Despite the importance of recognizing neuroendocrine differentiation when diagnosing tumors of the thoracic cavity, the sensitivity of traditional neuroendocrine markers is suboptimal, particularly ...for high-grade neuroendocrine carcinomas such as small cell lung carcinoma and large cell neuroendocrine carcinoma. To increase sensitivity, neuroendocrine markers are routinely ordered as panels of multiple immunostains where any single positive marker is regarded as sufficient evidence of neuroendocrine differentiation. Insulinoma-associated protein 1 (INSM1) is a well-validated transcription factor of neuroendocrine differentiation that has only recently been evaluated for diagnostic use. We performed INSM1 immunohistochemistry on a large series of thoracic neuroendocrine and non-neuroendocrine tumors and compared its performance to synaptophysin, chromogranin, and CD56. INSM1 was positive in 94.9% of small cell lung carcinomas and 91.3% of large cell neuroendocrine carcinomas, compared with 74.4% and 78.3% with the combined panel of traditional markers. INSM1 also stained all (100%) of the atypical carcinoids, typical carcinoids and mediastinal paragangliomas, but only 3.3% of adenocarcinomas and 4.2% of squamous cell carcinomas. Overall, INSM1 demonstrated a sensitivity of 96.4% across all grades of thoracic neuroendocrine tumors, significantly more than the 87.4% using the panel of traditional markers (P=0.02). INSM1 is sufficiently sensitive and specific to serve as a standalone first-line marker of neuroendocrine differentiation. A more restrained approach to immunohistochemical analysis of small thoracic biopsies is appropriate given the expanding demand on this limited material for therapeutic biomarker analysis.
Thyroblastoma is a novel thyroid malignancy included in the 5th Edition WHO Classification of Endocrine and Neuroendocrine Tumours. The majority of tumors now classified as thyroblastoma were ...originally regarded to be malignant thyroid teratomas. However, these neoplasms were recently recognized as a separate entity based on a distinctive constellation of primitive multilineage elements, including immature thyroid epithelium, undifferentiated or rhabdomyoblastic spindle cell proliferations, and neuroepithelial blastema, as well as recurrent DICER1 hotspot mutations. Thyroblastoma is an aggressive tumor that leads to death from disease in ~50% of patients, making it essential to differentiate this entity from a wide range of other thyroid tumors that show overlapping histologic features or DICER1 mutations. This review aims to provide a practical overview of the background, clinicopathologic features, molecular underpinnings, and differential diagnosis of this recently-described and molecularly-defined entity.
The molecular pathogenesis of poorly differentiated sinonasal carcinoma received significant attention in recent years. As a consequence, several unclassified carcinomas in the morphologic spectrum ...of sinonasal undifferentiated carcinoma have been reclassified as distinctive genetically defined variants or entities. Among the latter are NUT-rearranged carcinoma and SMARCB1-deficient carcinomas. In this study, we further characterize a rare variant of sinonasal undifferentiated carcinoma-like tumors characterized by inactivation of the SWItch/Sucrose Nonfermentable chromatin remodeler SMARCA4 (BRG1) detectable by immunohistochemistry. Patients were 7 males and 3 females aged 20 to 67 years (median, 44). Tumors originated in the nasal cavity (6), nose and sinuses (2), or at unspecified site (2). Six tumors were initially misdiagnosed as small cell neuroendocrine carcinoma (SCNEC) or large cell neuroendocrine carcinoma (LCNEC). Histologically, the tumors were composed of small basaloid (3 cases) or large epithelioid (7) cells disposed into nests and solid sheets with extensive areas of necrosis. No glands or other differentiating features were noted. Abortive rosettes were seen in 1 case. Immunohistochemistry showed consistent expression of pankeratin and absence of CK5, p63, p16, and NUT in all tumors tested. Other tested markers were variably positive: CK7 (2/6), synaptophysin (9/10; mostly focal and weak), chromogranin-A (4/10; focal), and CD56 (3/5; focal). All tumors showed total loss of SMARCA4 and retained expression of SMARCB1/INI1. Co-loss of SMARCA2 was seen in 1 of 8 cases. Limited data were available on treatment and follow-up. Two patients received surgery (1 also radiotherapy) and 3 received chemotherapy. Metastases (cervical nodes, liver, bone, and lung/mediastinal) were detected in 3 patients; 2 were alive under palliative chemotherapy at 8 and 9 months while 1 died of progressive lung disease at 7 months. Three patients (1 with brain invasion) died soon after diagnosis (1 to 3 mo). In total, 4 of 6 patients (66%) with follow-up died of disease (median, 3 mo). This series characterizes SMARCA4-deficient sinonasal carcinoma as a genetically distinct aggressive entity in the spectrum of undifferentiated sinonasal carcinomas. These variants add to the spectrum of SWItch/Sucrose Nonfermentable-deficient sinonasal carcinomas, at the same time expanding the topographic distribution of SMARCA4-related malignancies.
Although the definitions of sinonasal neuroendocrine and neuroectodermal neoplasms did not change substantially in the 5th edition WHO Classification of Head and Neck Tumours, the diagnosis of ...olfactory neuroblastoma (ONB), small cell neuroendocrine carcinoma, and large cell neuroendocrine carcinoma remains quite challenging in practice. Ambiguities surrounding the amount of keratin expression allowable in ONB and the amount of neuroendocrine differentiation seen in sinonasal undifferentiated carcinoma (SNUC) lead to significant diagnostic discrepancies at the high grade end of this tumor spectrum. Furthermore, a group of problematic neuroepithelial tumors that show overlapping features of ONB and neuroendocrine carcinoma have never been recognized in formal classification schemes. Since publication of the 5th edition WHO, two new tumor entities have been proposed that help resolve these problems. Olfactory carcinoma is defined by high grade keratin-positive neuroectodermal cells with frequent intermixed glands and shows recurrent Wnt pathway,
ARID1A
, and
RUNX1
alterations.
IDH2
-mutant sinonasal carcinoma is a molecularly-defined category that encompasses tumors with undifferentiated (SNUC), large cell neuroendocrine, and neuroepithelial phenotypes. This review will provide a practical overview of these emerging entities and their application to diagnostic challenges in the post-WHO sinonasal neuroendocrine and neuroectodermal tumor classification.
Adamantinoma-like Ewing sarcoma (ALES) is a rare variant of Ewing sarcoma that is defined by complex epithelial differentiation, including expression of cytokeratin and p40 and frequent keratin pearl ...formation. In recent years, ALES has been increasingly recognized in the head and neck, where it can mimic a wide range of small round blue cell tumors and basaloid carcinomas. However, there has been persistent controversy regarding whether ALES is best classified and managed as a sarcoma or carcinoma. This review summarizes the characteristic clinical, pathologic, immunophenotypic, and molecular features of ALES with an emphasis on differential diagnosis and tumor classification.
Evaluation of minor salivary gland biopsy can be fraught with a wide range of problems, including technical limitations due to the small size and distorted nature of tissue received and interpretive ...difficulties navigating the considerable morphologic and immunohistochemical overlap between widely disparate entities. As such, common pathologic findings can evoke a perplexing differential diagnosis that encompasses malignant, benign, and non-neoplastic processes. This review will present the diagnostic considerations that arise from four histologic patterns that are frequently encountered on minor salivary gland biopsies: squamous differentiation, tubular and cribriform growth, mucin production, and myxoid stroma. The discussion herein will emphasize practical strategies and priorities for navigating these differential diagnoses in a clinically-relevant and cost-effective manner.
Secretory carcinoma of the salivary glands, also known as mammary analogue secretory carcinoma, is a recently described tumor characterized by generally indolent clinical behavior and recurrent ...ETV6-NTRK3 fusions. However, a small subset of recent cases with high-grade histology, aggressive behavior, or alternate molecular findings are expanding the spectrum of this entity. In this case, a 59-year-old female presented with an infiltrative submandibular gland tumor that was originally classified as a high-grade acinic cell carcinoma, papillary-cystic variant. She developed persistent local disease and, 11 years after initial presentation, was found to have widespread metastases. Rereview of her primary tumor highlighted microcystic, papillary, and solid architecture, eosinophilic cytoplasm, vesicular nuclei with prominent nucleoli, abundant mitotic figures, and necrosis. Immunostains showed the tumor cells to be positive for S100 and mammaglobin and negative for DOG-1, and fluorescence in situ hybridization highlighted an ETV6 rearrangement, supporting a diagnosis of high-grade secretory carcinoma. Finally, next-generation sequencing demonstrated a novel ETV6-MET fusion. To our knowledge, this is the first ETV6-MET fusion reported in secretory carcinoma. This finding further expands the definition of secretory carcinoma while carrying implications for selecting appropriate targeted therapy.
Biphenotypic sinonasal sarcoma (BSNS) is a recently recognized low-grade sarcoma that exhibits both neural and myogenic differentiation. This unique dual phenotype stems from recurrent rearrangements ...in PAX3 , a transcription factor that promotes commitment along both lineages. While identification of PAX3 rearrangements by fluorescence in situ hybridization (FISH) can confirm a BSNS diagnosis, this assay is not widely available. This study evaluates whether an expanded immunohistochemical panel can facilitate recognition of BSNS without molecular analysis. Eleven cases of BSNS were identified from the surgical pathology archives of two academic medical centers. In 8 cases, the diagnosis was confirmed by FISH using custom probes for PAX3. In 3 cases FISH failed but histologic and immunophenotypic findings were diagnostic for BSNS. All 11 BSNS (100%) were at least focally positive for S100 as well as calponin and/or smooth muscle actin. In addition, 10 of 11 (91%) expressed nuclear β-catenin, 8 of 10 (80%) expressed factor XIIIa, 4 of 11 (36%) expressed desmin, and 3 of 10 (30%) expressed myogenin. All 11 tumors were negative for SOX10. While no single marker resolves immunohistochemical overlap between BSNS and its histologic mimickers such as nerve sheath tumors, an extended immunohistochemical panel that includes β-catenin and SOX10 helps to support the diagnosis of BSNS without the need for gene rearrangement studies.
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