Sinonasal malignant tumours are diverse, complex & uncommon cancers that account for only 0.5% of all cancers in body and about 3% of all Head & Neck cancers. Nonetheless, these are important as these offer considerable therapeutic challenge to Head & Neck oncologists because of the complex anatomy of the site, close proximity to the vital structures and delayed presentation following relatively non-specific symptoms. These are equally important from viewpoint of diagnostic pathology because of varied histologic types with overlapping morphologic features, translating into diverse biological behaviour. Newly described & rare entities add a new dimension to the existing complexities.

For a systematic approach to microscopic evaluation of sinonasal tumors in general, please refer to CAP guidelines of cancer protocols on “Upper aerodigestive tract” (www.cap.org). This write up elucidates the relatively specialized and newer entities pertaining to sinonasal region.

Squamous Carcinoma : It is a predominant type of cancer accounting for 46 to 80 % of all malignant tumours at this site, the non-squamous malignant tumours accounting for 20 to 30%. Though conventional squamous carcinoma is easy to diagnose as such on biopsy, the rare variants of squamous carcinoma, namely basaloid and spindle cell variant may be misdiagnosed as adenoid cystic carcinoma and sarcoma respectively. Awareness of the special types and application of appropriate immunohistochemical markers facilitate the diagnosis. There is a need to recognize these variants, since both are aggressive tumors with poor outcome.

Adenocarcinoma : It forms the bulk of non- squamous cancer. These are clearly divided into those taking origin from the surface mucosa [Non-salivary types] and those arising from seromucous glands [Salivary types].
Adenocarcinoma-Salivary Type: is much more common than Non-salivary type. It arises preferentially in the maxillary sinus & nasal cavity whereas Non-salivary type of adenocarcinoma arises in the ethmoid sinus. Adenoid cystic carcinoma is the most common subtype, accounting for 40-80% of salivary type of adenocarcinoma. Even though each type is further sub-divided, the distinction from each other can be made relatively easily based on the morphologic diagnostic criteria. Moreover the histologic subtype does not translate into significant difference in the management.

Adenocarcinoma-Non-salivary Type: is interesting & rare group of primary sinonasal tumours which can be further divided into low grade adenocarcinoma & Intestinal type of adenocarcinoma. It is important to recognize these tumours, as low grade adenocarcinomas have much better prognosis than Intestinal type which are usually of high grade. Primary sinonasal intestinal type adenocarcinoma should be diagnosed as such after ruling out metastasis from GI tract & lung primary.

Poorly Differentiated Malignant Tumours : It is a group of tumors composed mainly of small cells which poses diagnostic problems even to an experienced eye. Misinterpretation is very common on light microscopy due to lack of awareness of new entities & overlapping morphologic features. This notorious group includes sinonasal undifferentiated carcinoma [SNUC], sinonasal neuroendocrine carcinoma [SNEC] & poorly differentiated olfactory neuroblastoma. [ONB] Though all the three tumours form a spectrum of neuroepithelial tumours & share the anatomical site of ethmoid sinus, they differ in their cell of origin, degree of neuroepithelial differentiation & more importantly biologic behavior. ONB arises from pleuripotent progenitor cells of olfactory mucosa. SNEC from APUD cells of seromucinous glands & SNUC from Schneiderian epithelium. ONB displays bimodal peak of age incidence in second & sixth decade & hence enters the differential diagnosis of tumours occurring at higher age group also.

Scope and Limitations of Imaging : The modern imaging modalities delineate the local extent of tumour with its possible epicenter. They often indicate the malignant nature of the sinonasal mass, but do not help in their differential diagnosis into prognostically distinct clinico-pathologic categories. The onus of the accurate diagnosis of sinonasal cancer, thus, rests solely on the histopathologist.

Histologic Basis of Subtyping: Elvio Silva separated the ONB & SNEC of the nasal cavity based on microscopic features & proposed a new classification in the early eighties. He pointed out that the key microscopic feature for diagnosis of ONB is fibrillary material between the cells popularly known as “neuropil”. This is observed in 86% of cases of ONB in conjunction with Homer-Wright rosettes. The neuropil is never seen in SNEC. The interlobular fibrovascular stroma, sharply defined nests & sustentacular cells at the periphery of the nests are the other characteristic features of ONB.

Grading of ONB: The experience of Hyams & his colleagues at the AFIP supported the use of their grading system called “Hyams’ grading system” for ONB. Identification of grade I & II ONB which are differentiated tumours is easy & straightforward on light microscopy. The diagnosis of grade III ONB, though poorly differentiated, is also not difficult in view of focal but definite neurofibrillary background & occasional Flexner rosette which can be appreciated on light microscopy. However, the diagnosis of grade IV ONB can be rather difficult, as these tumours may fail to exhibit any kind of neuronal differentiation on light microscopy, especially in the limited material available in a biopsy. The lack of neuronal differentiation & aggressive histology thus lead to misinterpretation of high grade ONB as SNEC or SNUC.

Role of Ancillary Techniques: Immunohistochemistry [IHC] & electron microscopy [EM] are useful in distinguishing grade IV ONB from SNEC & SNUC as these highlight the neuronal differentiation which is not apparent on light microscopy. Focal synaptophysin & neurofilament protein immunopositivity in tumor representing neurofibrillary material & characteristic S100 positivity accentuating sustentacular cells clinch the diagnosis of ONB. Tumour cells may show focal positivity with CK but diffuse positivity is rarely evident.
Neurite like cell processes containing neurofilaments, longitudinally arranged microtubules & dense core neurosecretory granules with synaptic vesicles are ultrastructural diagnostic hallmarks in cases of poorly differentiated [grade III &IV] ONB. Detection of sustentacular cells puts any doubt to rest regarding the histologic type. Perez-Ordonez reviewed the cases reported as SNEC & demonstrated that ultrastructural features of these tumours were more in keeping with ONB rather than SNEC. A large number of cases previously reported as SNEC at our centre, upon review in conjunction with immunohistochemistry were reclassified as high grade ONB.

Differential Diagnosis: Neuroendocrine carcinoma, in Head & Neck region in general, arises in the mucosal areas rich in seromucous glands such as larynx & palate. The occurrence at sinonasal region is rare. SNEC may be covered by intact Schneiderian epithelium & associated with benign glandular epithelium. These tumors can show a range of cell types varying from small, polygonal to spindle shaped. It is the small cell type SNEC which closely mimics poorly differentiated ONB. Nesting pattern, nuclear moulding, high mitotic activity, necrosis & crushing artefacts are salient diagnostic features of small cell type SNEC. Lack of neurofibrillary background, Homer-Wright rosettes & sustentacular cells further distinguish it from ONB. However the distinction may be difficult on conventional light microscopy. In such a case diffuse & strong immunopositivity with CK/EMA distinguishes SNEC from ONB. Pathologists should be aware of these two closely related entities & should apply ancillary diagnostic techniques, whenever necessary to distinguish between the two. The need for distinction is obviously for much better survival associated with even higher grades of ONB & also different treatment modalities. Surgical resection involving craniofacial approach is the primary line of treatment in ONB.

SNUC is a rare but highly aggressive, rapidly enlarging, clinicopathologically distinctive type of carcinoma of sinonasal region. It is composed of light microscopically undifferentiated cells exhibiting minimal neuroendocrine differentiation immunohistochemically & ultrastructurally. Nuclear pleomorphism, prominent nucleoli, moderate amount of cytoplasm, distinct cytoplasmic border, invariable high mitotic activity, comedo type necrosis & vascular invasion are the salient histologic features which set SNUC apart from small cell type SNEC. The latter is characterized by monomorphic nuclei, indistinct nucleoli, scanty cytoplasm & indistinct cytoplasmic border. Both tumours usually show diffuse positivity with CK & EMA on IHC. SNEC, in addition, shows diffuse positivity with at least two neuroendocrine markers viz NSE, chromogranin and synaptophysin. SNUC shows only focal NSE positivity. In addition CK 7, CK 8 & CK 19 positivity may be encountered in SNUC. Moreover “in situ carcinoma” in the overlying epithelium, when present, supports the diagnosis of SNUC.

Prognosis : The Hyams’ grading system and Kadish’s staging system have been proved to be independent predictors of outcome in ONB. Grade of ONB also predicts the response to chemotherapy. Higher the grade, better is the response. This helps oncologists in planning the right treatment modality. Though SNUC & small cell SNEC have differing morphologic & immunohistochemical characteristics, both behave aggressively & share virtually indistinguishable clinical outcomes with higher rates of systemic failure. Among ONB, SNUC and SNEC, ONB represents the better differentiated tumor with the best prognosis. SNUC & SNEC on the other hand have dismal prognosis. Rosenthal has reported promising results in 2004 with overall 5 year survival rate of 93.1 % for patients with ONB, 64.2% for patients with SNEC and 62.5% for patients with SNUC, the least differentiated tumour. The improved outlook in SNUC is essentially following upfront aggressive chemo-radiotherapy for confirmed cases of SNUC.

Sino-nasal melanoma : It is easy to diagnose melanoma when pigmented. When amelanotic & composed exclusively of small round blue cells arranged in nests, it closely mimics SNEC. High index of suspicion is necessary for diagnosis. The favored sites for melanoma in sinonasal region are nasal cavity & maxillary antrum. Presence of scanty melanin pigment in tumor cells & junctional activity in the overlying epithelium along with strong S100 & HMB 45 immunopositivity are important distinguishing features. When in dilemma, particularly if HMB45 is negative & S100 is weakly positive, EM should be performed to look for premelanosomes which is an ultrastructural diagnostic hallmark of amelanotic melanoma. This rules out other rare primary tumours like malignant peripheral nerve sheath tumour & myoepithelial carcinoma which also show S100 positivity.

Clinicopathologic perspective :
Head & Neck oncologists should be fully aware of the morphologic diversity & overlapping morphologic features of the sinonasal malignant tumours, which lead to histopathologic diagnostic dilemma. Therefore, if the biopsy material is inadequate & IHC is non-contributory, pathologist should not hesitate to demand repeat biopsy which is preferable to attaining incomplete diagnosis. A piece of tissue should be fixed prospectively in glutaraldehyde for EM study at the time of biopsy.

An accurate histopathologic diagnosis is the pre-requisite for planning effective multimodality therapy as histologic type & grade together not only indicate the biological behaviour, but also reflect on chemosensitivity & radiosensitivity of an individual sinonasal tumour. In short, these serve as prognostic as well as predictive markers & have a great impact on the management.

Once surgical resection is performed, pathologist should clearly mention in the report the extent of microscopic involvement of the cribriform plate, ocular structures, pterygo-maxillary fossa, infratemporal fossa etc for accurate pathologic staging of the tumor. Besides, extension to pterygomaxillary fossa & invasion of dura are poor prognostic features. The status of all the resection margins should be noted which decides the adequacy of the resection. This in turn forms the basis for planning adjuvant therapy post- operatively. It is worth noting that complete resection is the most important prognostic factor irrespective of the histologic type or grade in an operable cancer & should be aimed at in early stages of the sinonasal cancer.

In conclusion, pathologists should be aware of diagnostic challenges and diagnostic criteria of newer entities of sinonasal malignant tumors. They should apply ancillary diagnostic techniques as well as evidence based guidelines judiciously. Accurate diagnosis and staging can be ensured if pathologists work in tandem with oncologists. In fact, joint multi-disciplinary meetings are crucial in planning the treatment strategy, based on histologic parameters and imaging findings. This will not only ensure optimal therapy but also spare the patient from potentially toxic therapy.

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