|Year : 2021 | Volume
| Issue : 2 | Page : 73-79
Small round cells in sinonasal tract: Pathologists approach for the “blues”
Hiran Kattilaparambil Ravindran
Department of Pathology, Burjeel Hospital, Abu Dhabi, United Arab Emirates
|Date of Submission||12-Sep-2021|
|Date of Acceptance||13-Sep-2021|
|Date of Web Publication||17-Dec-2021|
Dr. Hiran Kattilaparambil Ravindran
Burjeel Hospital, Abu Dhabi
United Arab Emirates
Source of Support: None, Conflict of Interest: None
The sinonasal cavities host a wide variety of undifferentiated malignancies with round cell morphology. The differential diagnosis is difficult for a practicing surgical pathologist, especially on very small sample, sometimes with artifactual changes. The correct classification is clinically relevant as it has implications on the management. Further, newer entities are added as we expand our understanding in these tumors. The aim of this review is to provide a comprehensive review of the variety of tumors we encounter, try for a broader classification based on histological hints as well as with an initial panel of immunohistochemistry. The further classification as individual entities is also described with their characterizing features, with a special reference to the ancillary testing to give a more objective picture. Overall, prognosis and general approach for managing the specific entity are also addressed in a nutshell.
Keywords: Esthesioneuroblastoma, head-and-neck cancers, sinonasal tumors, small round cell neoplasms
|How to cite this article:|
Ravindran HK. Small round cells in sinonasal tract: Pathologists approach for the “blues”. J Head Neck Physicians Surg 2021;9:73-9
|How to cite this URL:|
Ravindran HK. Small round cells in sinonasal tract: Pathologists approach for the “blues”. J Head Neck Physicians Surg [serial online] 2021 [cited 2022 Jan 20];9:73-9. Available from: https://www.jhnps.org/text.asp?2021/9/2/73/332722
| Introduction|| |
Sinonasal tract occupies a relatively small space in the head-and-neck region but has a complex anatomy and is notorious for the variety of neoplasm arising in them. The issue is more complex when there is a small round cell neoplasm arising in this location. Sinonasal tract malignancies occur at a low frequency (0.83 cases per 100,000 population per year). The differential diagnosis is challenging, particularly on small biopsy specimens and sometimes associated with artifactual changes (crushing/cautery artifact) in the sample. This article aims to discuss the differentials and to review the approach to these neoplasms.
| Approach|| |
For small round cell tumors, Lester Thomson recommends the mnemonic “MR SLEEP” or “MRS LEEP” as it highlights a series of tumors that must be considered in the differential diagnosis: Melanoma, mesenchymal chondrosarcoma, rhabdomyosarcoma, sinonasal undifferentiated carcinoma (SNUC), squamous cell carcinoma (including NUT carcinoma), small cell osteosarcoma, lymphoma, esthesioneuroblastoma (olfactory neuroblastoma), Ewing sarcoma/primitive neuroectodermal tumor, pituitary adenoma, and plasmacytoma. Even though this mnemonic encompasses common differentials for round cell neoplasms in this area, more recent entities are described in this area with significant treatment and prognostic implications. Hence, in this paper suggests another approach to try and classify (even though arbitrary as some immunohistochemistry [IHC] overlap) into broad categories such as epithelial, neurectodermal, mesenchymal, and hematolymphoid after a careful evaluation of histology and initial panel of IHC. The initial IHC recommendation varies with practice but is prudent to include epithelial markers such as pancytokeratin, neuroendocrine markers such as synaptophysin and hematolymphoid markers such as LCA, and some people also include Desmin (Marker for Rahbdomyosarcoma) and SOX-10 (Marker for Melanoma). Further IHC markers and molecular testing are done to depending upon the results with initial panel. The initial subcategorization into four different entities and then exclusion by doing further markers and ancillary testing is helpful in not missing the proper diagnosis for these difficult entities.
The tumors included in this category are strongly positive for epithelial markers, especially high-molecular-weight keratins and basal like keratins, but may show weak or patchy expression of neuroendocrine markers. If the tumor cells are diffusely and strongly positive for pancytokeratin, the differentials considered are nonkeratinizing and basaloid squamous cell carcinomas (as keratinizing ones are usually evident in histology with features of squamous differentiation), SMARCB-1 deficient carcinomas, NUT carcinomas, solid variant of adenoid cystic carcinoma (ACC), HPV-related carcinoma with adenoid cystic like features, SNUC, and lymphoepithelial carcinoma. Hence, the next panel generally includes more specific squamous markers such as p40, OSCAR, CK 5/6, p63, as well as specific marker like NUT, INI-1, EBER, myoepithelial markers like S100, Calponin, actin, and HPV-related markers such as p16 and HPV-ISH. Of the squamous markers, p40 is considered most specific. [Chart 1].
Nonkeratinizing squamous cell carcinomas
They show no obvious squamous differentiation in H and E sections but are positive for specific squamous markers such as p40, OSCAR, CK 5/6, and p63. 30%–50% cases show high risk HPV which may be associated with improved survival, although the prognostic significance is not as clearly defined as it is in the oropharynx. Basaloid squamous cell carcinomas are distinguished based on the morphology alone as immunohistochemical features are similar.
NUT carcinoma is a poorly differentiated carcinoma that shows abrupt squamous differentiation and is defined by the presence of NUTM1 gene rearrangement by IHC, FISH, RT-PCR, or by NGS. They are positive for PanCK, p40, CK 5/6, and p63. CD34 is seen in 55% cases. They can show positivity for neuroendocrine markers, p16 and TTF-1. Prognosis is poor with overall median survival of 9.8 months.
Adenoid cystic carcinoma
ACC is a salivary gland tumor and the especially the solid variant of ACC shows a similar immunohistochemical profile, as in basaloid squamous cell carcinoma although p63 is usually positive at the periphery of the tumor nests, and p40 expression is more limited. Myoepithelial markers are helpful (S100, Calponin, actin, and p63) and are in the periphery of the nests with CD117 and PanCK more in ductal areas. If they show marked nuclear atypia with mitosis and necrosis possibility of HPV-related carcinoma with adenoid cystic like features needs to be considered in the differential. Surface epithelial dysplasia, absence of MYB gene rearrangement, and HPV association are used for separating these entities.
Adamantinoma-like Ewing sarcoma
Adamantinoma-like Ewing sarcoma is a rare tumor that demonstrates the EWSR1-FLI1 translocation characteristic of Ewing sarcoma despite overt epithelial differentiation including diffuse expression of cytokeratins and p40.
SMARCB-1 deficient carcinomas
They are positive for pan-cytokeratins and show variable expression of p63 and p40. SMARCB1 (INI1) is negative and fluorescence in situ hybridization shows SMARCB1 deletion. The prognosis is poor with more than half of patients suffering disease-specific death.
Sinonasal undifferentiated carcinoma
SNUCs are rare, clinically aggressive tumors without glandular or squamous features. They are positive for panCK and simple keratins such as CK7 and CK8 but are more squamous specific isoforms such as p40 and CK 5/6. They show variable positivity for neuroendocrine markers and p63. They are CD117 positive and are consistently p16 is positive regardless of HPV status. The prognosis is poor with improvements in recent years with aggressive multimodality therapy. Patient survival is significantly better with primary surgical resection.
The tumors included in this category are neurectodermal in origin or show a strong positivity for neuroendocrine markers and show weak or patchy cytokeratin positivity. The high-molecular-weight keratins and basal like keratins are not diffusely expressed in this group [Chart 2].
Olfactory neuroblastoma (aesthesioneuroblastoma)
Olfactory neuroblastoma [Figure 1], [Figure 2], [Figure 3], [Figure 4] is unique to this site. It is a malignant neurectodermal tumor often localized to superior nasal cavity and ethmoid sinuses. Hyams grading is related to the degree of maturation, amount of neuropil, mitoses, necrosis, and pleomorphism and is strongly correlated to outcome. The neoplastic cell nests are positive for neuroendocrine markers such as synaptophysin, chromogranin, and CD56 with peripheral sustentacular cell staining for S100 and Glial fibrillary acid protein (GFAP). The closer differentials in a low grade tumor are pituitary adenoma and SNUCs are difficult to differentiate from a high-grade aesthesioneuboblastoma. The cases are primarily managed surgically with radiation and chemotherapy in certain settings. The outcome is primarily related to the grade and stage of the tumor.
|Figure 2: Individual cells have moderate eosinophilic/clear cytoplasm. H and E, ×100|
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|Figure 3: S100, immunohistochemistry highlighting the peripheral sustentacular cells|
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This tumor is not to be missed in the vast sea of malignant small round tumors of sinonasal tract. Morphologically might mimic a low grade olfactory neuroblastoma if the tumor has predominant nesting pattern but the presence of sustentacular cells highlighted by S100 and GFAP in aesthesioneuroblastoma is a useful hint as these tumors also are strongly positive for the neuroendocrine markers. IHC for CAM 5.2 and presence of pituitary hormones as well as transcription factors in the tumor nests are other helpful features in differentiation. These tumors are treated with antihormonal therapy or surgery and radiation if surgical management is not feasible.
Sinonasal neuroendocrine carcinomas show morphological and immunohistochemical features of neuroendocrine differentiation. They can be small cell or large cell depending on the size of the cells. They show strong reactivity with at least one of the neuroendocrine markers; synaptophysin, chromogranin, CD56, and often show perinuclear dot like staining with cytokeratins (AE1/AE3 and CAM 5.2) and EMA. P16 is strongly expressed but are consistently negative for EBER.
Sinonasal mucosal melanomas
Mucosal melanomas [Figure 5], [Figure 6], [Figure 7], [Figure 8] arise from the melanocytes of the lining mucosa. Immunohistochemistry is the key to diagnose these tumors when pigmentation is absent. S100 and SOX10 are more useful than HMB-45, tyrosinase, MITF, and melan A as the degree of expression varies. Outcome is poor in spite of the multimodality treatment probably by the high tumor stage by the time of detection.
|Figure 5: Atypical cells mainly located in subepithelial zone. H and E, ×100|
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|Figure 6: Melanoma cells with prominent nucleolus. Minimal focal melanin pigment may be appreciated. H and E, ×400|
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The neoplasms included in this category include wide variety of mesenchymal tumors, but of special importance in this area are mesenchymal chondrosarcoma, rhabdomyosarcoma, small cell osteosarcoma, and Ewings/PNET.
A biphasic tumor showing small round cell neoplasm as well as islands of differentiated hyaline cartilage. The neoplastic cells are positive for CD99, CD56, and NSE and variable with GFAP, desmin. They are negative for keratins and S100. Regulator of chondrogenesis, SOX9, is a helpful marker. These tumors are treated by primary resection followed by chemotherapy.
Rhabdomyosarcoma [Figure 9] and [Figure 10] with its subtypes such as embryonal, alveolar, and pleomorphic form an important group of small round cell neoplasm. They are characteristically positive for desmin, Myo D1, and myogenin. Chromosomal translocations of t(2;13)(q35;q14) and t(1;13)(p36;q14), resulting in PAX3-FOXO1 (FKHR) and PAX7-FOXO1 (FKHR) gene fusions have been found to be specific molecular markers for alveolar rhabdomyosarcomas and can be identified in approximately 80% cases. These tumors are managed by surgery, chemotherapy, and radiation.
Small cell osteosarcoma and Ewings/PNET
The presence of osteoid is required for the diagnosis of small cell osteosarcoma; it is often focal, making the diagnosis often extremely difficult. The t(11;22) (q24;q12) translocation is diagnostic for Ewing sarcoma/PNET as CD99 is usually positive in both these entities. The treatment of small cell osteosarcoma has not been optimized (owing to its rarity), small cell osteosarcoma is most often treated like conventional osteosarcoma, with neoadjuvant chemotherapy followed by surgical resection.
The sinonasal tract is involved by a wide range of hematolymphoid malignancies, including lymphomas of B- and T-cell lineage, extramedullary plasmacytoma, granulocytic sarcoma, and histiocytic sarcoma. Of particular importance in the sinonasal area are nasal natural killer (NK)/T-cell lymphomas and plamacytomas. NK/T cell lymphomas; [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15]: They have a characteristic angiocentric/angioinvasive growth pattern and are positive for CD2, cytoplasmic CD3 (CD3e), CD56, granzyme B, TIA-1, and perforin. EBV is detected using Epstein − Barr Virus by in situ hybridization (ERER-ISH). Plasmacytomas tend to have nucleus pushed to one end and show characteristic clock phase chromatin pattern. They are positive for CD38 and CD138 with light chain restriction for Kappa or Lambda.
|Figure 11: Small round cells with perivacular pattern and areas of necrosis. H and E, ×100|
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| Conclusion|| |
Sinonasal small round cell neoplasms were pathologist's blues. Careful correlation of site of origin, radiology, and histology along with pertinent positive and negative IHC studies as well as ancillary testing would make the life easier for a pathologist.
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