—  SPECIALTY CONFERENCE  —

Genitourinary Pathology

Case 5 - Malignant Oncocytoma of the Kidney (with secondary clear cell changes), Metastatic to Mediastinum

Juan Rosai
Istituto Nazionale Tumori
Milano, Italy


Click on each slide thumbnail image for an enlarged view
Clinical History:
60-year-old female with a left renal mass discovered in June 2000, during the course of a post-laparoscopic cholecystectomy sonographic control. The CT scan confirmed the presence of a 4 cm mass in the left kidney. A left radical nephrectomy with para-aortic lymphadenectomy was carried out in October 2000. Gross examination revealed a 3.8x3.5x2.8 cm well-circumscribed solid brown mass in the renal cortex. The renal capsule, pelvis, renal vessels, adrenal gland and lymph nodes were free of tumor.

In a follow-up control carried out in February 2002, a mediastinal mass was detected in the chest x-ray, resulting in compression and anterior displacement of the trachea. The thyroid gland was not involved. This mass was biopsied.

The sections submitted are from the renal tumor removed in 2000.

Diagnosis: Malignant oncocytoma of the kidney (with secondary clear cell changes), metastatic to mediastinum


Case 5 - Figure 1 - Kidney, low power.
Case 5 - Figure 2 - Kidney, high power.


Case 5 - Figure 3 - Mediastinum, low power.
Case 5 - Figure 4 - Mediastinum, high power.

Discussion
This patient had oncocytic neoplasms with secondary cytoplasmic clearing involving kidney and mediastinum. The marked morphologic similarities they exhibited strongly favors the interpretation that one is a metastasis from the other rather than two independent primaries. Furthermore, the sequence of events and the immunohistochemical profile of the tumors (particularly their negativity for thyroglobulin and TTF-1) favors the interpretation that this tumor represents a malignant oncocytoma of the kidney that has metastasized to the mediastinum rather than the reverse.

The evolution of our concepts concerning the nature and behavior of renal oncocytomas is a very good model to reflect upon the theoretical underpinnings and shortcomings of tumor nomenclature and classification schemes. Is is well known that tumors predominantly or exclusively composed of oncocytes can arise in many sites, most of these tumors being of epithelial and specifically glandular derivation. This includes kidney, thyroid, parathyroid, salivary glands and adrenal cortex, but also lesions such as glomus tumor, GIST, and - in the specific case of the kidney – angiomyolipoma and carcinoid tumor (12, 21). It would seem reasonable to assume that the basic molecular genetic mechanism that leads to the oncocytic state is similar at all of these sites, at least when it involves epithelial glandular cells. One would have also assumed that the approach taken towards oncocytic neoplasms concerning their position in the classification scheme of the tumors of the respective organs would have been similar. Alas, this is not the case. Whereas in some sites they are regarded as not particularly significant variants of major tumor types (such as oncocytic follicular tumors of thyroid or parathyroid, oncocytic medullary carcinomas, and oncocytic carcinoid tumors), in the kidney they are thought to represent a tumor type of its own, very distinct from all others and particularly from renal cell carcinoma. It was not always so. The younger members of the audience may not be aware of the fact that until the mid seventies, renal neoplasms composed of oncocytic cells were seen in a similar light as oncocytic tumors in other organs. Specifically, they were thought to be oncocytic variants of renal cell carcinomas. It was the paper by Klein and Valensi in 1976 14 that led to a radical change in that approach. Spurred by that publication and supported by additional articles on the subject written in subsequent years (1, 2, 9, 10,13, 16, 23, 28), the belief took hold that renal oncocytoma were tumors sui genesis which behaved nearly always in a benign fashion, the latter feature lending indirect confirmation and great clinical significance to the proposed segregation. Previous papers which had shown that renal oncocytomas could behave in a malignant fashion 19 were reevaluated in the light of this new approach, and the malignant cases were reclassified in other categories.

There is no question that oncocytic renal neoplasms are endowed with a set of distinctive and rather spectacular features at various levels, beginning with their gross appearance. Their mahogany brown color (probably due to pigment present within mitochondria) is very well known, as it is the presence of a central scar, a feature which however is less than constant. At the cytologic level, the abundant granular deeply acidophilic cytoplasm is of course the defining feature of the tumor, together with the predominantly tubular or alveolar (rather than papillary or solid) architecture. Equally distinctive is the ultrastructural appearance, with its cytoplasmic abundance of mitochondriae, many of which show various types of morphologic aberrations 26 . With the advent of immunohistochemistry, other markers for these tumors have appeared, some dependent upon the numerous mitochondria and others situated in other portions of the cytoplasm. The latter include:

  1. Presence of cytokeratins 8 and 18, sometimes with a dot-like appearance (24) ;
  2. Consistent presence of keratin 14;6 
  3. Presence of globular filamentous cytoplasmic bodies at the EM level (4, 5) ;
  4. Presence of extracellular hyaline globules, corresponding at the EM level to concentric multilayered accumulations of basement membrane material 11 ;
  5. Occasional occurrence of intracytoplasmic lumina in the tumor cells, detectable at the EM level;15, 20, 25  tumor cells with these features have been called oncoblasts;
  6. Lack of vimentin.

As impressive as the oncocytic change is at various levels, the decision as to whether oncocytoma is to be regarded as a distinctive entity within the family of renal epithelial neoplasms should largely depend on whether it fulfills or not at least one of these criteria: 1 A unique molecular genetic make-up suggestive of a specific pathogenesis; 2 A distinct histogenesis; 3 A particular clinical presentation regarding patient's age, sex, or antecedent factors; 4  Most importantly, a natural history which is different from that of the other epithelial renal neoplasms.

Renal oncocytoma fails to meet the first three criteria 16 . In particular, the argument as to whether it arises from the distal tubules, proximal tubules, or some other portions of the nephron seems as sterile as those histogenetic disquisitions have proved for other renal epithelial tumors or – for that matter – for histogenetic considerations of topographic nature in general 8 .

The most powerful argument in favor of the segregation of renal oncocytoma from the other epithelial tumors of this organ lies in its allegedly benign nature. I believe this assumption is largely the result of the artificial and arbitrary way that renal oncocytoma has been defined, which includes lack of mitotic activity or necrosis and absence of nuclear alterations other than those typically associated with the oncocytic state and sometimes referred to as "degeneration" nuclear atypia (scattered huge nuclei with prominent nucleoli).28  Conceptually, there is no reason why the definition of oncocytoma should be so restricted. If a tumor is composed of oncocytes, it would seem logical to regard it as an oncocytoma independently of any other feature. Certainly no restrictions even remotely resembling those above stated have ever been proposed for oncocytomas at any other sites. In any event, it should not be too surprising that oncocytomas restricted by those qualifiers behave in a benign fashion. By way of analogy, one wonders what the metastatic rate for clear cell carcinomas of the kidney would be if they were defined similarly. Another analogy would be to restrict the diagnosis of thyroid oncocytomas to those thyroid oncocytic neoplasms which lack mitoses, necrosis, and/or capsular/vascular invasion, and that exhibit a low nucleo-cytoplasmic ratio.

That a histogenetic relationship exists between renal oncocytoma and renal cell carcinoma (particularly of the chromophobe type) is suggested by the following reported findings:

  1. The fact that some renal cell carcinomas have fields identical to oncocytomas 2 , sometimes described as "in situ" changes;18 
  2. The existence of a renal tumor developing after successful treatment of neuroblastoma, that has been designated as oncocytoid renal cell carcinoma (sic);22 
  3. The existence of a hybrid tumor between oncocytoma and chromophobe cell carcinoma that has been called the eosinophilic subtype of chromophobe cell carcinoma (sic);7 
  4. The fact that keratin 14, consistently expressed in renal oncocytoma, is occasionally may also be found in granular renal cell carcinomas and the eosinophilic variant of chromophobe renal cell carcinomas (6) ;
  5. The similarities in the immunohistochemical profile of renal oncocytoma and chromophobe renal cell carcinoma, which includes the expression of cytokeratins 8 and 18,24  the lack of vimentin,24  and the strong expression of paxillin (a cytoskeletal component of focal adhesions and links betweel F-actin and integrin);17 
  6. The fact that the dominant mass in cases of so-called renal oncocytosis can be an oncocytoma, a chromophobe renal cell carcinoma, or a tumor combining features of both cell types;30 
  7. The fact that in a number of cases of renal oncocytosis, some of the smaller nodules have the appearance of chromophobe cell carcinoma or dysplay hybrid features.30 

It has been well established in the thyroid gland and other sites that neoplastic oncocytic cells can undergo secondary cytoplasmic clear changes, and that this clearing is usually due to the cystic dilatation of the mitochondriae, although other mechanisms can be operative 3 . There is mounting evidence that the same phenomenon can occur in renal oncocytomas 15, 27, 29 . We believe that the case presented at this session is an example of this phenomenon. Interestingly, in the thyroid gland there is a sugggestion that oncocytic neoplasms with clear cell changes are more likely to be malignant than those without it,3  and we suspect that this may also be true for their renal counterparts. As a matter of fact, one could view chromophobe renal cell carcinoma as an malignant oncocytoma in which a very special type of cytoplasmic clearing has taken place, probably governed by additional genetic alterations and which is accompanied by a greater likelihood of manignant behavior 7 .

References

  1. Amin MB, Crotty TB, Tickoo SK, Farrow GM. Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol 1997; 21: 1-12.
  2. Barnes CA, Beckman EN. Renal oncocytoma and its congeners. Am J Clin Pathol 1983; 79: 312-318.
  3. Carcangiu ML, Sibley RK, Rosai J. Clear cell change in primary thyroid tumors. A study of 38 cases. Am J Surg Pathol 1985; 9: 705-722.
  4. Bonsib SM, Bray C. Cytokeratin-containing globular filamentous bodies in renal oncocytoma. Ultrastruct Pathol 1991; 15: 421-529.
  5. Bonsib SM, Bromley C, Lager DJ. Renal oncocytoma: Diagnostic utility of cytokeratin-containing globular filamentous bodies. Mod Pathol 1991; 4: 16-23.
  6. Chu PG, Weiss LM. Cytokeratin 14 immunoreactivity distinguishes oncocytic tumour from its renal mimics: An immunohistochemical study of 63 cases. Histopathology 2001; 39: 455-462.
  7. Cochand-Priollet B, Molinie V, Bougaran J, Bouvier R, Dauge-Geffroy MC, Deslignieres S, fournet JC, Gros P, Lesourd A, Saint-Andre JP, Toublanc M, Vieillefond A, Wassef M, Fontaine A, Groleau L. Renal chromophobe cell carcinoma and oncocytoma. A comparative morphologic, histochemical, and immunohistochemical study of 124 cases. Arch Pathol Lab Med 1997; 121: 1081-1086.
  8. Cohen C, McCue PA, Derose PB. Histogenesis of renal cell carcinoma and renal oncocytoma. An immunohistochemical study. Cancer 1988; 62: 1946-1951.
  9. Davis CJ, Jr., Mostofi FK, Sesterhenn I A, Ho CK. Renal oncocytoma. Clinicopathological study of 166 patients. J Urogenit Pathol 1991; 1: 41-52.
  10. Eble JN, Hull MT. Morphologic features of renal oncocytoma: A light and electron microscopy study. Hum Pathol 1984; 15: 1054-1061.
  11. Gatalica Z, Miettinen M, Kovatich A, McCue PA. Hyaline globules in renal cell carcinomas and oncocytomas. Hum Pathol 1997; 28: 400-403.
  12. Hannah J, Lippe B, Lai-Goldman M, Bhuta S. Oncocytic carcinoid of the kidney associated with periodic Cushing's syndrome. Cancer 1988; 61: 2136-2140.
  13. Hartwick RW, el-Naggar AK, Ro JY, Srigley JR, McLemore DD, Jones EC, Grignon DJ, Thomas MJ, Ayala Ag. Renal oncocytoma and granular renal cell carcinoma. A comparative clinicopathologic and DNA flow cytometric study. Am J Clin Pathol 1992; 98: 587-593.
  14. Klein MJ, Valensi QJ. Proximal tubular adenomas of kidney with so-called oncocytic features. A clinicopathologic study of 13 cases of a rarely reported neoplasm. Cancer 1976; 38: 906-914.
  15. Koller A, Kain R, Haitel A, Mazal PR, Asboth F, Susani M. Renal oncocytoma with prominent intracytoplasmic vacuoles of mitochondrial origin. Histopathology 2000; 37: 264-268.
  16. Kovacs G, Welter C, Wilkens L, Blin N, Deriese W. Renal oncocytoma. A phenotypic and genotypic entity of renal parenchymal tumors. Am J Pathol 1989; 134: 967-971.
  17. Kuroda N, Guo L, Toi M, Naruse K, Miyazaki E, Hayashi Y, Yoshikawa C, Ashida S, Shuin T, Enzan H. Paxillin: Application of immunohistochemistry to the diagnosis of chromophobe renal cell carcinoma and oncocytoma. Appl Immunohistochem Mol Morphol 2001; 9: 315-318.
  18. Lense E, Siegel R, Hewan-Lowe K, Costa MJ. In situ oncocytic change in association with multiple renal cell adenocarcinomas. Arch Pathol Lab Med 1991; 115: 1067-1069.
  19. Lieber MM, Tomera KM, Farrow GM. Renal oncocytoma. J Urol 1981; 125: 481-485.
  20. Lizak JS, Farhood A, Verani R. Intracytoplasmic lumina in a case of bilaterally multifocal renal oncocytomas. Arch Pathol Lam Med 1994; 118: 275-280.
  21. Martignoni G, Pea M, Bonetti f, Brunelli M, Eble JN. Oncocytoma-like angiomyolipoma. A clinicopathologic and immunohistochemical study of 2 cases. Arch Pathol Lab Med 2002; 126: 610-612.
  22. Medeiros LJ, Palmedo G, Krigman HR, Kovacs G, Beckwith JB. Oncocytoid renal cell carcinoma after neuroblastoma: A report of four cases of a distinct clinicopathologic entity. Am J Surg Pathol 1999; 23: 772-780.
  23. Perez-Ordonez B, Hamed G, Campbell S, Erlandson RA, Russo P, Gaudin PB, Reuter VE. Renal oncocytoma: A clinicopathologic study of 70 cases. Am J Surg Pathol 1997; 21: 871-883.
  24. Pitz S, Moll R, Storkel S, Thoenes W. Expression of intermediate filament proteins in subtypes of renal cell carcinomas and in renal oncocytomas. Distinction of two classes of renal cell tumors. Lab Invest 1987; 56: 642-653.
  25. Shimazaki H, Tanaka K, Aida S, Tamai S, Seguchi K, Hayakawa M. Renal oncocytoma with intracytoplasmic lumina: A case report with ultrastructural findings of "oncoblasts". Ultrastruct Pathol 2001; 25: 153-158.
  26. Simmons JL, Jaqua RA, Peterson KG. Ultrastructural evaluation of renal cell oncocytomas. Ultrastruct Pathol 1996; 20: 395-397.
  27. Slagel D, Bonsib SM. Renal oncocytoma with unusual features. Case report and review of morphologic variants of oncocytoma. J Urol Pathol 1995; 3: 223-233.
  28. Tickoo SK, Amin MB. Discriminant nuclear features of renal oncocytoma and chromophobe renal cell carcinoma. Analysis of their potential utility in the differential diagnosis. Am J Clin Pathol 1998; 110: 782-787.
  29. Tickoo SK, Lee MW, Eble JN, Amin M, Christopherson T, Zardo RJ, Amin MB. Ultrastructural observations on mitochondria and microvesicles in renal oncocytoma, chromophobe renal cell carcinoma, and eosinophilic variant of conventional (clear cell) renal cell carcinoma. Am J Surg Pathol 2000; 24: 1247-1256.
  30. Tickoo SK, Reuter VE, Amin MB, Srigley JR, Epstein JI, Min KW, Rubin MA, Ro JY. Renal oncocytosis: A morphologic study of fourteen cases. Am J Surg Pathol 1999; 23: 1094-1101.