Section 4 -

Oncocytic Tumors Margaret Brandwein-Gensler U.S.A.

Oncocytic tumors are relatively rare, representing 1.9% of over 8000 parotid consultations received at the AFIP. [1] A series of 68 patients with oncocytic salivary tumors, 84% occurred in the parotid, 11% in the submandibular gland and 5% were incidental findings within cervical lymph node. [2] There is no gender predilection. [2, 3] A history of previous radiation exposure has been documented in 20% of patients with oncocytic tumors, and these patients tend to present two decades earlier. [2] Familial association, and association with Birt-Hogg-Dube syndrome have been reported. [4, 5] Bilateral oncocytomas may occur in 7% of cases, these are usually associated with diffuse oncocytosis rather than single tumor nodules. [2, 5, 6] Blanck noted that bilateral oncocytomas occur more frequently than the coincidence of other bilateral salivary tumors. [6] On gross examination, parotid or submandibular oncocytomas may appear as single, small, well-circumscribed, brown tumors, which may have central star-like fibrosis. Cyst formation may be seen. Oncocytomas may also occur as part of a generalized process, oncocytosis, in which the entire gland undergoes oncocytic metaplasia and hyperplasia. In this case the glandular architecture is entirely replaced by multiple brown, tan nodules, some which central scarring, with some dominant tumor nodules. Histologically, most oncocytic tumors are solid, with a variable cystic component. The oncocytes form organoid nests and trabeculae. Cytologically, oncocytes can be cuboidal with abundant bright pink granular cytoplasm and decreased ratio compared to normal parotid ductal cells. They can also have a columnar shape, in which case the nuclear\cytoplasmic ratio remains relatively normal. Oncocytic nuclei are typically very round and centrally placed, the nucleoli may be single and prominent. "Pyknocytes", oncocytes with shrunken condensed nuclei, may be seen. The presence of tall oncocytes with tapered ends, binucleated cuboidal oncocytes, and pyknocytes may be useful is distinguishing oncocytomas from other salivary neoplasms (see below). Tumor hyalinization can be present entrapping nodules of oncocytes and giving a false impression of invasion. Likewise, oncocytomas may be hypervascular with dilated vessels, giving the false effect of vascular invasion. Clear cell change within oncocytes, a seemingly contradictory concept, may cause diagnostic confusion for clear cell oncocytomas may resemble acinic cell carcinomas. [2, 7] An association between clear cell oncocytosis, prior facial radiotherapy, bilateral multifocal disease, and recurrence after parotidectomy has been seen. [12] Ultrastructural examination has shown that glycogen accumulation may be responsible for this clear change. [9, 10] Careful histological examination reveals eosinophilic oncocytes scattered among the clear oncocytes. Oncocytosis of the surrounding parotid gland is also very common; it produces a "checkerboard" pattern of parotid adipose tissue and oncocytic nodules. This finding may also be helpful in establishing the diagnosis of oncocytoma, as opposed to other clear cell entities. The pathological differential diagnosis includes acinic cell carcinoma, clear cell carcinoma, mucoepidermoid carcinoma, high-grade salivary duct carcinoma and metastatic renal cell carcinoma. The balloon cell variant of melanoma is also a "clear cell" tumor and may metastasize to periparotid lymph nodes. Identification of tapered oncocytes, binuclear oncocytes, pink granular cytoplasm, and surrounding parotid oncocytosis is very helpful in establishing the correct diagnosis. Phosphotungstic acid hematoxylin stain, incubated over for 48 hours (rather than the standard overnight incubation) is also helpful; the mitochondria appear as cytoplasmic blue granules under oil immersion microscopy. Electron microscopy (EM) may be the final arbitrator in distinguishing mitochondria from zymogen granules. The ultrastructural morphological alterations seen in oncocytomas suggest that tumorigenesis is primarily due to mitochondrial alterations. There is a growing awareness of the significance of mitochondrial DNA (mtDNA) deletions in various disease states, and point mutations in a number of cancers, including head and neck carcinoma. Deletions in mtDNA have been associated with cigarette smoking. Warthin's tumors, which are also characterized by abundant, morphologically altered mitochondria, have been clearly associated with smoking. [11] Therefore it is logical to investigate the role of mtDNA mutations in Warthin's tumors and oncocytomas. [12, 13, 14] mtDNA deletion at 4977bp ("common deletion") was found in parotid tissues of both smokers and non-smokers, with an age accumulation effect. However point mutations (specific base substitutions) were present in the parotid tissue of 5 of 23 smokers, but not in any of the 16 non-smokers. [13] The majority of parotid and submandibular oncocytomas behave in a benign fashion after resection, even if rare aggressive features such as perineural invasion have been identified. [2] Local recurrence is unusual and often the result of persistent multifocal oncocytosis in the remaining deep parotid lobe. Malignant parotid or submandibular oncocytomas are very unusual, but have been documented. These tumors may be either locally aggressive or infiltrative or can metastasize, either to cervical lymph nodes or in a widespread fashion to CNS, bone, liver and lung. [2, 15, 16, 17, 18, 19] Although many of these reports have short follow-up periods, some papers have documented a protracted course with single or multiple local recurrences and distant metastases. Tumor related mortality might occur up to a decade after the original diagnosis. Malignant parotid and submandibular oncocytomas usually appear aggressive from the onset, only rarely may there be evidence of pre-existing benign oncocytoma or oncocytosis. References Auclair PL, Ellis GL, Gnepp DR, et al: Salivary gland neoplasms: General consideration. In: Surgical Pathology of the Salivary Glands, Ellis G, Auclair P, Gnepp DR , and Ed. WB Saunders Philadelphia PA, 1991, pg. 144. Brandwein MS, Huvos AG: Oncocytic tumors of major salivary glands. A study of 68 cases with follow-up of 44 patients. Am J Surg Pathol 1991, 15:514-28. Thompson LD, Wenig BM, Ellis GL: Oncocytomas of the submandibular gland. A series of 22 cases and a review of the literature. Cancer 1996; 78:2281-7. 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