Case 5 -
Malignant Oncocytoma of the Kidney (with secondary clear cell changes), Metastatic to Mediastinum
Istituto Nazionale Tumori
Click on each slide thumbnail image for an enlarged view
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
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.
Malignant oncocytoma of the kidney (with secondary clear cell changes), metastatic to
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:
- Presence of cytokeratins 8 and 18, sometimes with a dot-like appearance (24)
- Consistent presence of keratin 14;6
- Presence of globular filamentous cytoplasmic bodies at the EM level (4, 5)
- Presence of extracellular hyaline globules, corresponding at the
EM level to concentric multilayered accumulations of basement membrane material 11 ;
- 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
- 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
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:
- The fact that some renal cell carcinomas have fields identical to
oncocytomas 2 , sometimes described as "in situ" changes;18
- The existence of a renal tumor developing after successful treatment of
neuroblastoma, that has been designated as oncocytoid renal cell carcinoma (sic);22
- The existence of a hybrid tumor between oncocytoma and chromophobe cell
carcinoma that has been called the eosinophilic subtype of chromophobe cell carcinoma
- 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) ;
- 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
- 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
- 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 .
- Amin MB, Crotty TB, Tickoo SK, Farrow
GM. Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80
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- Barnes CA, Beckman EN.
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- 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.
- Bonsib SM, Bray C. Cytokeratin-containing globular filamentous bodies in
renal oncocytoma. Ultrastruct Pathol 1991; 15: 421-529.
- Bonsib SM,
Bromley C, Lager DJ. Renal oncocytoma: Diagnostic utility of cytokeratin-containing globular
filamentous bodies. Mod Pathol 1991; 4: 16-23.
- 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.
- 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,
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- Cohen C, McCue PA, Derose PB. Histogenesis of renal cell
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- Davis CJ, Jr., Mostofi FK, Sesterhenn I A, Ho CK. Renal oncocytoma.
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- Eble JN, Hull MT. Morphologic features of renal oncocytoma: A light and
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- Gatalica Z, Miettinen M, Kovatich A, McCue PA. Hyaline globules in renal
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- 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.
- 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.
- Klein MJ, Valensi QJ. Proximal tubular adenomas of kidney with so-called
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- Koller A, Kain R, Haitel A, Mazal PR, Asboth F, Susani
M. Renal oncocytoma with prominent intracytoplasmic vacuoles of mitochondrial origin. Histopathology
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- Kovacs G, Welter C, Wilkens L, Blin N, Deriese
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- Kuroda N, Guo L, Toi M, Naruse K, Miyazaki E, Hayashi
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- Lense E, Siegel R, Hewan-Lowe K, Costa MJ. In situ
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- Lieber MM, Tomera KM, Farrow GM. Renal oncocytoma. J
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- Lizak JS, Farhood A, Verani R.
Intracytoplasmic lumina in a case of bilaterally multifocal renal oncocytomas. Arch Pathol Lam Med 1994;
- Martignoni G, Pea M, Bonetti f, Brunelli M, Eble JN.
Oncocytoma-like angiomyolipoma. A clinicopathologic and immunohistochemical study of 2 cases. Arch
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- Medeiros LJ, Palmedo G, Krigman
HR, Kovacs G, Beckwith JB. Oncocytoid renal cell carcinoma after neuroblastoma: A report of four cases
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- Perez-Ordonez B, Hamed G, Campbell S, Erlandson RA, Russo P, Gaudin PB,
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- Pitz S, Moll R, Storkel S, Thoenes W. Expression of
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- Shimazaki H, Tanaka K, Aida S, Tamai S, Seguchi K, Hayakawa M. Renal
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- Tickoo SK, Amin MB. Discriminant nuclear features of renal
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- Tickoo SK, Lee MW,
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- Tickoo SK, Reuter VE, Amin MB, Srigley JR, Epstein JI, Min KW, Rubin MA, Ro
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