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TFEs-associated renal cell carcinomas

Wednesday 14 October 2009

Renal translocation carcinomas are uncommon tumors generally arising in children and young adults. In the pediatric literature they have sometimes been referred to as ’juvenile carcinomas’. Most translocation carcinomas (about 90%) involve the transcription factor E3 (TFE3) located on Xp11.2.

The most common fusions are ASPL-TFE3 and PRCC-TFE3 but others have been described including PSF –TFE3, NonO-TFE3 and Clathrine-TFE3.67, 69 Xp11.2 translocation carcinoma is recognized in the 2004 WHO renal tumor classification.4 Another rare group of renal carcinomas showing a translocation [t (6; 11) (p21; q12)] involving transcription factor EB (TFEB) has been reported.

In one large series TFEB carcinomas numbered only 2 of 31 cases (6.4%). Both TFE3 and TFEB belong to the microphthalmia transcription factor (MiTF) subfamily, which also includes MiTF and transcription factor EC (TFEC). Argani and Ladanyi67 have proposed to regroup these neoplasms into the category of ’MiTF/TFE family translocation carcinomas’. Importantly, the translocations associated with TFE3 and TFEB are associated with overexpressed proteins that can be identified by immunohistochemistry. TFE3 nuclear staining is specific for the Xp11.2 translocation and nuclear TFEB staining is specific for [t (6; 12) (p21; q12)].

Translocation carcinomas are generally found in children and young adults and the average age in a recent large series was 24.7 years, with a median of 20 years and with a female to male ratio of 2.5:1. These tumors account for at least one-third of carcinomas seen in childhood and adolescence. Rare examples are found in adulthood and in one study the prevalence of renal carcinomas across all ages was estimated to be about 1%. Occasional examples of translocation carcinoma have been associated with a history of prior chemotherapy.

Most patients with translocation carcinoma present symptomatically with hematuria, abdominal pain, abdominal mass or fever; however, about one-third of patients present asymptomatically. In one series, 42% of patients presented with lymph node or visceral metastases.

The tumors are generally large (6–7 cm mean diameter) with some being up to 20 cm.67, 69 They have a macroscopic appearance similar to clear cell renal cell carcinoma. Variegated coloration and necrosis are often identified.

There is a tendency towards extra-renal extension and regional node involvement at diagnosis.

Histologically, papillary, nested and compact (solid) patterns of growth are seen. A mixture of large clear and eosinophilic cells is often present. The presence of a papillary tumor in which the papillae are lined by large clear cells should raise the possibility of translocation carcinoma, especially in a young patient. A nested pattern containing cells with voluminous, clear or granular eosinophilic cytoplasm should also suggest the possibility of a translocation carcinoma. Psammoma bodies and intracytoplasmic hyaline droplets are frequent findings, although foam cells and lymphoid infiltrates are uncommon. Necrosis is present in about one-third of cases. The nuclei are generally large with open chromatin and prominent nucleoli. Mitoses are regularly present.

In the initial description of TFEB translocation carcinoma, a biphasic growth pattern consisting of nests of large polygonal eosinophilic cells and intermingled clusters of small epithelial cells centered on hyaline nodules, was emphasized.70 Although initially thought to be specific for the TFEB carcinomas, this biphasic pattern may also be seen in carcinomas associated with TFE3 fusion.

By immunohistochemistry, translocation carcinomas lack or only weakly express keratins and have variable vimentin expression.

Epithelial membrane antigen and CK7 are typically negative. These tumors characteristically express CD10, renal cell carcinoma antigen, racemase (AMACR; P504S) and E-cadherin. TFEB associated tumors regularly express melanocytic markers (HMB45, Melan A), whereas occasional expression of these markers is seen in the TFE3-positive carcinomas. From a practical perspective, the typical phenotype of translocation carcinoma (CK7-, racemase+, CD10+, EMA-) helps separate them from clear cell renal carcinoma (CK7-, racemase-, CD10+, EMA+) and papillary carcinoma (CK7+, racemase+, CD10+, EMA+).

TFE3 and TFEB immunostains are sensitive and specific markers for their respective translocation carcinomas (Figure 23), although the stains can be technically difficult to perform and are best done by laboratories where there is sufficient volume to ensure quality. The sensitivity of TFE3 staining when compared with genetic studies ranges from 82 to 97.5%.

There are rare examples of genetically confirmed translocation carcinomas where weak or absent TFE3 staining was noted; however, in general a moderate to strong nuclear staining pattern should be recognizable at relatively low magnification.

Ultrastructurally, most Xp11.2 carcinomas show features, including intracytoplasmic fat and glycogen, microvilli and cell junctions, similar to clear cell renal cell carcinoma. Most ASPL–TFE3 carcinomas contain membrane bound cytoplasmic granules and occasionally rhomboidal crystals identical to those seen in alveolar soft part sarcoma.72 In PRCC-TFE3 carcinomas intracisternal microtubules, similar to those seen in malignant melanoma, may be noted.

A confirmation of the diagnosis of translocation carcinoma requires immunohistochemical identification of the nuclear transcription factor (TFE3, TFEB) and/or cytogenetic or molecular genetic (FISH, PCR) identification of the translocation.67, 69 Gene expression profiling of translocation carcinomas shows them to be distinct from other well recognized subtypes of renal carcinoma.69 Furthermore, TFE3 and TFEB tumors cluster together adding support for the unifying concept of the MiTF/TFE tumor family.

The differential diagnosis of translocation carcinoma consists of other sporadic renal cell carcinomas (clear cell, papillary and unclassified), which may occur in children and young adults. Separation among these entities requires detailed microscopy and immunohistochemistry, sometimes coupled with molecular genetic analyses. There should be a high index of suspicion for translocation carcinoma in tumors showing papillary and nested patterns, where there is a mixture of clear and eosinophilic granular cells.

The presence of voluminous cells may also be a clue to the diagnosis. The presence of psammoma bodies and hyaline droplets are also helpful. The characteristic immunoprofile, with absent or weak cytokeratin expression and positivity for CD10, racemase, E-cadherin and melanoma-associated antibodies, should initiate immunohistochemical investigation for transcription factors and genetic and/or molecular studies.

From a clinical outcome perspective, TFE3 translocation carcinomas seem to have a relatively indolent course, despite their often advanced stage at presentation.

Late recurrences, including one over three decades after original diagnosis, have been seen. Although the overall follow-up interval of reported cases remains relatively short (11–81 months), only 13.6% of cases have resulted in tumor-related deaths, which is low considering the percentage of tumors that are metastatic at presentation. Too few TFEB translocation carcinomas have been reported in the literature to accurately comment on the biological outcome, although tumor-related death associated with this type of tumor has been reported.

Types

- TFE3-associated renal cell carcinoma
- TFEB-associated renal cell carcinoma

- TFEs-associated renal cell carcinomas

References

- Cathepsin-K immunoreactivity distinguishes MiTF/TFE family renal translocation carcinomas from other renal carcinomas. Martignoni G, Pea M, Gobbo S, Brunelli M, Bonetti F, Segala D, Pan CC, Netto G, Doglioni C, Hes O, Argani P, Chilosi M. Mod Pathol. 2009 Aug;22(8):1016-22. PMID: #19396149#