Sine Qua Non: Oncocytoma

Abstract

Oncocytomas of the salivary gland are uncommon neoplasms that are characterized by polygonal cells with abundant granular eosinophilic cytoplasm and relatively uniform nuclei. They are benign in nature and have a low recurrence rate with complete surgical excision. Though uncommon, oncocytic and clear cell variants of malignant tumors may histologically mimic oncocytomas and identification of their distinguishing features is essential. A classic example of an oncocytoma is discussed.

History: A 63-year-old female patient presented to otolaryngology clinic after a 1.6 cm superficial left parotid mass was identified on imaging. The mass was first identified incidentally on CT scan of the orbits to evaluate for causes of the hypertropia. The CT scan incompletely showed an ovoid hyperattenuating lesion within the superficial left parotid gland. The patient underwent further evaluation with MRI, which confirmed a 1.4 × 0.7 × 1.6 cm mass that had diminished T1 and T2 signals without restricted diffusion (Fig. 1). High-resolution postcontrast imaging showed thin peripheral enhancement and small central vessels. Per the patient, the lesion was present for approximately 1 year and fluctuated in size. The physical examination performed revealed a palpable mass, which had ultrasound findings compatible with a lymph node. Fine needle aspiration was performed, which revealed scant tissue composed of predominantly benign salivary components with a few clusters of oncocytes (Fig. 2). No features of a lymph node were identified. The patient was scheduled for a superficial parotidectomy and 12 months following the procedure, the patient had fully recovered, and imaging (MRI) showed no evidence of parotid pathology.

Fig. 1.

T2-weighted MRI with hypointense tumor of the left parotid gland

Fig. 2.

Cell block from FNA of left parotid gland showing clusters of oncocytes

Histologic findings: Gross examination of the resected tissue revealed an irregular excision with a well-circumscribed, rubbery, tan-red lesion. Microscopic examination demonstrated a circumscribed, partially encapsulated mass surrounded by mature adipose and normal salivary gland tissue (Fig. 3). The cells were arranged in solid sheets, nests, and trabeculae separated by thin fibrovascular septa. Occasional acinar formations were identified (Fig. 4). The cells consisted of abundant, granular eosinophilic cytoplasm with round to ovoid vesicular nuclei, often with a single prominent nucleolus. Mitoses, invasive features, necrosis, and an inflammatory infiltrate were not identified. The surgical specimen was diagnosed as an oncocytoma.

Fig. 3.

Oncocytoma and surrounding normal salivary gland tissue and adipose

Fig. 4.

Tubular/acinar formations within the oncocytoma

Discussion: Oncocytomas of the salivary glands are benign neoplasms, composed of large, mitochondria-rich epithelial cells called oncocytes, that account for approximately 2% of all salivary neoplasms. The parotid gland is the most commonly affected site (70–80%), though cases have also been reported in the submandibular and minor salivary glands [1]. Oncocytomas are tumors of late adulthood, typically affecting patients in their 6th-8th decade of life. Patients with a history of radiation exposure or those that develop the tumor in the submandibular gland may develop the lesion at a relatively younger age [1]. Children usually do not develop this tumor; however, exceptions exist. For instance, Zhou et al. reported a case of a 6-year-old male patient with a parotid gland oncocytoma who had no known history of radiation exposure [2]. Studies have reported no overall sex predilection, and ethnically, these tumors are generally found in patients of Caucasian descent [3].

Oncocytomas have excellent prognosis, and complete surgical excision, which is the treatment of choice, is generally curative [2, 4–6]. Radiation therapy is not recommended since oncocytes are radioresistant [5]. Recurrence of oncocytomas has been reported in less than 20% of cases and is generally associated with inadequate excision or multifocality [4, 6–8]. Although existing literature does not provide any conclusive evidence of malignant transformation, some case reports have indicated it to be possible [2, 8–12], and long-term follow-up is recommended after excision [2, 5, 6].

Based on clinical features alone, oncocytomas are not distinguishable from other benign and low-grade salivary tumors [6, 7]. Patients are usually asymptomatic, presenting with a painless, slow-growing, solitary mass or swelling [6, 7, 13]. The tumors are rarely cystic, and tend to be soft, well-circumscribed, tan to light brown in color, and 3–4 cm in size. The location at onset is usually unilateral but bilateral presentation has been observed in ~ 7% of cases [6]. Although benign in nature, on rare occasions oncocytomas can result in facial nerve palsy by pinching, and potentially causing ischemia, of the facial nerve [14]. In most cases, however, they tend to be non-threatening, and can exist for years without any harmful manifestation.

Pre-operative diagnosis of oncocytomas based on radiologic imaging or fine-needle aspiration cytology (FNAC) tends to be challenging due to the presence of overlapping features between salivary gland neoplasms. Ultrasonography observations, which typically include a hypoechoic mass with well-defined borders, are non-specific and can be associated with other benign parotid tumors such as pleomorphic adenomas [6, 15]. CT imaging commonly shows a well-demarcated mass displaying homogenous enhancements, which is also indicative of Warthin tumors (papillary cystadenoma lymphomatosum) and basal cell adenomas [4, 15–17]. On technetium-tcc99m pertechnetate radionuclide scans of salivary glands, oncocytomas show intense uptake of the nuclide, leaving Warthin tumors as the only other strong differential [4, 5]. Differentiation between Warthin tumors and oncocytomas using MRI images have been attempted with variable success. Oncocytomas are typically reported as being hypointense on T1 and T2-weighted images, and isointense with respect to native parotid gland on fat-saturated T2 and postcontrast T1 images. In contrast, Warthin tumors are usually observed to be hypointense on T1-weighted images and hyperintense on T2-weighted images [4–6, 14, 15, 18–21]. However, this is not always the case. For instance, Özcan et al. reported a deep lobe parotid gland oncocytoma with hyperintensity on T1 and hypointensity on T2 images [22] while Hamada et al. reported one with hypointensity on T1 and intermediate signal intensity to partial hyperintensity on T2 images [14]. A recent study by Kato et al. found that diffusion-weighted (DW) MR imaging with measurement of apparent diffusion coefficients (ADC) can help differentiate between Warthin tumors and oncocytomas since the latter tend to show higher ADCs and lower signal intensity ratios (SIR) on DW images [23]. However, further research is needed to confirm these findings.

FNA smears from oncocytomas show cohesive 2- and 3-dimensional groups of uniform, polygonal cells with abundant granular cytoplasm. Other cytologic features include well-defined intercellular borders, central, round, nuclei with prominent nucleoli, relatively clean background without lymphoid cells, lack of cytoplasmic vacuoles, and lack of mitotic activity [7, 24]. Based on these characteristics, it is challenging to differentiate oncocytomas from other oncocytic salivary gland tumors, and the reported sensitivity of FNAC is only about 29% [8]. Therefore, histopathology remains the gold standard for diagnosis.

Histologically, oncocytomas are well-circumscribed, encapsulated neoplasms consisting of oncocytes arranged in various patterns. The cells can be arranged in solid sheets, trabeculae, acini, and nests. The oncocytes are epithelioid cells consisting of abundant eosinophilic, granular cytoplasm. Their nuclei are uniform and round, with vesicular chromatin and prominent nucleoli. Histochemically, these tumors stain with PTAH, which demonstrates blue cytoplasmic granules representing the mitochondria. Furthermore, they will stain with immunohistochemical stains to include EMA, CK 8/18, CK19, basal cell markers (p63 and CK 5/6), and anti-mitochondrial antibodies. They notably will not stain for myoepithelial markers (SMA and calponin), PAX2, PAX8, S100, and SOX10 [2, 3]. The absence of these markers helps distinguish oncocytomas from mimickers described later. Oncocytomas do not harbor characteristic molecular alterations; therefore, characteristic genetic abnormalities of entities in the differential can be used to distinguish them from oncocytomas [3].

The differential diagnosis for oncocytomas can be broad, including non-neoplastic changes, benign neoplasms, and malignant neoplasms. Oncocytes can be found increased in number in normal salivary glands in association with aging. In fact, areas of oncocytic metaplasia are commonly seen in the normal salivary glands of older patients, and are frequently present in salivary gland tumors such as pleomorphic adenomas, basal cell adenomas, cystadenomas, mucoepidermoid carcinomas (MEC), and polymorphous adenocarcinomas. Histopathological features can help separate tumors displaying oncocytic metaplasia from oncocytomas, which consist predominantly of oncocytic cells [7, 25].

In addition to oncocytic metaplasia, non-neoplastic oncocytic changes in the salivary glands also include oncocytic hyperplasia, more commonly known as oncocytosis. When clustered as in nodular oncocytic hyperplasia, the line distinguishing a hyperplastic process from a neoplastic process such as in an oncocytoma becomes blurred. Nodular oncocytic hyperplasia may present as a clinically relevant mass, like an oncocytoma, and it may be very difficult to reliably differentiate between the two even through histological evaluation. In this scenario, the presence of a well-developed capsule, and unifocality of the oncocytic proliferation, is suggestive of an oncocytoma [1, 24, 25].

Though frequently microscopically unambiguous, some of the morphologic variations in architecture and cytology of oncocytomas should bring into consideration other neoplasms with oncocytic features. In some cases, oncocytomas can undergo cystic changes resulting in the formation of multiple cysts lined by oncocytes. A Warthin tumor, which is almost exclusively found within the parotid gland, classically demonstrates cysts lined with an epithelium composed of a double layer of oncocytes. However, Warthin tumors are also notable for a prominent lymphoid component that frequently includes germinal centers underlying the epithelium, which would not be seen in an oncocytoma [1, 2]. Another benign salivary gland neoplasm containing cysts with oncocytic epithelial lining is an oncocytic papillary cystadenoma. In these lesions, it is not common to observe extraluminal solid growth of oncocytes; instead, fibrous connective tissue is seen between the cysts. In contrast, an oncocytoma contains additional oncocytes with a delicate fibrovascular stroma separating the cysts. All three of these lesions are treated with surgical excision and are unlikely to recur if completely excised [1].

Oncocytomas can also exist as a clear cell variant. This variant appears to possess fewer mitochondria and a “clear” cytoplasm due to intracytoplasmic glycogen accumulation, along with displacement of organelles to the cell periphery and/or fixation artifacts. Such a feature should give rise to concern for clear cell malignancies, in particular metastatic renal cell carcinoma (RCC). While the two entities can share similar cytologic features, the infiltrative architectural pattern of a renal cell carcinoma, paired with a patient history consistent with metastatic RCC, helps clarify the diagnosis. Furthermore, immunohistochemical stains such as p63, which stains the basal-type cells in an oncocytoma but is negative in an RCC, and PAX-8 and PAX-2 which highlight the cells in an RCC but not an oncocytoma, can further clarify the diagnosis [25].

As the most common malignant salivary gland neoplasm, MEC is also an important consideration in the differential diagnosis of oncocytomas. MECs have variable architecture, dependent upon their grade, and are histologically characterized by the presence of three different cell types: epidermoid cells, mucous cells, and intermediate cells. Well-differentiated MECs tend to be well-circumscribed, with multiple mucin-filled cystic areas and a predominant population of mucous cells. On the other hand, high-grade MECs can appear to be more solid with intermediate and epidermoid cell types dominating and containing an infiltrative pattern. While the above-described features are not present in oncocytomas, there are two variants of MEC, the oncocytic variant and clear cell variant, that should not be overlooked when considering the diagnosis of an oncocytoma. The oncocytic variant of a MEC, and to a lesser extent, a MEC with oncocytic metaplasia can demonstrate a generalized population of oncocytes; however, cystic pools of mucin along with other characteristic features of a MEC can help to distinguish it from an oncocytoma. The same holds true for the clear cell variant of a MEC which contains an expanded population of clear cells. However, in cases where oncocytes or clear cells are by far the predominant cell type and the MEC variant is substantially mucin-depleted, the distinction may not be clear on H&E alone. For these cases, one can perform further analysis by ensuring that the tissue was adequately sampled and obtaining ancillary studies. Special stains such as Alcian blue, mucicarmine, and PAS-D can help identify the presence of mucous cells which should be non-existent to rare in an oncocytoma. Furthermore, most MECs are characterized either by a CRTC1-MAML2 [t(11;19)(q21;p13)], or less commonly a CRTC3-MAML2 [t(11;15)(q21;q26)] gene fusions which can be detected via RT-PCR or FISH. These gene fusions are not present in an oncocytoma [3, 26]. Distinguishing an oncocytoma from the oncocytic and clear-cell variants of MECs, or any other salivary gland neoplasm with oncocytic variants, is of crucial importance for patient care.

Lastly, a malignant, but exceedingly rare (< 1% of salivary gland tumors) counterpart of an oncocytoma, oncocytic carcinoma, is worth considering [1]. While oncocytic carcinomas can sometimes co-occur with, or be preceded by, oncocytomas, there is no definitive evidence suggesting that oncocytomas undergo malignant transformation to oncocytic carcinomas. Like oncocytomas, oncocytic carcinomas are also characterized by numerous polyhedral cells with abundant granular, eosinophilic cytoplasm and centrally placed nuclei. However, while the cells in an oncocytoma tend to be uniform, those in an oncocytic carcinoma may demonstrate a variable amount of pleomorphism, especially in the high-grade variants. They are also often unencapsulated with an infiltrative growth pattern (invasion into adjacent tissue or perineural and lymphovascular invasion), increased mitotic activity, and necrosis, all of which are features that are not seen in an oncocytoma. These lesions commonly recur and metastasize and should not be missed [1].

In summary, oncocytomas are benign salivary gland neoplasms composed of almost exclusively oncocytic cells within a well-defined capsule. They are rarely of clinical consequence and there is a lack of evidence in support of their ability to undergo malignant transformation. Their clinical and radiologic features are not unique and their diagnosis should not be made without histopathologic support. Although there are multiple entities with oncocytic variants, making their diagnosis via FNA and in some cases core biopsy challenging, the histologic examination of an excision specimen is often not a diagnostic dilemma.

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