Search

Tumor necrosis and squamous and/or mucinous metaplasia was found in 4 of 26 oncocytic salivary gland tumors (24 Warthin's tumors and 2 oncocytomas). The necrosis was extensive in two cases, producing architectural and cytologic atypia sufficient to simulate a squamous carcinoma. In a third tumor, necrotic and inflammatory debris occurred within dilated tumor spaces exhibiting squamous and mucinous foci, suggesting low-grade mucoepidermoid carcinoma. Adequate sampling revealed Warthin's tumors in all four cases. An additional 13 tumors showed incidental foci of squamous metaplasia, often accompanied by stromal scarring but without necrosis. Four of these tumors also had focal mucinous metaplasia. In the adjacent non-neoplastic salivary gland, oncocytic metaplasia of ducts was seen in 22 glands; there were 7 oncocytic cysts and 3 oncocytic nodules. The tumor necrosis and metaplasia are reminiscent of necrotizing sialometaplasia of the minor salivary gland, thought to be ischemic in origin. The etiology of necrotizing squamous/mucinous metaplasia described here and the extent to which oncocytosis contributes to these changes is unknown. Possibly the extravasation of oncocytic and/or mucinous secretions or cyst contents may result in the reactive changes observed. Necrotizing sialometaplasia and squamous/mucinous metaplasia of oncocytic tumors appear to be related only morphologically, but the shared histologic features may be useful in excluding the diagnosis of salivary gland carcinoma.

A case report of a multifocal oncocytic adenomatous hyperplasia occurring in a parotid gland is presented. The differential diagnosis of (multicystic) Warthin's tumor is discussed.

A 74-year-old woman presented with a large retroperitoneal mass incidentally detected by abdominal computerized tomography (CT) (fig. 1). Clinical examination and blood and urine evaluation were unremarkable. Surgery for an oncocytic adrenocortical tumor of uncertain malignant potential on the left side had been performed 7 years earlier and the patient had received percutaneous radiation (44.2 Gy). On December 27, 1999 she underwent thoracoabdominal nephrectomy, splenectomy, hemicolectomy, partial pancreas resection and right oophorectomy due to extensive infiltration of the tumor. Convalescence was uneventful. Histological examination revealed a predominantly (approximately 90%) oncocytic carcinoma with isolated spongiocytic foci infiltrating the retroperitoneal fat tissue, kidney, spleen, colon and right ovary (fig. 2). Tumor cells stained positive for vimentin and negative for pancytokeratin monocyte nuclear factor 116 and cytokeratin 18, S100, epithelial membrane antigen, synaptophysin and chromogranin, exhibiting identical histopathological features compared to the primary tumor removed 7 years earlier. Microsatellite analysis yielded loss of heterozygosity of chromosomes 3p, 9p, 13q and 17p (see table).

Histochemistry and electron microscopy have now enabled investigators to define precisely the oncocyte of salivary tissue. By these techniques, all oncocytes are characterized by a rich complement of mitochondria and most often by high oxidative enzyme activity. The routine light microscopic appearance of oncocyte, i.e., swollen and eosinophilic, is in large part due to its increased mitochondrial content but is non-specific and may be simulated by other cytoplasmic components such as endoplasmic reticulum, lysosomal bodies, secretory granules and other cell organelles. The term, oncocytoid, should be used for cells not fulfilling minimal his-tochemical requirements for the oncocyte.

A rare case of salivary gland pleomorphic adenoma, in which the majority of cells were oncocytic, is reported. The patient, a 53-year-old man, presented with a parotid gland mass that was otherwise asymptomatic. Surgical treatment consisted of a superficial parotid lobectomy. The specimen was prepared in standard fashion and studied by light and electron microscopy. The microscopic features were characteristic of salivary gland pleomorphic adenomas, however, both epithelial and "mesenchymal" elements were oncocytic. Such changes may occur focally in pleomorphic adenomas, but we were unable to find documentation of a wholly oncocytic variant in a review of the medical literature. From our clinical data and previous reports of pleomorphic adenomas with focal oncocytosis, it is concluded that such changes likely do not alter prognosis in affected patients. The possible significance of this lesion in regard to the histogenesis of salivary gland pleomorphic adenomas is discussed.

Electron microscopic study was made on precancerous and cancerous lesions in glandular stomach of rats induced by MNNG. Three types of lesions, were found: regenerative glandular hyperplasia, adenomatous hyperplasia and adenocarcinoma. These were compared with the fine structure of similar lesions produced by X-irradiation in the glandular stomach of mice. The precancerous lesion in the present study demonstrated formation of adenomatous hyperplasia by epithelial cells which included mucoid cells characterized by sparce surface microvilli, a few erratic terminal webs, small number of mucous granules, many small mitochondria, and a bizarre nucleus. The development of these mucoid cells seems to be related with the growth of gastric carcinoma. The ultrastructure of adenocarcinomas revealed many structural variations or abnormalities of cellular differentiation. They were classified into 1) surface and pit mucous cell type, 2) pyloric gland cell type, 3) goblet cell type, 4) paneth cell type, 5) intestinal epithelial cell type, 6) endocrine cell type, 7) oncocyte type, 8) filament-rich cell type, and 9) anaplastic cell type involving intracellular microcyst cells. Filament-rich cells were found in poorly differentiated adenocarcinoma or scirrhous carcinoma and may be derived from metaplasia of tumor cell.

Two cases of renal tumor presenting diagnostic difficulties are reported. In one case, fine-needle aspiration biopsy from a large neoplasm yielded only oncocytes, but histologic examination showed also islets of renal cell carcinoma. The tumor caused pain, and computed tomography demonstrated inhomogeneity of its inner composition. In the second case there was a silent, small neoplasm, and both cytologic and histologic specimens showed a mosaic pattern of renal cell carcinoma and oncocytes. The diagnostic difficulties are discussed on the basis of these two cases and reports in the literature.

The epithelial components of 10 Warthin's tumors (adenolymphomas) were studied by immunohistochemical technique. The neoplastic epithelium consisted of tall columnar apical cells and irregularly shaped basal cells. IgA was predominant in the columnar cells and in the intraluminal secretion of the tumor. IgG-containing cells were scattered in 8 of 10 cases, but no IgM was detected. Carcinoembryonic antigen (CEA), normally absent from striated ducts, was found in small groups of neoplastic columnar cells.Warthin's tumor, therefore, seems to be composed of neoplastic duct epithelium, most of which is highly differentiated with retention of immunoglobulin transport and appearance of CEA. Immunoglobulins and CEA were found in the tall columnar cells, but they were almost negative in the basal cells. It was suggested that the tall columnar epithelial cells of Warthin's tumor were different from basal cells in point of their functional state.

An oncocytoma of the right ovary in a 22-year-old Japanese woman was examined by light and electron microscopy. The tumor was composed of oxyphilic cells with a granular cytoplasm. Electron microscopic studies revealed mitochondrial hyperplasia, a characteristic feature of the oncocyte . This may be the first report of an oncocytoma in the ovary.

Oncocytes are characterized under light microscope by swollen cytoplasm with acidophilic and granular appearence and frequently by pyknotic nuclei. These cells can be found not only in salivary glands and other exocrine and endocrine organs but also in some tumors. Generally, oncocytes appear to increase in frequency with advancing age, but their genesis and biologic significance remain still obscure. In this study, the appearence and the histological pattern of oncocytes in the human labial salivary glands were systematically examined, and the possible mode of development and the significance of these cells were also discussed. One hundred cases of the labial salivary glands were randomly collected from autopsies, and serial sections were made. The designation of oncocytes was in accordance with Hamperl's description. The results were as follows;1) Oncocytes were found in 85 cases (85.0%), ranging in age from two to 93. Although oncocytes occurred in greater number in elder cases, oncocytes were found in 50-to-70% of those who was under forty. The frequency was slightly higher in females than in males. 2) The frequent presence of oncocyte was noted in the duct systems, especially in the interlobular, intralobular and main excretory ducts. 3) In both acini and ducts, oncocytes were generally gathered in small groups but also occurred singly. Therefore, all of these epithelial elements ofthe salivary glands may be able to transform into oncocytes. 4) When oncocytes were found in moderately to heavy concentration, the oncocytes stratified in papillary projection, adenomatous pattern, conglomeration microtubular structures, etc., and it is thought that these findings suggest proliferative disposition of oncocytes. The highest changes of these were found in 8 cases of 50 to 70 years old. 5) There was no definite correlation between oncocytic changes and fibrosis, atrophy with fatty replacement, regenerative process due to radiation or lymphoid cell infiltration, etc. 6) From the above-mentioned light microscopic findings of oncocytes in the human labial salivary glands, it is assumed that the occurrence of oncocytic changes have some relationship with the aging. However, oncocytic changes may not be the result of degenerative one of the salivary glands associated with aging. 7) Under electron microscopy, the cytoplasm of oncocyte was completely filled with nonoriented mitochondria of various sizes and shapes. Moreover, the cristae of mitochondria were markedly increased in number and in length, and there were no intramitochondrial granules. Organellae, other than mitochondria, were sparse.As a results of this investigation and review of various reference literature, a hypothesis is put foward that the significance of oncocytes is a manifestation trying to compensate for functional defects by an increased number of mitochondria and the surface area of menbrane. The mitochondrial proliferation may occur in the abscence of obvious functional needs. Another possibility is that the oncocytic transformation represents a “mitochondrial disease” or “mitochondriopathia” of epithelial cells. The determination of the function of oncocytes willrequire more specific physiological and biochemical studies. And it must be decided whether oncocytes occurring in normal salivary glands and tumors are same cytological characteristics or not.

Both oncocytoma cells of the parotid gland involving the surrounding skin and oncocyte cells in the normal trachea were compared using electron microscopy from the point of view of structural differences between neoplastic and non-neoplastic oncocyte cells.The oncocytoma cells were similar to the first class of oncocytes, while non-neoplastic oncocyte cells belonged to the second class, according to the Tandler's classification of oncocytic cells. The first class includes those cells that contain extremely pleomorphic mitochondria which lack intramitochondrial dense granules, and which sometimes contain inclusions of various types. The second class of oncocytes is composed of cells with greatly elevated numbers of mitochondria which are relatively normal in appearance, but which also lack intramitochondrial dense granules.It is presumed that oncocytoma is not produced by a simple hyperplasia of oncocyte cells but rather by neoplastic oncocyte cells and that oncocytoma is not produced via a process of metaplasia of glandular cells to oncocyte cells but is rather a direct neoplastic proliferation of glandular cells.

Multinodular hyperplastic foci of oncocytes found in mouse submandibular glands were examined ultrastructurally, and their morphogenesis discussed. The oncocytic foci showed lobular architecture surrounded by myoepithelial cells, and tubular formations were frequently present. The cytoplasm of the oncocytes was distended by tightly-packed and non-oriented mitochondria which varied in size and shape. Furthermore, varying numbers of electron-dense fine granules, which were remnants of secretory granules of granular duct cells, were scattered in the cytoplasm. Within the salivary gland parenchyma neighboring the hyperplastic foci of oncocytes, intermediate-type cells between oncocytes and normal salivary gland epithelia were found. The result of the present study shows that the oncocytic change has a tendency to be more frequent in the granular ducts and less in the striated ducts, and that some oncocyte-transformed cells proliferate to form nodular hyperplastic foci.

WITH THE hope that this contribution may add in a small and perhaps indirect way to the advancement of cancer research, I call attention to the occurrence of peculiarly enlarged epithelial cells, or oncocytes, in glandular tissue (salivary glands, pancreas, thyroid gland, parathyroid, hypophysis, fallopian tubes, mucosa of the nose and larynx) and to their not yet fully confirmed occurrence in the liver, testes and stomach. They occur predominantly in persons past middle age. Their suggestive relation to the cancer cell and their availability for study and observation in surgically removed noncancerous tissues of living patients should aid in determining clinical associations and histochemical reactions. The presence of these cells have been reported also in benign tumors of human organs. Among laboratory animals they have, thus far, been noted in the dog. The literature concerning these cells extends over a period of about fifty years. The first recorded observation was

In 105 Autopsien von Neugeborenen und Kindern bis 9 Jahren und in 100 Biopsien von Knaben zwischen 9 und 17 Jahren werden die Gonaden auf das Vorkommen eosinophil granulierter onkocytenartiger Zellen im Keimepithel gepruft. Im Gesamtuntersuchungsgut kommen derartige Zellen bei 19 Knaben, d.h. bei 9,2% der Falle vor. Bei unausgewahlten Autopsiefallen sind sie nur bei annahernd 3 % der Beobachtungen zu sehen, bei Biopsien dagegen, die aus dystopen Hoden der spateren prapuberalen Altersstufe stammen, bei 16% der Falle. Morphologisch erinnern die eosinophil gekornten Zellen an Onkocyten anderer Organe. Die Granula weisen aber gewisse gestaltliche und farberische Eigenschaften auf, die mit denjenigen typischer Onkocyten nicht ubereinstimmen. Auch spricht das Auftreten dieser Zellen im Keimepithel des fruhen Kindesalters gegen die Identitat derartiger gekornter Zellen mit Onkocyten. Da die eosinophil gekornten Zellen vor allem in dystopen oder dysplastischen Hoden gefunden werden, kommt ihrem Nachweis bei Kindern moglicherweise eine gewisse Bedeutung fur die prognostische Beurteilung der spateren Hodenentwicklung zu.

A bronchial neoplasm consisted of cells with abundant, finely granular, eosinophilic cytoplasm. Ultrastructurally, this granularity was due to mitochondrial hyperplasia thus fulfilling the criterion of a true oncocyte. Although the terms “pulmonary oncocytoma” and “oncocytic carcinoid” have been used in the past, this is apparently the first pulmonary tumor in which mitochondrial hyperplasia has been demonstrated thereby confirming the accuracy of the term oncocytoma in this particular instance. The bronchial mucosal glands adjacent to the tumor contained numerous foci of oncocytes and are considered the most likely source of the neoplasm.

A case of oncocyte-type renal cell carcinoma was reported. The tumor had developed from the upper posterior portion of the left kidney and was well circumscribed. However, the tumor showed expansion into the intraparenchymal space, invasive growth, and venous invasion. Marked cell atypia was not observed.

A case of ovarian adenocarcinoma mainly composed of oncocytes was studied by light and electron microscopy. Oncocytes, characterized by granular and eosinophilic cytoplasm by light microscopy possessed numerous mitochondria at the ultrastructural level. These oncocytes were classified into two types: typical and condensed oncocytes. Typical oncocytes seemed to be active, whereas condensed oncocytes were thought to be involved in a degenerative process. The two types of cells showed a close similarity to oncocytes in other organs (e.g., thyroid, parathyroid and salivary glands). This appears to be the first report of an ovarian oncocytic tumor.

Twenty-nine cases of human tracheal glands were studied in electron microscopy. The materials used in this study were taken from patients whose ages ranged from 1 to 90 years old of both sexes.The tracheal glands were composed of occasionally branched tubulo-alveolar glands consisting of the duct and the terminal portion of both mucous and serous type, and furthermore, smoothmuscle type myoepithelial cells surrounding the outside of the terminal portions.Both oncocytes and oncocytic cells appeared everywhere in the gland, both in the duct and also in the terminal portion epithelium. They were generally seen in a cluster, but sometimes in solitary form within the glandular epithelium.Oncocytes were tightly packed with an unusually large number of atypical hypertrophied mitochondria. On the other hand, the oncocytic cells contained variable numbers of such atypical large mitochondria in addition to usual cell organelles. These findings in the oncocytic cells are strongly suggestive that the oncocytic cell is a transitional type cell between the normal glandular cell and the typical oncocyte within the gland. Atypical mitochondria in such cells were almost devoid of intramitochondrial granules, and had conspicuously larger sizes than those of usual ones.These atypical hypertrophied mitochondria were often provided with tightly packed bundles of longitudinally or arcuately arranged cristae, as well as a dilated matrix with either dense globules or crystalloid inclusions. The cells containing such peculiar mitochondria had to some extent similar characteristics to those of the usual glandular cells. However, in this study no myoepithelial cells exhibited any morphological signs of transforming into oncocytes or oncocytic cells.Increased numbers of oncocytes and oncocytic cells tended to be seen more frequently in aged individuals, and thus this oncocytic degeneration of the gland may be considered as one of the changes due to aging within the glandular tissues of man.In some cases, a few annulate lamellae connected to the limiting membrane of the rough endoplasmic reticulum were observed, however, their functional significance remains obscure.

The oncocyte is a peculiar cell found in the aging parotid gland. A precise definition of oncocytic tumors in now available using histochemical and electron microscopic techinques. Oncocytic carcinomas are very rare; only a handful have been cited in the literature. This is the first description of the electron microscope features of oncocytic carcinomas we can find in the literature. The cells of these carcinomas are characterized by mitochondrial hyperplasia, pleomorphism and atypism. The cells contained few other subcellular organelles and no myofilaments or glycogen as previously described in benign oncocytomas. In addition to these electron microscopic features, the clinical presentation, treatment, and biologic course of these three cases of oncocytic carcinoma and two cases of benign oncocytoma will be presented.

Oncocytes, cells displaying marked cytoplasmic acidophilia and granularity, are present in the acini and ducts of normal human salivary glands. These cells apparently originate by a process of sequential transformation of normal epithelial cells. In the early forms, there is a great increase in the number of mitochondria, which are typical in morphology. In later oncocytes, these organelles undergo striking changes in form and size. These mitochondrial changes are accompanied by the gradual disappearance from the oncocyte of other cytoplasmic membrane systems and of plasmalemmar specializations. It is suggested that the structurally modified mitochondria are biochemically deficient.

An oncocytoma of the submaxillary gland was examined by light and electron microscopy. Two different types of oncocytes were seen. The most prevalent was the usual polyhedral, epithelial oncocyte. The second type of oncocyte has not previously been described, to our knowledge, and consisted of an elongated cell with myofibrils and mitochondrial hyperplasia, a myoepithelial oncocyte. It is concluded that, regardless of cell type, an oncocyte should be defined by the ultrastructural characteristic of mitochondrial hyperplasia. The fine structural features of the hyperplastic mitochondria suggest that they may be secondary to quantitative mitochondrial enzyme(s) deficiency.

The Warthin tumor represents the second most frequent benign tumor of the parotid gland and is characterized by the presence of oncocytes rich in structurally and functionally altered mitochondria. Next to its role in metabolism, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is also implicated in cellular mitophagy. Immunohistochemistry was carried out on Warthin tumor and normal control (parotid gland with striated ducts) tissues, using anti-GAPDH specific antibodies followed by digital image analysis. Laser capture microdissection was used to isolate the oncocytic tumor cell and normal control striated duct compartments for RNA extraction and qPCR. Warthin tumor oncocytes exhibited a markedly spotted GAPDH staining pattern exhibiting cells with cytoplasmic and nuclear, only nuclear or none GAPDH staining. A significantly lower (p < 0.0001) total GAPDH signal was detected in Warthin tumor oncocytes. Similarly, significantly lower (p < 0.005) GAPDH mRNA levels were seen in oncocytes compared with normal ductal cells. To exclude the possibility of this GAPDH staining pattern being a general feature of oncocytic neoplasms of different organs, we tested a cohort of renal oncocytoma and oncocytic chromophobe carcinoma; none showed this type of staining. The observed progressive GAPDH loss in Warthin tumor oncocytes could be implicated in the pathogenesis of Warthin tumors.