Oncocytoma

* Background.-Renal oncocytoma has several features that overlap with other renal neoplasms, including the eosinophilic subtype of chromophobe cell carcinoma. In fact, strict criteria for renal oncocytoma have not been well defined and remain a matter of controversy. Ultrastructural studies or sophisticated methods such as flow cytometry and cytogenetic techniques can be of great use in distinguishing the two tumors, but are difficult to propose as routine methods because of their limited availability.

Objective.-To further characterize the histologic criteria of these tumors, we undertook a retrospective study to define the utility of routinely available histochemical and immunohistochemical techniques.

Design and Setting-Twenty-one cases of chromophobe cell carcinoma, eosinophilic subtype, and 103 cases of oncocytoma were tested with histochemical (Perls, periodic acid-Schiff, and Hale's colloidal iron) and immunohistochemical (peanut agglutinin antigen and UEA-1 for lectins; cytokeratin KL1, epithelial membrane antigen, vimentin, S100 protein, and lysozyme) staining.

Results.-The antibodies tested and the histochemical staining using Hale's colloidal iron allowed eosinophilic

chromophobe cell carcinoma to be distinguished by its characteristic reaction pattern. Seventy-six percent of the chromophobe cell carcinomas showed a microvacuolated pattern, and 89% of the renal oncocytomas showed an apical positivity with Hale's colloidal iron staining (P

Conclusion.-Our study demonstrated that a precise morphologic description associated with simple histochemical and immunohistochemical techniques provides sufficient criteria for a high level of discrimination between the eosinophilic subtype of chromophobe cell carcinoma and renal oncocytoma. (Arch Pathol Lab Med. 1997;121:1081-1086)

Strict attention has been provided to the diagnostic criteria of oncocytoma and chromophobe cell carcinoma. After initial microscopic examination, 93 tumors were classified as oncocytomas, 16 as chromophobe cell carcinomas, and the remaining 21 cases were open to discussion. Cases that were previously classified by all participating pathologists without any discrepancy and that were confirmed by available ultrastructural study (Fig 1) were considered the gold standard, and their histochemical and immunohistochemical profiles were recorded. The 21 remaining cases were classified following the same criteria. Five cases were recognized as chromophobe cell carcinomas, and 10 cases as oncocytomas. Six cases could not be definitively identified; four cases had immunohistochemical discrepancies, and two cases involved chromophobe cell carcinoma and oncocytoma feature association. Finally, 21 chromophobe cell carcinomas of eosinophilic subtype (Fig 2) and 103 renal oncocytomas were identified (Fig 3).

The clinicopathologic features of the 124 cases are summarized in Tables 2 and 3. Applying the Furhmann grading scheme, 9 chromophobe cell carcinomas were grade 2, 5 were grade 3, and 7 were grade 4; of the renal oncocytomas, 8 were grade 1, 51 were grade 2, 28 were grade 3, and only 12 cases exhibited some foci of grade 4. Applying the Robson staging criteria, most of the cases were stage 1: 17 chromophobe cell carcinomas were stage 1, 2 were stage 2, and 1 was stage 3; 88 renal oncocytomas were stage 1, 3 were stage 2, 2 were stage 3, and only 1 was stage 4.

The histochemical and lectin staining results are summarized in Table 4. Twelve chromophobe cell carcinomas (57%) and 57 renal oncocytomas (55%) were positive for periodic acid-Schiff, the former with a granular feature in 11 cases and the latter with a vacuolated positivity in 36 cases. Hale's colloidal iron staining produced the most striking differences, showing a characteristic microvacuolated cytoplasmic pattern in 76% of the chromophobe cell carcinomas, whereas apical positivity was observed in 89% of the renal oncocytomas (Fig 4). Lectin studies revealed that 24% of the chromophobe cell carcinomas and 9% of the renal oncocytomas expressed UEA-1. In these cases, only a few cells were positive. For chromophobe cell carcinomas, peanut agglutinin antigen (PNA) reacted in 38% of the cases, with microvesicular cytoplasmic reactivity in 24% and with both apical and microvesicular cytoplasmic positivity in 14%. For renal oncocytomas, PNA reacted in 48% of the cases, with apical positivity in 47%.

The immunoprofile of the cases is summarized in Table 5. In chromophobe cell carcinomas, 15 (71%) of the 21 cases were positive with cytokeratin KL1. A peripheral cell accentuation and a microvesicular cytoplasmic pattern were observed in 14 cases (66%) (Fig 5, a). Only one case showed apical cytoplasmic positivity. With anti-epithelial membrane antigen (EMA), 18 (86%) of the 21 chromophobe cell carcinomas reacted, with a peripheral cell membrane accentuation in five cases and a cytoplasmic diffuse positivity in five cases. In 10 cases, an apical cytoplasmic reactivity pattern was observed (Fig 5, b). Lysozyme, vimentin, and S100 protein were expressed in six, two, and one chromophobe cell carcinomas, respectively. In renal oncocytoma, cytokeratin KL1 reacted with 86 (83%) of the 103 cases, with peripheral cell membrane positivity in 47 cases and apical positivity in 39 cases without microvesicular cytoplasmic patterns (Fig 6, a). With antiEMA, 98 (95%) of the 103 renal oncocytomas reacted with typical apical cytoplasmic staining in 72 cases (Fig 6, b). Only 10 cases presented peripheral cell membrane positivity. Lysozyme, vimentin, and S100 protein were expressed by 10, 12, and 23 renal oncocytomas, respectively.

Chi-square tests, using Fisher's exact test when expected cell frequencies were less than 5, showed that morphologic parameters (side, site, color, fibrous scar, necrosis, etc) (Tables 2 and 3) were not significant variables for a diagnosis between chromophobe cell carcinoma and renal oncocytoma. Chi-square tests revealed that the type of histochemical and immunohistochemical positivity was helpful in differentiating chromophobe cell carcinomas from renal oncocytomas. Differences between Hale's colloidal iron staining with a microvacuolated pattern (observed in 76% of chromophobe cell carcinomas) and with an apical pattern (observed in 89% of renal oncocytomas), as well as differences between PAS positivity with a granular feature (observed in 52% of chromophobe cell carcinomas) and with vacuolated positivity (observed in 34% of renal oncocytomas) were significant (P

COMMENT

Macroscopically, chromophobe cell carcinomas and renal oncocytomas are described differently?15 The gross appearance of typical oncocytomas is characteristically described as a well-circumscribed, solid, homogeneous, tanbrown mass with variable scanning, with or without a capsule, and varying in size from 0.3 to 20 cm.5s,1-19 Areas of significant hemorrhage and apparent necrosis are uncommon.5,7,20 Central, myxoid, fibrotic scarred areas are common18 in larger tumors.4 These tumors are usually solitary, but multifocal and bilateral oncocytomas have occasionally been described.418,21 No preference for the right or left kidney, or any peculiar site within the kidney, has been found for renal oncocytoma.'8 The gross appearance of characteristic chromophobe cell carcinomas is usually a uniform, soft grey or beige, well-circumscribed tumor, varying in size from 2 to 22 cm.1,22 Areas of hemorrhage and apparent necrosis are more common, and central, myxoid, fibrotic scarred areas are uncommon.? These tumors are usually solitary and are located medially within the kidney.22 In our series, statistical analysis found that morphologic parameters were not significant for a diagnosis between chromophobe cell carcinoma and renal oncocytoma. All results concerning the side, site, color, fibrous scarring, size, hemorrhage, cystic areas, necrosis, and well-circumscribed borders were not significant. Using stratified analysis with the Mantel-Hanszel test,l3 only the value of the polar site of the tumor and the tan color were significant for the diagnosis of renal oncocytomas (P = .03).

In most cases, the microscopic appearances of chromophobe cell carcinoma and renal oncocytoma are distinctive and allow their diagnosis,l,5,6,22-24 but in some cases, as pointed out in our series, the differences between the two tumors are unclear. In spite of difficulties in distinguishing the two tumors, little effort has been made to further characterize their histochemical and immunohistochemical features.5.fi

The apical positivity with Hale's iron staining observed in renal oncocytomas and the microvacuolated pattern observed in chromophobe cell carcinomas are clearly the most important findings of our study, because this staining has always previously been described as positive only in chromophobe cell carcinomas.6 la 2427 These characteristics are the result of many vesicular structures inside the cytoplasm, as demonstrated by electron microscopy.63 The PAS positivity feature is significant also, but it is missing in 50% of the cases.

In general immunohistochemical studies have found no distinguishing pattern that allows separation of chromophobe cell carcinoma from renal oncocytoma.5,6 Previous reports do not lend themselves to comparative studies or any conclusions, because the given figures in these reports have been based on different methodologies. Some authors performed their investigations on frozen sections,28 and some series with a small number of cases were based on formalin-fixed, paraffin-embedded tissues.52-37 Only a few stains or antibodies were studied in each case, using either monoclonal or polyclonal antibodies,21-33 particularly cytokeratins, with different antigen specificities. Therefore, the results reported could not be compared. With anti-EMA antibodies, chromophobe cell carcinomas and oncocytomas show strong cytoplasmic expression.337 Both oncocytic cells and neoplastic cells of chromophobe cell carcinomas express cytokeratin KL1, Cam 5.2, cytokeratin AEl, and cytokeratins 7, 8,18, and 19.32,3,37-39

In our series, the EMA and KL1 reactive patterns with apical cytoplasmic positivity observed in 69% and 37%, respectively, of the renal oncocytomas, as well as the peripheral cell accentuation or cytoplasmic positivity observed in 48% and 66%, respectively, of the chromophobe cell carcinomas, are significant (P = .05) characteristics in distinguishing between the two tumors. The significant positivity pattern we observed with PNA (an apical positivity pattern in 47% of the renal oncocytomas and diffuse cytoplasmic pattern in 24% of the eosinophilic subtype of chromophobe cell carcinomas) differs from previous studies, which reported that reactions for PNA in renal oncocytomas were negative in most cases.31 The 24% of UEA-1-positive chromophobe cell carcinomas confirmed the results reported by Ortmann et al.33 In one renal oncocytoma and six chromophobe cell carcinomas, a few cells reacted with S100 protein and lysozyme. Positive reactions for S100 and lysozyme have not been reported in previous studies.3239 Vimentin staining may be helpful if any possibility of confusion with clear cell carcinoma exists, because it has been shown to be usually negative in oncocytomas and chromophobe cell carcinomas.202931323,no But unusual positivity, as we observed in two chromophobe cell carcinomas and in 12 renal oncocytomas, has been described.2,31,38 Nevertheless, the results of these antibodies are not significant, because their positivity has been found only in a few cases and in a few cells.

Recently, molecular cytogenetic techniques have shown normal and abnormal karyotypes with balanced and unbalanced translations in most renal oncocytomas5,4142 and a combination of allelic losses for chromophobe cell carcinomas; these characteristics do not occur in other types of renal tumors.27 While molecular ultrastructural studies and cytogenetic techniques are more precise, they are rarely available. Our study provided a systematic comparative analysis of several antibodies and lectins that are routinely used on conventional specimens.

Our study pointed out that Hale's colloidal iron staining

is not specific for chromophobe cell carcinoma, as it also stains cells of oncocytoma. The type of positivity differs between the two tumors, however, producing a microvesicular cytoplasmic pattern in chromophobe cell carcinoma and apical positivity in oncocytomas. In the same way, we demonstrated that the type of positivity observed is more helpful than positivity with antigen reactivity alone, especially with EMA and cytokeratin antibodies, for distinguishing between the eosinophilic subtype of chromophobe cell carcinomas and renal oncocytomas.

This study was financially supported by the Comite de Paris (Ligue Nationale contre le Cancer).

Participants of this study included G. Bertrand, MD (Centre de Pathologie Paul Papin, Angers); C. Bor, MD (Centre de Biologie Medicale, Chartres); N. Bove, MD (Centre Hospitalier Universitaire, Amiens); E Buzelin, MD (Centre Hospitalier Universitaire, Hotel Dieu, Nantes); H. Chapuis, MD (Centre Hospitalier General Nimes); C. Deminiere, MD (Centre Hospitalier Universitaire, Hopital Pellegrin, Bordeaux); A. Gaulier, MD (Centre Hospitalier General Victor Dupouy, Argenteuil); A. M. Kadi, MD (Centre Hospitalier General, La Roche sur Yon); O. LanguilleMimoune, MD (Cabinet d'Anatomie et de Cytologie Pathologiques, Paris); M. Pluot, MD (Hopital Robert Debre, Reims); and P. Texier, MD (Hotel Dieu Hospital, Paris).

Accepted for publication April 1, 1997.

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From the Services d'Anatomie et Cytologie Pathologiques, Assistance Publique-Hopitaux de Paris, Hopital Lariboisiere, Paris, France (Drs Cochand-Priollet and Wassef and Ms Groleau); Assistance Publique Hopitaux de Paris, Hopital Louis Mourier, Colombes, France (Drs Molinie and Fontaine); Centre Medico-chirurgical de la porte de Choisy, Paris, France (Dr Bougaran); Department of Pathology, Edouard Herriot Hospital, Lyon, France (Dr Bouvier); Department of Pathology, Bichat Hospital, Paris, France (Drs Dauge-Geffroy and Toublanc); Department of Pathology, Hopital Delafontaine, St Denis, France (Dr Deslignieres); Department of Pathology, Necker Hospital, Paris, France (Dr Fournet); Department of Pathology, Hopital d'Instruction des Armees, Begin Hospital, St Mande, France (Dr Gros); Department of Pathology, St Louis Hospital, Paris, France (Dr Lesourd); Department of Pathology, Centre Hospitalier Universitaire, Angers, France (Dr Saint-Andre); Department of Pathology, Cochin Hospital, Paris, France (Dr Vieillefond).

Reprint requests to Service d'Anatomie Pathologique, Hopital Lariboisiere, 2 Rue Ambroise Pare, 75010 Paris, France (Dr Cochand Priollet).

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