To the editor: ALK activation by chromosomal rearrangement in renal cell carcinoma (RCC) was first demonstrated by two independent pediatric pathology studies 2 years ago.1, 2 These reports coincided with the successful results of the clinical trial that tested targeted therapy with crizotinib in ALK-positive lung cancer.3 Consequently, two recently published large series of adult RCCs cumulatively identified four new ALK-rearranged tumors.4, 5 Current data, combined from four independent studies during 2010–2012, include six ALK-rearranged tumors in a representative cohort of 884 RCCs of main morphologies arising in pediatric and adult patients of diverse ethnicities (Table 1).

Table 1 Clinicopathologic characteristics and fusion partners of ALK-rearranged renal cell carcinomas
Full size table

The overall frequency of ALK rearrangement in RCC is low (approximately 0.7%) and no rearrangement has been detected in 505 cases of clear-cell RCC.4, 5 Further studies should clarify whether the molecular mechanism of clear-cell RCC governed by loss of VHL and ALK activation are mutually exclusive. Hereditary and some sporadic papillary RCCs are driven by MET tyrosine kinase,6 and testing of both kinases in papillary RCCs appears to be rational especially because crizotinib combines anti-ALK and anti-MET activities.

Sukov et al5 found substantial proportions of both clear-cell and papillary RCCs with increased ALK gene copy numbers that correlated with poorer outcome in the clear-cell subtype. ALK amplifications with activating point mutations are known to occur in neuroblastomas;7 it would be interesting to explore a possibility of this mechanism in RCCs with ALK amplifications.

All authors paid close attention to morphologic and clinical features of ALK-positive RCCs and the handful of cases shows several trends. Thus, both pediatric cases affected children of African-American descend caring the sickle cell trait; the tumors were arising in the renal medulla and exhibited similar morphologies. Mariño-Enríquez et al2 classified their tumor as renal medullary carcinoma (RMC); we1 did not label ours as RMC because it lacked extreme clinical aggressiveness characteristic of RMC.8, 9 Retention of INI1 by immunohistochemistry was also not in favor of RMC.10 In a retrospect, both pediatric cases shared all clinicopathologic characteristics and the same VCL–ALK fusion. A consensus should be reached whether they belong to the least aggressive part of the RMC spectrum or favorable clinical course and intact INI1 are significant enough to distinguish them from RMCs.

Three of four adult cases had papillary morphology. The case of Sugawara et al4 was classified as papillary type 2A and cases of Sukov et al5 as papillary with clear eosinophilic cytoplasm; all three tumors were positive for CK7. The ALK fusion partner of the papillary type 2A RCC of Sugawara et al4 was EML4, implicated in most of the cases of pulmonary ALK-associated carcinoma; fusion partner(s) of cases of Sukov et al5 are not known, but VCL, participating in pediatric ALK-positive RCCs, was excluded. The 4th adult ALK-positive RCC had different variant morphology and TPM3 as the ALK fusion partner.4

Thus, five of six ALK-positive RCCs cluster in two groups: two VCL–ALK-positive pediatric tumors with characteristic histology (solid growth, abundant eosinophilic cytoplasm, intracytoplasmic lumina) and three adult tumors with papillary architecture and other than VCL–ALK fusion partner(s). Morphologic spectrum of ALK-rearranged tumors, however, is not limited to these two groups. The common feature of all ALK-positive RCCs is eosinophilic cytoplasm mentioned in all studies,1, 2, 4, 5 but this characteristic is hardly specific. It appears that prediction of ALK rearrangement cannot be accurately drawn from tumor histology and at this time it would be impractical to recognize ALK-positive RCC as a separate pathologic subtype. However, the broader availability of new generation technologies may change the current tumor classification faster than we think and ALK-positive carcinomas, or ALKomas, will find their niche.

The overall 5-year survival of renal cancer is 70.6%; however, 17% of patients have distant metastatic disease and in this group the 5-year survival is only 11.6%.11 Thus, although the frequency of ALK rearrangement in RCC is low, patients with distant metastatic disease can be tested and, if positive, tried with crizotinib or other ALK inhibitors to determine whether targeted therapies are as effective in RCC as they proved in pulmonary adenocarcinoma.