Genetic Alterations in Salivary Gland Tumors: Overview

Salivary gland tumors are a diverse group of neoplasms that can present unique genetic alterations, making their study crucial for diagnostic accuracy and targeted therapeutic strategies. Each subtype is defined by distinct chromosomal rearrangements, gene fusions, or mutations, which are crucial for differentiating between tumor types and understanding their pathogenesis.

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1. Secretory Carcinoma

Chromosome Involved: t(12;15) (p13;q25)
Gene Fusion: ETV6-NTRK3 fusion
Microscopy: The tumor is characterized by a microcystic pattern, often showing abundant pink secretion. These tumors generally exhibit low-grade nuclear atypia.
IHC: They are typically positive for mammaglobin, S-100 , SOX-10, GATA-3 and Pan-TRK.

This image shows a high-resolution histopathological slide of salivary gland tumor cells, highlighting the structural changes at a microscopic level. The cellular alterations reflect underlying genetic mutations, which are critical in diagnosing and understanding the behavior of these tumors. The detailed view demonstrates irregularities in cellular morphology, which correlate with specific genetic markers commonly found in malignant salivary gland tumors — Image: hisham.h.alshuaibi

Clinical Significance: Secretory carcinoma is relatively indolent but can metastasize. The ETV6-NTRK3 fusion is a hallmark genetic alteration, providing a target for therapies using TRK inhibitors, which have shown efficacy in other tumors harboring this fusion.

2. Hyalinizing Clear Cell Carcinoma

Chromosome Involved: t(12;22)
Gene Fusion: EWSR1-ATF1 gene fusion
Microscopy: Histologically, this tumor displays clear cells in nests and cords, often within a hyalinized stroma.

Clinical Significance: This tumor is distinguished from other clear cell tumors by the presence of the EWSR1-ATF1 fusion, a critical diagnostic marker. This gene fusion is also observed in other tumors, such as clear cell sarcoma, making molecular confirmation essential.

3. Mucoepidermoid Carcinoma

Chromosome Involved: t(11;19) (q21;p13)
Gene Fusion: CRTC1-MAML2 gene fusion
Microscopy: This tumor is a mix of mucus-secreting, epidermoid, and intermediate cells. It demonstrates a cystic architecture with mucus lakes and nests of epidermoid cells.
IHC: Positive for pancytokeratin, p63, p40, EMA, CK7, CK14 and membrane bound muffins like (MUC1, MUC2, MUC4, MUC5AC and MUC5B).

Clinical Significance: The CRTC1-MAML2 fusion is characteristic of mucoepidermoid carcinoma, especially the low- and intermediate-grade variants. Its presence correlates with a favorable prognosis and is a useful diagnostic marker when morphology is ambiguous.

4. Adenoid Cystic Carcinoma

Chromosome Involved: t(6;9) (q22-23;p23-34)
Gene Fusion: MYB-NFIB fusion
Microscopy: Adenoid cystic carcinoma is known for its cribriform pattern, often described as “Swiss cheese-like,” along with solid and tubular growth patterns.
IHC: Positive for CK7 , CAM 5.2 and c-kit (CD117)

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Clinical Significance: The MYB-NFIB fusion is present in the majority of adenoid cystic carcinomas. These tumors are slow-growing but have a high propensity for perineural invasion and distant metastasis. The MYB gene fusion is important in diagnostics and research, although therapeutic targeting of this fusion has not yet yielded effective treatments.

5. Polymorphous Adenocarcinoma

Gene Involved: PRKD1 hotspot mutation
Microscopy: Characterized by cytologic uniformity and architectural diversity, these tumors show infiltrative growth with patterns such as trabecular, papillary, and cribriform.
IHC: Positive for SOX-10, S-100 and CK7. p63 is variably positive, whereas, p40 is negative (important to differentiate from mucoepidermoid carcinoma)

Clinical Significance: PRKD1 mutations are a defining feature of this tumor. The tumor’s low metastatic potential and favorable prognosis make distinguishing it from other salivary gland adenocarcinomas crucial, especially from adenoid cystic carcinoma, which is more aggressive.

6. Salivary Duct Carcinoma

Gene Involved: HER2 amplification, p53 mutations, AR (androgen receptor)
Microscopy: Histologically, salivary duct carcinoma mimics high-grade ductal carcinoma of the breast, with intraductal and invasive growth patterns, central necrosis, and prominent nucleoli.
IHC: Positive stains – AR, GATA-3 and GCDFP-15

Clinical Significance: HER2 amplification and androgen receptor positivity provide avenues for targeted therapy, similar to breast cancer treatment strategies. Trastuzumab and androgen deprivation therapies are potential treatments for patients with this aggressive carcinoma.

7. Pleomorphic Adenoma / Carcinoma Ex Pleomorphic Adenoma

Chromosome Involved: 8q12, 12q14-15
Genes Involved: PLAG1, HMGA2
Microscopy: Pleomorphic adenomas show a mix of epithelial, myoepithelial, and stromal components, while carcinoma ex pleomorphic adenoma shows malignant transformation with features of pleomorphic adenoma still recognizable.

Clinical Significance: The presence of PLAG1 and HMGA2 rearrangements helps in the diagnosis of pleomorphic adenoma. When malignancy arises from pleomorphic adenoma, known as carcinoma ex pleomorphic adenoma, it can become aggressive and challenging to treat.

8. Salivary Mucinous Adenocarcinoma (Newly Updated in latest WHO)

Gene Involved: AKT1 E17K mutation
Microscopy: This is a rare entity showing gland-forming structures with mucin production.

Clinical Significance: AKT1 mutations have been linked to oncogenesis in multiple tumor types, and their presence in salivary mucinous adenocarcinoma offers a new molecular target for therapy.

9. Microsecretory Adenocarcinoma (Newly Updated in latest WHO)

Gene Involved: MEF2C-SS18 fusions
Microscopy: A newly described entity with microglandular architecture and clear cytoplasm. Secretions in microsecretory carcinoma are BASOPHILIC (unlike secretory carcinomas, which are eosinophilic)

Microsecretory adenocarcinoma with numerous basophilic secretions.

IHC: Positive stains: S-100, SOX-10 and p63. Negative for p40.

Clinical Significance: The MEF2C-SS18 fusion distinguishes microsecretory adenocarcinoma from other salivary gland tumors.

10. Acinic Cell Carcinoma

Gene Involved: Mutations in NR4A3, BRAF, and RET have been observed in some cases, but no characteristic gene fusion is universally identified.
Microscopy: Acinic cell carcinoma (AciCC) typically shows cells that resemble normal acinar cells of the salivary glands, with abundant basophilic or amphophilic granular cytoplasm. Histologically, it often exhibits a variety of growth patterns, including solid, microcystic, follicular, and papillary-cystic patterns. The granular cytoplasm, attributed to zymogen granules, is a key diagnostic feature.
IHC: Pancytokeratin EMA.,CEA, DOG 1. The chromosomal rearrangement t(4;9)(q13;q31) results in the translocation of the active enhancer, which leads to upregulation of the target gene NR4A3. Hence, NR4A3 is strongly and diffusely expressed in acinic cell carcinoma.

Clinical Significance: Acinic cell carcinoma is generally considered a low- to intermediate-grade malignancy, although high-grade transformation can occur. It has a relatively good prognosis compared to other salivary gland malignancies but can recur or metastasize, particularly in higher-grade variants. Molecular studies have revealed various mutations, such as NR4A3, BRAF, and RET, which may be helpful for targeted therapies in the future, though no specific gene fusion defines this tumor.

Summary

References

WHO Classification of Head and Neck Tumors (5th Edition)- 2022

FRCPath Part-1 Histopathology Course