Clear cell neoplasms in salivary glands: Clearly a diagnostic challenge

REVIEW ARTICLE

Clear Cell Neoplasms in Salivary Glands: Clearly a Diagnostic Challenge Gary L. Ellis, DDS Although infrequent, salivary gland tumors with a dominant population of clear staining cells present problems in differential diagnosis. Mucoepidermoid carcinoma, acinic cell adenocarcinoma, "clear cell" oncocytoma, epithelial-myoepithelial carcinoma, clear cell adenocarcinoma, and metastatic renal cell carcinoma are considered in the differential diagnosis. This review focuses on this heterogenous group of clear cell neoplasms and attempts to clarify some of the features that help distinguish one neoplasm from another. Ann Diagn Pathol 2: 61-78, 1998. This is a US government work. There are no restrictions on its use.

Index Words: clear cells, neoplasms, salivary glands clear (klir) adjective. (1) Containing nothing. (2) Free

from doubt or confusion; certain. (3) Plain or evident to the mind; unmistakable. (4) Free from what dims, obscures, or darkens; unclouded. (5) Free from impediment, obstruction, or hindrance.

p

LEASE INDULGE the play on words in the title. In reference to clear cells in neoplasms of the salivary glands, many pathologists would regard all but definition one from above as quite contrary to their experience. As a consultant pathologist on salivary gland diseases at the Armed Forces Institute of Pathology for many years, I have observed that clear cells within neoplasms of the salivary glands often have created diagnostic dilemmas and challenges as well as controversy over the classification of such neoplasms among referring pathologists. Quite frankly, at times they can cause similar problems even for so-called experts on salivary gland neoplasms. This review focuses on this heterogenous group of clear cell neoplasms and attempts to clarify some of the features that help differentiate one neoplasm from another. Actually, clear cells occur fairly commonly among a From the Department of Veterans'Affairs Special Reference Laborato~ for Pathology, Department of Oral and Maxillofacial Pathology, Armed Forces Institute ofPathology, Washington, DC. The opinions hereinpresentedare theprivate views of the author and are not to be construedas reflectingthe views of the Department ofDefense, the Department of theArmy, or the Department of Veterans'Affairs. Address reprint requests to Ga?y L Ellis, DDS, Department of Oral and Maxillofacial Pathology,Armed ForcesInstitute ofPathology, 6825 16th St NW,, Bldg 54, Washington, DC This is a US government work. There are no restrictionson its use. 1092-9134/98/0201-0007$00.00/0

wide variety of salivary gland neoplasms, including mixed tumors, myoepitheliomas, oncocytomas, mucoepidermoid carcinomas, acinic cell adenocarcinomas, polymorphous low-grade adenocarcinomas, and adenoid cystic carcinomas (Fig 1). In most cases, they constitute only a minor component of the cellular constituency of these neoplasms, and the appropriate classification of the tumors is easily established on the basis of typical features that are apparent (Fig 1). In some tumors, however, clear cells constitute the major cellular component, and it is in this situation that the diagnostic challenge is greatest. In rare instances, clear cells may be the major component of such tumors as mucoepidermoid carcinoma, acinic cell adenocarcinoma, and oncocytoma. Although more difficult, an experienced observer can usually properly classify such tumors on the basis of their morphological growth patterns and foci with histopathologic features "typical" of these tumors. On the other hand, this association of clear cells with mucoepidermoid carcinomas and acinic cell adenocarcinomas, unfortunately, has misled some pathologists to inappropriately classify many other clear cell tumors in the salivary glands. Clear cells are the principal diagnostic feature in two salivary gland neoplasms, epithelialmyoepithelial carcinoma and clear cell adenocarcinoma (refreshingly obvious terminology). Even metastatic clear cell tumors, such as renal cell carcinoma, can be difficult to differentiate from primary clear cell neoplasms of the salivary glands. In epithelial neoplasms, light microscopic cytoplasmic clarity results from one or more factors, such as intracellular accumulation of nonstaining compounds (glyco-

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moid and intermediate cells, 6,7and a transition between epidermoid and clear cells is usually evident focally (Fig 2). The clear cells are in addition to the mucocytes in these tumors, which typically have a very pale basophilic, foamy cytoplasm with standard hematoxylin and eosin stains. Mucicarmine stain can be very useful for highlighting mucocytes and distinguishing them from the other clear cells (Fig 3). I am adverse to a diagnosis of mucoepidermoid carcinoma in the absence of mucocyte differentiation. On the other hand, I find its presence very indicative of mucoepidermoid carcinoma because other salivary gland tumors that may have abundant clear cells (oncocytoma, epithelial-myoepithelial carcinoma, clear cell adenocarcinoma, acinic cell adenocarcinoma, and metastatic renal cell carcinoma) generally have no or only rare mucocytes.3,8-12In many mucoepidermoid carcinomas, glycogen can be demonstrated in the clear cells with periodic acid-Schiff (PAS) staining with and without prior digestion of the tissue with diastase (Fig 4). The quantity of clear cells in mucoepidermoid carcinomas does not influence the grade or prognosis for these tumors. Other features, such as solid versus cystic

Figure 1. Clear cells in adenoid cystic carcinoma are common and characteristic. This tumor is readily recognized as adenoid cystic carcinoma by the tubular and cribriform growth patterns, hyalinized pseudolumens (actually connective tissue spaces) and periepithelial tissues, and hyperchromatic, angular shaped nuclei.

gen, lipid, mucin), a scarcity of cell organelles, or artifact induced during tissue fixation or processing) Each of these mechanisms probably contributes to the population of clear cells in salivary gland neoplasms. Mucoepidermoid Carcinoma

In the context of salivary gland neoplasia, mucoepidermold carcinoma is the condition in which abundant clear cells are most often encountered. There are two factors that make this so; mucoepidermoid carcinoma is the most common malignant neoplasm and, after mixed tumor, is the most common neoplasm of salivary glands, and clear ceils are common in mucoepidermoid carcinomas3 -5 On average, clear cells account for about 10% of the cell population of mucoepidermoid carcinomas and, rarely, may comprise a large portion of the tumors. 3,5 In most cases, the clear cells appear to be modified epider-

Figure 2. Mucoepidermoid carcinoma has clear cells in juxtaposition to epidermoid cells.

Clear Cell Neoplasms in Salivary Glands

Figure 3. Mucicarmine stain highlights mucocyte differentiated cells among other nonreactive clear cells in mucoepidermold carcinoma.

growth, number of mitotic figures, pleomorphism, necrosis, and perineural invasion, are more determinant for assessing grade and prognosis than the quantity of any of the cellular components, such as mucous cells, squamous cells, and intermediate cells. 5,13 A c i n i c Cell A d e n o c a r c i n o m a

For a reason that is not quite clear to me (pun intended), clear cells and a diagnosis of acinic cell adenocarcinoma have a logical link for many pathologists. I have consulted on many cases of clear cell dominant tumors in which the primary consideration of the referring pathologists was acinic cell adenocarci-

Figure 4. Much of the staining with PAS (A) is abolished when the tissue has been digested with diastase (B), indicating glycogen in the cells of this mucoepidermoid carcinoma with clear cells.

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Figure 5. Clear cells are quite prominent, which is unusual, in an acinic cell adenocarcinoma of the parotid gland.

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acinic cell adenocarcinoma. 1°,21,22In some tumors, serous acinar differentiated cells may be sparse, and PAS stain can be useful to highlight the cytoplasmic secretory (zymogen) granules (Fig 6). Because mucous globules also stain with PAS, mucicarmine-stained tissue sections should be evaluated in conjunction with PASstained sections to rule out mucocyte differentiation. The clear cells in acinic cell adenocarcinoma do not contain glycogen and probably represent fixation or tissue processing artifactual changes and alterations of cytoplasmic organelles. On the basis of immunohistochemical similarities, Takahashi et a123speculated that the clear cells transform from neoplastic acinar cells. Using electron microscopy, Echevarria22 found that artifactual changes probably produce the light microscopically clear cells, and Chaudhry et a124found dilatations of rough endoplasmic reticulum, lipid inclusions, enzymatic degradation of secretory granules, and intracytoplasmic pseudolumens.

Figure 6. PAS stain of a diastase-digested tissue section of an acinic cell adenocarcinoma with clear cells shows cytoplasmic secretory granules.

noma. In fact, I believe that even some reported cases of bilateral, multifocal acinic cell adenocarcinoma are most likely clear cell variants of multinodular oncocytic hyperplasia (see later discussion).14,15 1 believe there has been an overemphasis of clear cells in acinic cell adenocarcinomas that has erroneously lead to diagnoses of acinic cell adenocarcinomas solely on the basis of clear cells. 14-19In my and others' experience, clear cells are found in only about 6% of acinic cell adenocarcinomas and form a major portion of the neoplastic cell population in only about I% (Fig 5). l°,2° Clear cells are a much more frequent component of mucoepidermoid carcinomas than acinic cell adenocarcinomas and are the principal diagnostic feature of epithelial-myoepithelial carcinomas and clear cell adenocarcinomas. I consider the demonstration of serous acinar cell differentiation requisite for a diagnosis of acinic cell adenocarcinoma and doubt the existence of a purely clear cell variant of

Figure 7. Multiple irregular-shaped foci of clear cells in an organoid pattern in the parotid gland are a manifestation of nodular oncocytic hyperplasia. There is no stromal reaction to the nodules of clear cells. A striated duct (arrow) has partially undergone clear cell ohange.

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The quantity of clear cells in acinic cell adenocarcinomas does not influence the grade or prognosis for these tumors. Schemes to stratify acinic cell adenocarcinomas by grade have not been widely accepted, and generally these are regarded as low-grade neoplasms. 10,21,25-38

"Clear Cell" Oncocytoma and Nodular Oncocytic Hyperplasia The majority of nonmucinous, epithelial, clear cell dominant neoplasms of salivary gland are at least low-grade malignant tumors. 3,~9An exception, however, is the rare, benign, clear cell tumor of the parotid gland that can be recognized as a variant of benign oncocytoma.8,40-42 Oncocytic tumors occur predominantly in the parotid glands of older adults, and are histologically characterized by masses of large, eosinophilic cells known as oncocytes, which occur normally ill the parotid glands of aging individuals.43 Nodules of oncocytes may occur singly or multiply, including bilateral, and are referred to as oncocytoma and nodular oncocytic hyperplasia. 41 The distinction between a large nodule of oncocytic hyperplasia and oncocytoma, the putative benign neoplasm of oncocytes, is subtle, perhaps semantic, and not particularly important. The characteristic, intensely eosinophilic, granular cytoplasm of oncocytes and oncocytomas is caused by markedly increased numbers of cytoplasmic mitochondria. Electron microscopic examination provides the unequivocal evidence for the oncocytic nature of cells, but cytoplasmic staining ofmitochondria with phosphotungstic acid-hematoxylin (PTAH) is useful, easier, and more economical.41,43 Paradoxically, clear cells dominate some lesions. 8 Clear cells have been noted to be particularly common in multinodular oncocytic hyperplasia (Fig 7).41,44,45Clear cell oncocytoma has the same morphological growth pattern as typical oncocytoma (Fig 8). The tumor is composed of well circumscribed and, sometimes, encapsulated mass of large polyhedral cells arranged in an organoid pattern with thin, vascular fibrous septa (Fig 8). Small lumina are evident in the center of some of the organoid islets. Most of the tumor cells have clear cytoplasm on H&E-stained sections, but some cells have variable amounts of eosinophilic cytoplasm adjacent to the cell membrane. In a few cases, aggregates of prominently eosinophilic, typical oncocytes may be seen within and/or adjacent to the clear cell tumor nodules (Fig 9). In some cases, there are randomly scattered, small foci of clear cells within the salivary parenchyma in the pattern of oncocytosis or nodular oncocytic hyperplasia (Fig 7). I have noted a transition from typical

Figure 8. In this oncocytoma, nests of large, polygonal clear cells are separated by very thin fibrovascular septa in an organoid pattern. Lumens with proteinaceous material are evident in the center of some nests. The cells have small, round, eccentric nuclei.

eosinophilic cells to clear cells in intralobular salivary gland ducts in some cases (Fig 7). Similar to typical oncocytomas, clear cell oncocytomas stain positively with PTAH in contrast to the near absence of staining of the surrounding normal salivary gland acini. Staining with PAS before and after diastase digestion of tissue reveals varying amounts of intracytoplasmic glycogen, which is the principal reason for the light-microscopic clarity of these cells (Fig 10).4° Clear cell oncocytoma is not infiltrative but is frequently multifocal (nodular oncocytic hyperplasia), and this distinction is important. In fact, the pattern of scattered, discrete foci without a stromal reaction can be very helpful in distinguishing between oncocytoma and primary or metastatic clear cell carcinoma (Fig 7). The clear cell variant of oncocytoma occurs predominantly in middle-aged and older white women. 8 The parotid gland is nearly always the site of occurrence, but

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Figure 9. In the center of this field, intensely stained oncocytes contrast with the clear cytoplasm of the oncocytes surrounding them.

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Figure 10. Much of the staining with PAS (A) is abolished when the tissue has been digested with diastase (B), indicating glycogen in the cells of this clear cell oncocytoma. I have seen one tumor in the submandibular gland. 42 Interestingly, I have documented an instance of familial occurrence in two sisters. As stated, there has been bilateral occurrence. 8,41 Swelling is usually the only sign or symptom. Like typical oncocytoma, treatment is local excision. Recurrence is known to have occurred in 2 of 10 cases I have previously studied, which I believe probably represented multinodular disease rather than aggressive biological behavior. 8 Epithelial-Myoepithelial Carcinoma

As the terminology indicates, this is a biphasic neoplasm of ductal and myoepithelial cells in which large, clear, myoepithelial differentiated cells predominate. Kleinsasser et a146 may have been first to describe this tumor, which they called salivary duct carcinoma, but it was Donath et a147who really defined it. It was not until

10 years after Donath et al's 47 report in the German language literature in 1972 that Corio et aP 8 introduced this tumor to the English language literature. In retrospect, tumors in many reports of both malignant and benign clear cell tumors of salivary glands would be more appropriately classified as epithelial-myoepithelial carcinomas. 49-57This includes a description of clear cell adenoma that was included in the fascicle on salivary gland tumors from the second series of AF1P's Atlas of Tumor Pathology. 5a Two types of cells in varying proportions are evident within the tumor nodules. 3,59-61 Ductal elements, composed of cuboidal, intercalated duct-like, eosinophilic cells that usually border small lumens, are surrounded by large, polygonal, clear staining myoepithelial cells (Fig 11). A variable amount of pale eosinophilic or amphophilic cytoplasm is present in some otherwise clear cells. The clear cells contain glycogen that can be

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Some epithelial-myoepithelial carcinomas are wellcircumscribed or even partially encapsulated, but nests of tumor ty30ically infiltrate adjacent tissues. Many tumors are multilobular. Immunohistochemical studies report the ductal cells as immunoreactive for cytokeratin and the clear cells as immunoreactive for S-100 protein, 1~,6°,6~64 but I have found these reactions to be variable (Fig 15). In the clear cells reactivity for smooth muscle actin is frequently intense whereas reactivity for myosin and vimentin is more variable. The bicellular features are also evident with electron microscopy. Electron-dense cells with features of duct luminal cells border small lumens and are surrounded by more electron-lucent cells with features ofmyoepithelium, which include arrays of microfilaments with focal densities, subplasmalemmal plaques, and multilayered basal lamina.~2,48,55,G5 Recent evaluations indicate an average incidence of

Figure 11. IntenseLy stained, cuboidal cells that line small lumens are surrounded by large, polygonal cells with clear cytoplasm in this epithelial-myoepithelial carcinoma. Peripheral to the clear cells is a hyalin material that is excessive basal lamina.

demonstrated with PAS staining. The ductal structures, which may contain eosinophilic, PAS positive-diastase resistant secretory material in the lumens, are usually conspicuous among the numerous clear cells but are sparse in some tumors (Fig 12). The architecture of the tumors varies from sheets to organoid nodules to discrete tumor nests, and they may be solid or cystic. Papillary projections composed of the biphasic cell population may partially or completely fill the cystic spaces (Fig 13). The stroma varies from loose fibrous to hyalinized tissue. Mucicarmine stains are negative. Adjacent cell nests are frequently separated by a PASpositive basement membrane, which may be markedly thickened and produce a hyalinized appearance (Figs 11 and 13). Mitotic figures are rare, but foci of necrosis and perineural and intravascular growth are occasionally seen (Fig 14).

Figure 12. Cuboidal ductal cells are present in this epithelialmyoepithelial carcinoma but are less conspicuous than those in Fig 11.

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available, but most tumors have been treated by surgical excision. Sometimes adjunctive radiation therapy has been used, especially when the completeness of excision was in doubt. Clear Cell A d e n o c a r c i n o m a

Figure 13, In this cystic epithelial-myoepithelial carcinoma, papillary projections of tumor cells retain the bicellular architecture of dark staining, cuboidal, luminal cells and more peripheral, large, clear staining myoepithelial cells. Basal lamina material is prominent in the papillae of tumor. about 1% of salivary gland neoplasms, and this corresponds to the AfXP's experience) ,53,61,62,65-67Three quarters of these tumors occur in the parotid gland, whereas the remainder develop about equallyin the submandibular gland and minor salivary glands. The peak incidence is in the seventh decade of life, and the mean age of patients is about 60 years. A majority of patients are women. Although tumors have been up to 12 cm in largest dimension, 2 to 3 cm is typical. Occasionally, patients have experienced pain or facial weakness. In general, epithelial-myoepithelial carcinoma is a low-grade malignancy with recurrences in more than 30%, lymph node metastases in about 20% of patients, and occasional distant metastasis and deaths. 4a,59,6163,66-68 However, one reported series found increased incidence of metastases and deaths from tumor associated with nuclear atypia in greater than 20% of tumor cells. 6° Little data for treatment recommendations are

Notwithstanding the refinement of concepts of clear cell tumors and the categorization of a large group of these tumors as epithelial-myoepithelial carcinomas, there remains a small group of clear cell tumors that do not have the distinctive bicellular morphology ofepithelial-myoepithelial carcinoma. These monophasic clear cell tumors have been classified as clear cell adenocarcinoma. 3 Clear cell adenocarcinomas are composed of a monomorphous population of polygonal-to-round cells with clear cytoplasm, although in some cases some of the cells have pale eosinophilic cytoplasm (Fig 16). The cells are generally larger than normal acinar cells with round, eccentric nuclei that frequently contain small nucleoli. Some tumors have a moderate degree of nuclear pleomorphism, but mitotic figures are rare. Cytoplasmic glycogen varies from marked to not demonstrable with PAS staining. The adjectiveglycogen-rich has been applied by some authors to clear cell adenocarcinomas with marked glycogen content9 ,7° Intracytoplasmic mucins are ordinarily absent, but a rare mucous cell does not dissuade from the diagnosis because no epidermoid component is present to suggest mucoepidermoid carcinoma. The tumor cells are arranged in sheets, nests, or cords, but any one neoplasm is usually reasonably uniform in appearance (Fig 17). Although microcysts occasionally occur, ductal structures are generally absent. The stroma varies from interconnecting, thin fibrous septa to thick bands that may be cellular, hyalinized or loosely collagenous (Figs 16-18). Milchgrub et a111 reported a series of these tumors as hyalinizing clear cell adenocarcinomas, and other reports have adopted this terminology.l,71-74This terminology may become commonly accepted and preferred within the pathology community, but, in my experience, fibrosis and hyalinization are not conspicuous in some clear cell adenocarcinomas. Because distinguishing hyalinizing from nonhyalinizing clear cell adenocarcinomas has not yet been shown to have prognostic significance, I have thus far not appreciated the utility of subtyping clear cell adenocarcinomas. The tumors are poorly circumscribed and usually infiltrate adjacent tissues, including mucosa, bone and nerves. Immunohistochemical studies have given variable

Clear Cell Neoplasms in Salivary Glands

Figure 14. Perineural and perivascuLar growth of tumor is evident in this epithelial-myoepithelial carcinoma of the parotid gland.

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Figure 15. In this epithelial-myoepithelial carcinoma, immunohistochemical staining shows strong reactivity for cytokeratin in the luminal cells (A) and strong reactivity for S-100 protein in the most peripheral myoepithelial cells (B).

results. Most tumors are at least focally immunoreactive for cytokeratin, but both positive and negative immunoreactMty for S-100 protein, glial fibrillary acidic protein, actin, and vimentin have been reported. H,69,7°,75-77Michalet a178 have proposed segregating monomorphous clear cell carcinomas into those with and those without myoepithelial differentiation by their histological and immunohistochemical criteria, but, similar to my comments on hyalinizing and non-hyalinizing, at this time the usefulness of this separation is unknown. Ultrastructural investigations report features of duct cell differentiation hut not myoepithelial differentiation. H,55,7°,75,76,79 In mucosa near the maxillary or mandibular alveolar ridges, distinction from clear cell odontogenic carcinoma requires clinical, radiological, and histopathologic correlation.8°-82Radiographic evidence of a centralized, destructive osseous lesion indicates odontogenic rather than salivary gland origin. Because the diagnosis and reporting of clear cell neoplasms has been inconsistent, incidence rates are

difficult to derive; however, these are uncommon salivary gland neoplasms. 83 Clear cell adenocarcinomas have comprised about one percent of epithelial salivary gland neoplasms reviewed at the AFIP. 3 Nearly 60% of these have involved the minor salivary glands, and most reported cases have involved the minor salivary glands.lL64,74-76The palate, buccal mucosa, tongue, floor of the mouth, lip, and retromolar and tonsillar areas have been involved. The peak incidence is in the sixth to eighth decades of life, and only one case has been reported in a child.G9 There is no sex predilection. Mucosal ulceration and pain occur with some tumors, but swelling is the only sign in most cases. Durations of the tumors have ranged from 1 month to 15 years. The size of the primary tumor is usually 3.0 cm or less. Clear cell adenocarcinomas are low-grade neoplasms. Only a few tumors have metastasized to cervical lymph nodes, and no deaths attributable to clear cell adenocarcinoma are known.II,71 Excision is the primary therapy.

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Figure 16. Clear ceil adenocarcinoma of the palate contains variably sized and shaped nests of clear cells without evidence of ductal lumens or duct luminal cell differentiation,

Metastatic R e n a l Cell C a r c i n o m a

Metastatic carcinoma in the salivary glands from primary tumors located below the clavicle is uncommon, but the kidney is one of the more common infraclavicular primary sites for tumors that metastasize to the head and neck.84,a5 Several metastatic renal cell carcinomas have been reported in the salivary glands, and discovery of metastatic tumor may be the first indication of a primary renal carcinoma. 86-99 In my opinion, distinguishing primary clear cell adenocarcinoma, or even clear cell oncocytoma, from metastatic renal cell carcinoma in the salivary gland can be more difficult than distinguishing any of the primary clear cell dominant tumors one from another. Both primary clear cell adenocarcinoma and metastatic renal cell carcinoma may be glycogen positive, may have a solid, organoid growth pattern, exhibit infiltration, frequently have little cytological atypia, have few mitoses, and may be composed of nearly all clear cells (Fig 19).9 Mucicarmine positivity would favor a salivary gland primary tumor, but primary clear cell adenocarcinoma

of salivary gland is usually negative for intracytoplasmic mucin as well. Demonstration of intracytoplasmic lipid would favor renal cell carcinoma, but frozen tissue sections are needed because lipids are usually eluted during tissue processing. In my experience, renal cell carcinomas usually present a more heterogeneous architecture and are more vascular than primary clear cell carcinomas (Fig 20). Small capillaries may be evident in clear cell adenocarcinoma, but, in renal cell carcinoma, the vascular channels are often conspicuous, dilated, and even sinusoidal. Hemorrhage and hemosiderin are generally more prominent in metastatic renal cell carcinoma. The more pleomorphism and cytological atypia, the less likely the tumor is a primary clear cell adenocarcinoma. In some cases, it may not be possible to confidently differentiate between primary and metastatic carcinoma, and further clinical evaluation for a renal primary tumor should be performed. Clearly, clear cell neoplasms of salivary glands are diagnostic challenges, but if a definite differential diag-

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Figure 17.

Unlike the tumor in Fig 16, this clear cell adenocarcinoma is composed of large sheets of clear cells.

Figure 18. There is marked sclerosis and hyalinization of the stroma of a clear cell adenocarcinoma of the floor of the mouth.

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Figure 19. Metastatic clear cell carcinoma in the parotid gland from a primary in the kidney has a distinct organoid pattern. There is prominent fibrosis along the periphery of the tumor,

Figure 20. Metastatic renal clear cell carcinoma in the parotid gland has prominent vascular channels that outline the organoid nests of tumor cells.

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nosis is brought to bear and then analyzed for appropriate discriminatory criteria, the appropriate diagnosis can be determined in most cases.

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