Dedifferentiated secretory breast carcinoma with fibrosarcomatous features harboring an ETV6‐NTRK3 fusion in both components

Abstract

Secretory carcinomas are low‐grade translocation‐driven carcinomas occurring in patients over a wide age range. These tumors most frequently arise in the breast and salivary gland, but may occasionally arise at other anatomic sites, such as the skin, the thyroid gland or the upper or lower respiratory tract. In concert with their low‐grade morphology, secretory carcinomas most often follow an indolent clinical course. However, rare cases have shown dedifferentiation (also known as high‐grade transformation) and aggressive clinical behavior. To date, the dedifferentiated component in all molecularly confirmed cases of secretory carcinoma has taken the form of a high‐grade carcinoma. Here we present a case of an ETV6‐NTRK3 fusion‐positive secretory carcinoma of the breast with sarcomatous dedifferentiation. The sarcomatous component showed an infantile or adult fibrosarcoma‐like morphology including a herringbone fascicular pattern and a hemangiopericytic vascular pattern. By immunohistochemistry, the sarcomatous component showed focal CD34 immunoreactivity and loss of all of the markers expressed in the conventional secretory carcinoma component, including SOX10, S100, GATA‐3, AE1/AE3 and E‐cadherin. Fluorescence in situ hybridization analysis revealed that the sarcomatous component retained the ETV6‐NTRK3 fusion, but also acquired homozygous deletion of CDKN2A. The tumor followed an aggressive clinical course and the patient eventually succumbed to her disease 14 months after diagnosis. The histomorphologic and molecular genetic features of this tumor are discussed, including its ability to mimic kinase‐rearranged infantile or adult fibrosarcomas at extramammary sites and the theragnostic importance of its distinction from conventional metaplastic spindle cell carcinomas in the breast.

Triple-Negative Breast Cancer Histological Subtypes with a Favourable Prognosis

“…It mainly occurs in females [ 11 ] but has also been reported in males, summarized by Ghilli et al [ 127 ], in whom it may exhibit a more aggressive clinical course [ 128 ]. A similar tumour type may be seen in salivary glands (previously referred to as mammary analogue secretory carcinoma, MASC) and occasionally in the thyroid gland, skin and respiratory tract [ 129 ]. Rare cases of secretory carcinoma in situ have also been reported [ 130 , 131 ].…”

“…Since the description of the initial series by McDivitt and Stewart, several hundred SCs have been reported, mostly as single case reports, small single institutional series and two larger database analyses [ 138 , 139 ]. These are summarized in Supplementary Table S6 [ 124 , 125 , 127 , 129 , 130 , 131 , 132 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 ]. In 2018, Garlick reviewed 89 cases previously published and these are included in the table on the basis of his review [ 144 ].…”

“…De-escalating systemic treatment has also been advocated [ 143 ]. Rare tumours may demonstrate high-grade transformation similar to translocation driven salivary gland-type carcinomas [ 129 ] and may benefit from targeted anti-TRK treatment [ 141 , 149 ].…”

Fusion‐positive skin/adnexal carcinomas

“…A subset of tumors including cutaneous and mammary cases shows foci of high-grade transformation or dedifferentiation heralding aggressive clinical behavior. 41,42 The morphology of SC is highly variable. The prototypical tumors display closely packed sieve-like microcystic glands and tubular spaces containing abundant eosinophilic intraluminal secretions.…”

“…A wide age range is affected. A subset of tumors including cutaneous and mammary cases shows foci of high‐grade transformation or dedifferentiation heralding aggressive clinical behavior 41,42 . The morphology of SC is highly variable.…”