2 patients lacked information on this; 8 tumors were located in the left and 6 in the right breast; and 2 of the 10 patents tested by biopsy had sentinel lymph node metastases. One of these patients presented with distant tissue metastases, 12 re-presented with distant metastasis within 5–240 months of their initial diagnoses and treatments, and one lacked information on this. Eight of these patients died from their disease 7 to 240 months (mean survival time: 74.6 months) after their initial diagnosis, 4 were alive with their disease 7 to 84 months after their initial diagnosis, and 2 had no information on this. The metastases, which often were to multiple sites, were located in the lung (9 cases), liver (4 cases), bone (4 cases), skin (2 cases), kidney (1 case), mediastinum (1 case), pancreas (1 case), and/or lung's pleura (1 case).[8] Rare cases of MSC have presented in individuals who have or had and been treated for papillomatosis of breasts; this benign breast diseases is often associated with other breast carcinomas, the by far most common of which is MSC.[5]

As of 2019, only 6 cases presented with purely in situ (i.e. totally localized tumors that have not invaded tissues outside of the breasts' ducts) tumors (as reported in the English literature). The tumor tissues in all of these cases had at least one area with a papillary microscopic histopathology (see Pathology section).[16]

Histopathology of secretory carcinoma, high magnification. H&E stain. It characteristically shows nests of tumor surrounded by stroma, where the nests have microcystic and adenoid structures with eosinophilic secretions.

The microscopic histopathology of H&E-stained MSC tumors generally shows well-circumscribed solid tumors with multiple microcysts[13] and sheets of epithelial cells containing numerous vacuoles in their cytoplasm, signet ring cells (i.e. cells with one large cytoplasmic vacuole termed a globule), and extracellular droplet-like secretions resembling the cytoplasmic globules.[2] The sheets of cells are separated by bands of connective tissue.[5] In occasional cases, the cells in MSC tumors are arranged in a papillary (i.e. finger-like)[17] or tubular[14] pattern. The extracellular microcysts and intracellular vacuoles and globules stain red when stained with the H&E stain, consist of sulfated glycosaminoglycans and mucin-containing material,[4] and are identified using periodic acid-Shiff, PAD diastase, or Alician blue stains.[15] The term “secretory” for MSC is in recognition that the tumor cells vacuoles and globules are secreted extracellularly to give the tissues their microcystic appearance.[8] At least 2 cases of MSC had sarcoma-like malignant cells in portions of their tumors and a rapidly metastasizing disease.[18][19]

The diagnosis of MSC tumors rests on their occurrence in breast ductal tissue, their distinct microscopic histopathological features[2] plus, particularly in tumors showing a papillary histopathology,[17] the presence of in the tumor of cells that express the ETV6-NTRK3 fusion gene and/or its ETV6-NTRK3 chimeric protein.[1][15][16][17] While the ETV6-NTRK3 gene fusion occurs in many other tumor types (e.g. inflammatory myofibroblastic tumors, the cellular variant of congenital mesoblastic nephroma, and radiation-induced papillary thyroid carcinoma), these tumors' clinical presentations and histopathology findings distinguish them from MSC tumors.[13]

There have been no controlled studies that have evaluated the many different strategies that have been used to treat MSC tumors.[16] Studies have suggested that: 1) MSC tumor sizes less than 2[13] or 3[15] centimeters in widest dimension, tumors with circumscribed margins, tumors with no evidence of axillary lymph node metastasis,[15] tumors in individuals who are less than 20[13] or 30[14] years old at diagnosis, and/or tumors that are purely in situ[16] have more favorable prognoses; 2) MSC tumors with high rates of proliferation, tumors greater than 2 to 3 centimeters in widest dimension,[13][15] tumors that contain areas of sarcoma-like cells,[19] tumors in individuals older than 20 or 30 years,[13][14] and/or tumors that have spread to distant tissues[8] have less favorable prognoses.

In general, surgery has been considered the best treatment for MSC tumors but there is no consensus on the extent of this surgery.[15] Conservative surgery or simple mastectomy with biopsy of sentinel lymph nodes has been recommended for patients with MSC tumors that have more favorable prognoses. Removal of adjacent mammary tissue to the tumor to insure that all invasive tissue is removed has also been recommended since leaving tumor tissue behind after surgery runs a higher risk of local recurrences.[1] Tumors with unfavorable prognostic features have been treated with radical mastectomy. Since MSC tumors grow slowly, carry relatively good prognoses, and if metastasizing to distant tissues usually do so only 10 to 20 years after,[14] there is no strong evidence for the benefit of adjuvant chemotherapy and/or radiotherapy[4] A retrospective study of 190 patients with MSC that had not metastasized to distant tissue found that breast-conserving surgery plus radiotherapy gave significantly better survival times than simple mastectomy.[5] In general, conservative surgery, modified radical mastectomy, and radical mastectomy have been the most frequent procedures in adults while simple mastectomy, local excision with sentinel lymph node biopsy, and complete axillary dissection have been recommended as adequate treatment for children with MSC.[15] Further studies are needed to confirm that radiotherapy improves one or more of the latter treatment regimens.[5] In all cases, long-term follow-up examination, e.g. for at least 20 years after diagnoses, is strongly recommended.[1][14]

The rare cases of MSC tumors that spread to distant tissues on their initial presentation or after prior treatment have been treated with various chemotherapy regimens. Responses to these regiments have been poor to nil.[8][13][14] Recently, three individuals (two juvenile females and one 26 year old male) with ETV6-NTRK3 fusion gene-harboring MSC tumors that metastasized to distant tissues were treated with Larotrectinib, a drug which attacks the genetic abnormality underlying this disease. The drug is an orally available selective NTRKi inhibitor that blocks the NTRK3 protein's tyrosine kinase activity. It has produced good, fast-developing responses in the three reported MSC cases.[6][13][16] However, these three responses were partial, i.e. some tumor tissue remained after treatment.[23] Further studies are needed on a much larger number of individuals with MSC to define the efficacy of Larotrectinib, the duration of its effects, and the efficacy of other MTRK3 protein inhibitors such as Entrectinib.[6][23]

Overall, MSC has a favorable prognosis.[5][23] A study of 190 individuals treated for MSC that had not spread to distant tissues reported survival rates (excluding individuals dying of other causes) at 5, 10, and 20 years after initial treatment of 95.79, 93.16, and 93.16%, respectively.[1] The uncommon cases of MSC which have metastasize to distant tissues may also have prolonged survival times[8] but some have proven to be fatal with shorter survival times (e.g. 1 year after diagnosis).[13][15][19] Larotrectinib therapy may improve the survival times in individuals with MSC tumors that have poorer prognoses.[23]