Secretory carcinoma (SC) is a distinct and rare form of cancer. It often presents a diagnostic challenge because it resembles other, more common tumor types. SC was first recognized as a specific entity in the salivary glands, although its unique features were previously known in breast cancer. An accurate diagnosis is crucial for selecting the most effective therapeutic approach and management strategy.
Understanding Secretory Carcinoma
Secretory carcinoma is categorized by its unique appearance under a microscope. Cells are arranged in patterns such as microcystic, tubular, or papillary-cystic structures. These arrangements contain characteristic pink, protein-rich secretory material within the spaces, which gives the tumor its name. The cells typically have a low degree of abnormality and a granular or vacuolated appearance in their cytoplasm, reflecting their secretory nature.
The tumor’s molecular identity is its most defining characteristic, setting it apart from other cancers with similar histology. In over 90% of cases, SC is driven by a specific genetic alteration known as the ETV6-NTRK3 gene fusion. This fusion results from a chromosomal translocation, which joins the ETV6 gene on chromosome 12 with the NTRK3 gene on chromosome 15.
The resulting ETV6-NTRK3 fusion gene produces an abnormal protein that signals for constant cell growth and division. While originally identified in the breast, where it is known as mammary analogue secretory carcinoma, SC most frequently arises in the major and minor salivary glands, particularly the parotid gland. It has also been documented, though less commonly, in the skin and other soft tissues.
Diagnostic Confirmation Process
Diagnosing secretory carcinoma begins with clinical suspicion, typically identified through a physical examination or imaging, such as ultrasound or magnetic resonance imaging (MRI). A definitive diagnosis requires obtaining tissue from the suspected tumor, usually via a fine-needle aspiration or a core biopsy procedure. These samples are then sent for specialized pathological examination.
Pathologists first analyze the tissue sample under a microscope for the characteristic secretory features and cellular patterns. Because SC can look like other tumors, such as acinic cell carcinoma, confirmation requires specific molecular testing. Immunohistochemistry (IHC) is often used as an initial screening tool, applying a pan-Trk antibody to the tissue to detect the protein product of the NTRK gene fusion. A positive result, particularly nuclear staining, strongly suggests the presence of the genetic alteration.
Definitive confirmation of secretory carcinoma relies on detecting the ETV6-NTRK3 gene fusion itself. This is achieved using advanced molecular techniques. Fluorescence In Situ Hybridization (FISH) visually identifies the gene rearrangement in the cells. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) can also be utilized to detect the specific fusion transcript produced by the altered genes. The most comprehensive method is Next-Generation Sequencing (NGS), which can analyze multiple genes simultaneously and precisely identify the ETV6-NTRK3 fusion, confirming the molecular diagnosis.
Management and Treatment Strategies
For localized secretory carcinoma, the most effective intervention is surgical excision. This procedure involves the complete removal of the tumor along with a margin of surrounding healthy tissue. SC is generally considered a low-grade tumor with a favorable outlook, and complete surgical removal is often curative.
If the tumor is advanced, has recurred, or has spread to distant sites, systemic therapies become necessary. The ETV6-NTRK3 fusion provides a unique target for treatment, moving beyond traditional chemotherapy. This molecular signature makes the tumor highly sensitive to a class of medications called NTRK inhibitors, such as larotrectinib and entrectinib. These targeted drugs block the activity of the abnormal TRK fusion protein, shutting down the growth signal that drives the cancer.
Clinical trials have demonstrated high response rates with NTRK inhibitors in patients whose tumors harbor the gene fusion, regardless of the tumor’s origin site. In some situations, an unresectable tumor can be treated with an NTRK inhibitor first, which may shrink the mass enough to make a subsequent surgical removal, known as conversion surgery, possible. Following initial treatment, long-term follow-up and monitoring are necessary to detect any potential recurrence or late-stage spread. This surveillance often involves periodic physical exams and imaging studies.