Oncocytomas and Rare Renal Tumors 25

(1)

International agreement was reached on the histological classification of renal epithelial neoplasms with the new World Health Organization (WHO) classification of the tumors of the urinary system and male genital organs [1]. This classification defines malignant neoplasms as clear cells renal carcinoma, papillary renal carcinoma, chromophobe renal carcinoma, collecting duct carcinoma, and unclassified renal cell carcinoma. Benign neoplasms are papillary adenoma, renal oncocytoma, and metanephric nephradenoma or adenofibroma. Over the past few years new or rare distinctive kidney tumors have been described. This chapter presents examples of recently recognized tumor entities and discusses molecular alterations, which are important for the differential diagnosis. The fol- lowing tumors are described and discussed:

oncocytoma, mixed epithelial and stromal renal tumors, primary renal synovial sarcomas, renal primitive neuroectodermal tumors (PNETs), and mucinous tubular and spindle cell carcinomas. It is important to distinguish these tumor entities from the well-known frequent renal tumors because of different biological behavior and different therapeutical approaches.

Oncocytoma

Oncocytoma comprises approximately 5% of all neoplasms of renal tubular epithelium and is a

benign epithelial tumor [2–4]. The name comes from the predominant cell type, the so-called oncocyte (swollen cell). Oncocytes are round- to-polygonal cells with densely granular cytoplasm. Sporadic oncocytomas have a typical mahogany-brown cut surface and a central stellate scar (Fig. 25.1). Hemorrhage is present in up to 20% of cases [3]. Necrosis is extremely rare. The majority of oncocytomas present by an incidental discovery during a radiographic workup of unrelated conditions. Oncocytomas have a typical ultrastructure with numerous mitochondria in the cytoplasm [5]. Oncocytoma is composed of large cells with mitochondria ridge eosinophilic cytoplasm. It has been suggested that oncocytomas arise from the distal tubular system. Most oncocytomas occur spo- radically, although there are several cases that have been reported in the context of inherited tumor syndromes, e.g., the Birt-Hogg-Dubé syn- drome. There are also cases with a large number of oncocytic lesions with a spectrum of morphological features, including oncocytic tumors, oncocytic change in benign tubules, microcysts, and a lining of oncocytic cells and clusters of oncocytes within the renal interstitium. Such cases are called oncocytomatosis. The majority of the mitochondria are of normal size and shape. Somatic genetic alterations include translocation of t(5;11)(q35;q13). Some of the cases show loss of chromosome 1 and 14 [6–8].

Oncocytomas and Rare Renal Tumors

Holger Moch

301

(2)

302

Urological Cancers: Science and Treatment

Mixed Epithelial and Stromal Renal Tumors

The new WHO classiﬁcation of tumors includes the entity of mixed epithelial and stromal tumors. This is a complex renal neoplasm composed of a mixture of stromal and epithelial elements. some of these cases have been reported under different names, including cystic hamar- toma of the renal pelvis or adult mesoblastic nephroma [9–11]. The new WHO classiﬁcation accepts the term mixed epithelial and stromal tumor [1]. Importantly, there is a 6 : 1 predomi- nance of women over men, and all of the women are perimenopausal. There are histories of estrogen therapy in most of the reported cases [11].

Surgery has been curative in all cases. The tumors are composed of large cysts, microcysts,

and tubules. The large cysts are lined by colum- nar epithelium, which forms small papillary tufts (Fig. 25.2). Epithelium with müllerian characteristics has also been described. Areas of myxoid stroma and fascicles of smooth muscle cells may be prominent. By immunohistochem- istry, the spindle cells, which look like smooth muscle, have strong reactions with antibodies to actin and desmin. The nuclei of these spindle cells express also estrogen and progesterone receptors (Fig. 25.3). The epithelial elements are positive for antibodies to a variety of cytokeratins [12].

Little is known about the genetics of these tumors. The tumors lack the translocation t(12/15) and trisomies for chromosome 11, which are typical for mesoblastic nephroma [13]. Therefore, there is no genetic relationship between mesoblastic nephroma and mixed Fig. 25.1. Oncocytoma. Mahogany-brown cut surface with central stellate scar (left). Small eosinophilic cells (oncocytes (right).

Fig. 25.2. Mixed epithelial-stromal tumor. Large tumor with contact to renal pelvis (left). Not glancing inner surface of the cystic tumor (right).

(3)

epithelial stroma tumors, although the morphology is very similar. The tumors should not be called adult mesoblastic nephroma. It has been suggested that the tumors evolve by long-term hormone exposure.

Primary Renal Synovial Sarcomas

Synovial sarcoma of the kidney is characterized by a speciﬁc morphology and speciﬁc cytogenetic characteristics [14]. It consists of spindle cells and frequently has large cysts. Many cases show local recurrence after nephrectomy. Most cases are diagnosed between the ages of 20 and 50 years. Microscopically, tumors are characterized by monomorphic plump spindle cells (Fig.

25.4). The cysts are lined by mitotically inactive epithelial cells without striking cellular atypia.

The tumors have been previously described as

embryonal sarcoma of the kidney. There is a slight male predilection (1.6 : 1). No bilateral tumors were identiﬁed yet [15,16].

The spindle cells are immune reactive for epithelial membrane antigen (EMA), CD56, and sometimes CD99. They are nonreactive for desmin, actin, S100, and cytokeratins. The cyst epithelium is cytokeratin positive. Synovial sarcoma is cytogenetically characterized by the translocation t(X;18)(p11.2/q11.2), generating a fusion between the SYT gene on chromosome 18 and one member of the SSX family of genes (SSX1, SSX2, SSX4) on chromosome X [17,18].

Molecularly conﬁrmed primary synovial sarcomas of the kidney have demonstrated the characteristic SYT-SSX gene fusion (Fig. 25.4). In contrast to soft tissue synovial sarcoma, where the SYT-SSX gene fusion is more common than the alternative SYT-SSX2 form, the majority of renal synovial sarcomas have so far demon- strated the SYT-SSX2 gene fusion. There is a tendency for a predominance of monophasic Fig. 25.3. Mixed epithelial and stromal tumor. Spindle cell stroma with smooth muscle differentiation (left). Spindle cells react with antibodies to estrogen and progesterone (right).

(4)

304

spindle morphology of these tumors in the kidney, and there are more rarely biphasic tumors.

Although prognostic data are limited, there are case reports describing tumors that have responded to chemotherapy. However, recurrence is common.

In summary, primary renal synovial sarcoma is a distinctive tumor entity that should be considered in renal tumors consisting of spindle cells, especially in young adults.

Primitive Neuroectodermal Tumors of the Kidney

Primitive neuroectodermal tumors (PNETs) of the kidney are rare and of highly aggressive malignancy [19–21]. The tumors are composed of small uniform round cells, characterized by a translocation resulting in a fusion transcript of the EWS gene and the ETS-related family of oncogenes (Fig. 25.5). The neoplasms are rare.

The age of the described patients range from 4 to 69 years [22].

The mean age is 27 years. There is a predilection for males. Most patients present with fever, weight loss, and bone pain. The tumors are mostly more than 10 cm in diameter with replacement of the kidney. The weight of some

of these tumors is 1 kg or more. The tumor in the kidney is no different from the more common counterpart in the soft tissues. The immunophenotype of PNET is the expression of vimentin and the surface antigen of CD99 or HBA-71.

Some tumors also express pancytokeratin.

Virtually all of the reported PNETs of the kidney had the translocation t(11;22)(q24;q12) with the fusion transcript between the EWS gene (22q12) and the ETS-related oncogene FLI1 (11q24) (Fig. 25.6). However, there are also other variant translocations [22]. The diagnosis of renal PNETs must be considered in young patients with renal neoplasms, particularly those with advanced disease at presentation. Achieving an exact diagnosis has important clinical conse- quences because polychemotherapy and high- dose chemotherapy may lead to dramatic tumor reduction or even complete remission. In the past, aggressive multidrug chemotherapy has resulted in an improvement in the clinical outcome [23].

Mucinous Tubular Spindle Cell Carcinoma

Mucinous tubular spindle cell carcinoma are low-grade polymorphic renal epithelial neoplasms with mucinous tubular and spindle cell

1 2 3

1 2 3 4 M

SYT-SSX b-globin

100 bp 300 bp

A

B

Fig. 25.4. Synovial sarcoma of the kidney. Cystic change (upper left). Monomorphic small spindle cells (lower left).SYT-SSX fusion due to translocation t(X;18) (right). A: Taql-Digestion of PCR-Products (SSX1; SSX2; Positive Control); B: SSCP-Analysis (SSX1; SSX2; Positive Control).

(5)

Fig. 25.5. Primitive neuroectodermal tumor (PNET) of the kidney. Note geographic necrosis and sheet-like growth pattern (left). CD99 expression (right).

Fig. 25.6. PNET of the kidney.EWS-FLI1 translocation. A: Balanced chromosomal translocation t(11;22)(q24;12) in PNET of the kidney (upper left); B: EWS-FLI-1 fusion (t(11;22)(q24,12) or EWS-ERG fusion (t(21;22)(q22;12) (less common) are observed in PNETs; C: CT scan of a young patient showing a renal PNET (upper right); D: Nested PCR with primers that specifically detect EWS/FLI-1 and EWS-ERG chimeric transcripts (lower right).

A

B

C

D

(6)

306

features. The new WHO classification has included this new tumor subtype [1]. The tumors usually present as a symptomatic masses, often found on ultrasound [24]. There is a wide age range from 17 to 82 years and a male to female rate of 1 : 4 [25,26]. Macroscopically mucinous tubular and spindle cell carcinomas are well circumscribed and have gray or light tan cut surfaces (Fig. 25.7). The tumors are composed of tightly packed, elongated tubules separated by mucinous stroma. Sometimes the tumors simulate leiomyoma or sarcoma. Many of these tumors had been previously diagnosed as unclassified sarcomatoid carcinomas or as duct Bellini carcinomas. The tumors have a complex immunophenotype and stain for cytokeratin and EMA. Markers of proximal nephron such as CD10 are absent. On comparative genomic hybridization and fluorescence in situ hybridization, there is a characteristic combination of

chromosome losses, generally involving chromosome 1, 4, 6, 8, 13, and 14 [27,28]. The prog- nosis seems to be favorable.

It has been postulated that these tumors are related to the loop of Henle. However, the immunohistochemical and cytogenetic analysis showed complex immunophenotypes, but could not prove a derivation from the loop of Henle.

There was no genetic relationship to clear cell renal carcinomas [28].

Renal Cell Carcinoma in Children and Young Adults

In childhood, by far the most common renal neoplasms are nephroblastomas. Renal cell carcinomas are rare in children. The new WHO classiﬁcation includes new tumor types

Fig. 25.7. Mucinous tubular and spindle cell carcinoma composed of spindle cells and cuboidal cells forming cords and tubules. Note extracellular mucin.

(7)

that occur predominantly in children and young adults. Such tumors include renal cell carcinomas with the ASPL-TFE3 gene fusion and carcinomas with a PRCC-TFE3 gene fusion. Collectively, these tumors have been termed Xp11.2 or TFE3 translocation carcinomas [29].

Renal carcinomas associated with Xp11.2 translocations have a distinctive histopathologi- cal appearance, which is that of a carcinoma with papillary architecture composed of clear cells.

Some tumors have a more nested architecture and often feature cells with granular eosinophilic cytoplasm. The translocation carcinomas are characterized by cells with voluminous clear to eosinophilic cytoplasm and prominent nucleoli [30]. Psammoma bodies are sometimes extensive (Fig. 25.8).

The tumors have the distinctive immunohistochemical feature with nuclear immunoreactiv- ity for TFE3 protein. Only about 50% express epithelial markers such as cytokeratin and EMA.

The carcinomas are deﬁned by several different translocations involving chromosome Xp11.2, all resulting in gene fusions involving the TFE3 gene, which is a member of the basic helix- loop-helix family of transcription factors. Both the PRCC-TFE3 and ASPL-TFE3 fusion proteins retain the TFE3 DNA-binding domain. This domain localizes to the nucleus and can act as transcription factor [31,32].

Very little is known about the clinical behavior of these carcinomas. They usually present at an advanced stage. However, their clinical course thus far appears to be indolent. Most of these tumors show no virtual mutations [33].

Summary

New tumor entities have been described, which are characteristic for children or young adults.

The predominance of TFE translocation carci- nomas in the ﬁrst decades of life demonstrates that renal cell carcinomas in young patients contain genetically and phenotypically distinct tumors with further potential for novel renal cell carcinoma subtypes. The far lower frequency of clear cell carcinomas with VHL alterations in childhood compared to adults suggests that renal cell carcinomas in young patients have a unique genetic background.

Other tumors with apparent predilection for young age groups include clear cell carcinomas in the context of von Hippel–Lindau disease, carcinomas in combination with nephroblastomas, and renal cell carcinomas associated with neuroblastomas.

References

1. Eble J, et al. World Health Organization clas- siﬁcation of tumours. In: Kleihus P, Sobin L, eds.

Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon:

IARC Press, 2004.

2. Moch H, et al. Prognostic utility of the recently recommended histologic classiﬁcation and re- vised TNM staging system of renal cell carcinoma:

a Swiss experience with 588 tumors. Cancer 2000;

89(3):604–614.

3. Perez-Ordonez B, et al. Renal oncocytoma: a clin- icopathologic study of 70 cases. Am J Surg Pathol 1997;21(8):871–883.

Fig. 25.8. ASPL-TFE3 translocation tumor. Note papillary architecture (A) and psammoma bodies (B).

A B

(8)

308

4. Kovacs G, et al. The Heidelberg classiﬁcation of renal cell tumours. J Pathol 1997;183(2):131–133.

5. Tickoo SK, et al. 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(9):

1247–1256.

6. Fuzesi L, et al. Cytogenetic analysis of 11 renal oncocytomas: further evidence of structural rearrangements of 11q13 as a characteristic chromosomal anomaly. Cancer Genet Cytogenet 1998;

107(1):1–6.

7. Herbers J, et al. Lack of genetic changes at speciﬁc genomic sites separates renal oncocytomas from renal cell carcinomas. J Pathol 1998;184(1):

58–62.

8. Sinke RJ, et al. Fine mapping of the human renal oncocytoma-associated translocation (5;11) (q35;q13) breakpoint. Cancer Genet Cytogenet 1997;96(2):95–101.

9. Michal M. Benign mixed epithelial and stromal tumor of the kidney. Pathol Res Pract 2000;

196(4):275–276.

10. Michal M, Syrucek M. Benign mixed epithelial and stromal tumor of the kidney. Pathol Res Pract 1998;194:445–448.

11. Adsay NV, et al. Mixed epithelial and stromal tumor of the kidney. Am J Surg Pathol 2000;24(7):

958–970.

12. Moch H, et al. Mixed epithelial and stromal tumor of the kidney. Pathologe, 2004;25:356–361.

13. Pierson CR, et al. Mixed epithelial and stromal tumor of the kidney lacks the genetic alterations of cellular congenital mesoblastic nephroma.

Hum Pathol 2001;32(5):513–520.

14. Argani P, et al. Primary renal synovial sarcoma:

molecular and morphologic delineation of an entity previously included among embryonal sarcomas of the kidney. Am J Surg Pathol 2000;

24(8):1087–1096.

15. Kim DH, et al. Primary synovial sarcoma of the kidney. Am J Surg Pathol 2000;24(8):1097–1104.

16. Moch H, et al. Primary renal synovial sarcoma.

A new entity in the morphological spectrum of spindle cell tumors. Der Pathologe 2003;24(6):

466–472.

17. Mezzelani A, et al. SYT-SSX fusion transcripts and epithelial differentiation in synovial sarcoma.

Diagn Mol Pathol 2000;9(4):234–235.

18. Fligman I, et al. Molecular diagnosis of synovial sarcoma and characterization of a variant SYT- SSX2 fusion transcript. Am J Pathol 1995;147(6):

1592–1599.

19. Furman J, et al. Primary primitive neuroectodermal tumor of the kidney. Am J Clin Pathol 1996;

106:339–344.

20. Rodriguez-Galindo C, et al. Is primitive neuroectodermal tumor of the kidney a distinct entity?

Cancer 1997;79(11):2243–2250.

21. Quezado M, Benjamin DR, Tsokos M. EWS/FLI-1 fusion transcripts in three peripheral primitive neuroectodermal tumors of the kidney. Hum Pathol 1997;28(7):767–771.

22. Jimenez RE, et al. Primary Ewing’s sarcoma/primitive neuroectodermal tumor of the kidney: a clin- icopathologic and immunohistochemical analysis of 11 cases. Am J Surg Pathol 2002;26(3):320–327.

23. Casella R, et al. Metastatic primitive neuroectodermal tumor of the kidney in adults. Eur Urol 2001;39:613–617.

24. MacLennan GT, Farrow GM, Bostwick DG. Low- grade collecting duct carcinoma of the kidney:

report of 13 cases of low-grade mucinous tubulo- cystic renal carcinoma of possible collecting duct origin. Urology 1997;50(5):679–684.

25. Srigley J, Eble JN, Grignon DJ. Unusual renal cell carcinoma (RCC) with prominent spindle cell change possibly related to the loop of Henle. Mod Pathol 1999;12:107A.

26. Srigley J, et al. Phenotypic, molecular and ultrastructural studies of a novel low grade renal epithelial neoplasm possibly related to the loop of Henle. Mod Pathol 2002;15(1):182A.

27. Rakozy C, et al. Low-grade tubular-mucinous renal neoplasms: morphologic, immunohistochemical, and genetic features. Mod Pathol 2002;

15(11):1162–1171.

28. Weber A, Srigley J, Moch H. Mucinous tubular and spindle cell carcinoma of the kidney. A molecular analysis. Pathologe 2003;24(6):453–459.

29. Argani P, et al. Primary renal neoplasms with the ASPL-TFE3 gene fusion of alveolar soft part sarcoma: a distinctive tumor entity previously included among renal cell carcinomas of children and adolescents. Am J Pathol 2001;159(1):179–

192.

30. Renshaw AA, et al. Renal cell carcinomas in children and young adults: increased incidence of papillary architecture and unique subtypes. Am J Surg Pathol 1999;23(7):795–802.

31. Weterman MA, Wilbrink M, Geurts van Kessel A.

Fusion of the transcription factor TFE3 gene to a novel gene, PRCC, in t(X;1)(p11;q21)-positive papillary renal cell carcinomas. Proc Natl Acad Sci USA 1996;93(26):15294–15298.

32. Weterman MA, et al. Molecular cloning of the papillary renal cell carcinoma-associated translocation (X;1)(p11;q21) breakpoint. Cytogenet Cell Genet 1996;75(1):2–6.

33. Bruder E, et al. Morphologic and molecular characterization of renal cell carcinoma in children and young adults. Am J Surg Pathol 2004;28(9):

1117–1132.