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Kidney: ALK-rearranged renal cell carcinoma

Written2017-02Adrian Marino-Enriquez
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA USA;

(Note : for Links provided by Atlas : click)


Abstract Review on ALK-rearranged renal cell carcinoma, summarizing clinical and genetic data


ICD-Topo C649
Atlas_Id 6279
Phylum Urinary system: Kidney::Renal cell carcinoma
WHO/OMS Classification Urinary system


    ALK-rearranged renal cell carcinoma is a distinct type of renal cell carcinoma included in the so-called emerging/provisional RCC. The 2013 International Society of Urological Pathology (ISUP) Vancouver Classification of (adult) renal neoplasia identified a category of emerging or provisional new entities. Although these entities appeared to be distinct, these are rare tumors not fully characterized and additional reports will be needed to refine their diagnostic criteria and established clinical outcome.

Clinics and Pathology

Disease ALK-rearranged renal cell carcinoma is a distinct emerging type of RCC that commonly affects children and young adults. The disease is defined as a RCC harboring ALK gene rearrangements, resulting in oncogenic fusions with a variety of partner genes.
Epidemiology ALK-rearranged renal cell carcinoma is an uncommon type of RCC. Initially described in children, in which it may be over-represented, further investigations demonstrated that a small proportion of adult RCC belong to this ALK-rearranged category. Of 18 well-documented cases reported to date, 8 have been described in children (6-16 yo), and 10 in adults (33-61 yo). An association with sickle cell trait was observed in the first cases described, but this association seems inconsistent and may be limited to cases with a specific VCL/ALK gene fusion.
Clinics These form masses in the kidney. The majority of cases described so far have been confined to the kidney with a median size of 4.5 cm. Nodal extension at presentation has been observed; distant metastases are rare and have been observed more commonly in adult patients. The clinical course of ALK-rearranged RCC is frequently indolent, although rare cases, more frequently in adult patients, pursue a more aggressive clinical course.
Pathology Grossly, ALK-rearranged RCC are brown to tan solid masses that may be well circumscribed or infiltrative, usually located centrally with extension into the renal pelvis. Histologically, the tumors most commonly feature a solid architecture, with occasional trabecular and tubular features, and are composed of sheets of epithelioid cells with abundant palely eosinophilic cytoplasm and frequent intracytoplasmic lumina. Cell nuclei show high-grade features, with vesicular chromatin and prominent nucleoli -usually ISUP grade 3, but occasionally ISUP grade 4. Rhabdoid morphology or intracytoplasmic inclusions may be focally present. There is a prominent capillary network. Less frequently, ALK-rearranged RCC may show a predominantly papillary architecture, mucin deposition and focal psammomatous calcification. It is unclear if some of this features correlate with specific fusion partners. Immunohistochemically, the tumor cells consistently express ALK, CK7, EMA, and TFE3 (which should not be interpreted as evidence of TFE3 rearrangement, absent in this tumor type); nuclear INI1 expression is retained.
Treatment Treatment: surgical excision. Treatment with ALK inhibitors has provided clinical benefit in cases with advanced disease.


ALK Gene Fusions in renal cell carcinoma (RCC)
NeoplasmFusionAge Range (years) (n)
ALK-rearranged RCCt(2;10)(p23;q22) VCL/ALK6-16 (3)
ALK-rearranged RCCt(1;2)(q25;p23) TPM3/ALK12-49 (7)
ALK-rearranged RCCinv(2)(p22p23) STRN/ALK33,38 (2)
ALK-rearranged RCCinv(2)(p21p23) EML4/ALK52,53 (2)
ALK-rearranged RCCt(1;2)(p32;p23) HOOK1/ALK16 (1)
ALK-rearranged RCCALK/unknown44-61 (3)

Result of the chromosomal anomaly

Fusion Protein
Description ALK-rearranged RCC are characterized by fusion of the ALK tyrosine kinase gene with one of several gene partners including VCL, TPM3, STRN, EML4, and HOOK1 (Table 1). The originally described translocation in ALK-rearranged RCC was t(2;10)(p23;q22) which fuses the 5' end of VCL to the 3' end of ALK. So far, VCL/ALK fusions have been described only in ALK-rearranged RCC -interestingly, in 3 tumors affecting pediatric patients with sickle cell trait. Similarly, HOOK1/ALK fusion has been identified only in RCC. The TPM3/ALK, STRN/ALK and EML4/ALK gene fusions, however, are similar to those found in other tumor types such as inflammatory myofibroblastic sarcoma, thyroid carcinoma and lung adenocarcinoma. All of these ALK gene fusions result in oncogenic proteins that include the kinase domain of ALK, fused to structural protein motifs that enable direct or indirect oligomerization. The ALK fusion partners also contribute active promoters that lead to strong expression of ALK, which can be detected by immunohistochemistry.


Expanding the spectrum of ALK-rearranged renal cell carcinomas in children: Identification of a novel HOOK1-ALK fusion transcript.
Cajaiba MM, Jennings LJ, George D, Perlman EJ.
Genes Chromosomes Cancer. 2016 Oct;55(10):814-7.
PMID 27225638
Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets.
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Nat Commun. 2016 Oct 7;7:13131.
PMID 27713405
Renal cell carcinoma with novel VCL-ALK fusion: new representative of ALK-associated tumor spectrum.
Debelenko LV, Raimondi SC, Daw N, Shivakumar BR, Huang D, Nelson M, Bridge JA.
Mod Pathol. 2011 Mar;24(3):430-42.
PMID 21076462
ALK rearrangements-associated renal cell carcinoma (RCC) with unique pathological features in an adult.
Jeanneau M, Gregoire V, Desplechain C, Escande F, Tica DP, Aubert S, Leroy X.
Pathol Res Pract. 2016 Nov;212(11):1064-1066.
PMID 27554841
Two Cases of Renal Cell Carcinoma Harboring a Novel STRN-ALK Fusion Gene.
Kusano H, Togashi Y, Akiba J, Moriya F, Baba K, Matsuzaki N, Yuba Y, Shiraishi Y, Kanamaru H, Kuroda N, Sakata S, Takeuchi K, Yano H.
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PMID 26848800
ALK-Positive Renal Cell Carcinoma in a Large Series of Consecutively Resected Korean Renal Cell Carcinoma Patients.
Lee C, Park JW, Suh JH, Nam KH, Moon KC.
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PMID 24255633
ALK rearrangement in sickle cell trait-associated renal medullary carcinoma.
Mariño-Enrèquez A, Ou WB, Weldon CB, Fletcher JA, Pérez-Atayde AR.
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PMID 21213368
World Health Organization Classification of Tumours of the Urinary Systems and Male Genital Organs
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PMID 24025519
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Mod Pathol. 2012 Nov;25(11):1516-25.
PMID 22743654
TFE3-positive renal cell carcinomas are not always Xp11 translocation carcinomas: Report of a case with a TPM3-ALK translocation.
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Pathol Res Pract. 2016 Oct;212(10):937-942.
PMID 27450657
Genetic analysis and clinicopathological features of ALK-rearranged renal cell carcinoma in a large series of resected Chinese renal cell carcinoma patients and literature review.
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PMID 28199742


This paper should be referenced as such :
Adrian Marino-Enriquez
Kidney: ALK-rearranged renal cell carcinoma
Atlas Genet Cytogenet Oncol Haematol. 2018;22(6):260-262.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Translocations implicated (Data extracted from papers in the Atlas)

 t(1;2)(p32;p23) HOOK1/ALK
 t(1;2)(q25;p23) TPM3/ALK
 inv(2)(p22p23) STRN/ALK
 inv(2)(p21p23) EML4/ALK
 t(2;10)(p23;q22) VCL/ALK

External links

Mitelman database t(1;2)(p32;p23) [CaseList]     t(1;2)(p32;p23) [Transloc - MCList]   HOOK1/ALK Fusion - MCList]
Mitelman database t(1;2)(q25;p23) [CaseList]     t(1;2)(q25;p23) [Transloc - MCList]   TPM3/ALK Fusion - MCList]
COSMIC[ TPM3 ]   [ ALK ]
Mitelman database inv(2)(p22p23) [CaseList]     inv(2)(p22p23) [Transloc - MCList]   STRN/ALK Fusion - MCList]
Mitelman database inv(2)(p21p23) [CaseList]     inv(2)(p21p23) [Transloc - MCList]   EML4/ALK Fusion - MCList]
COSMIC[ EML4 ]   [ ALK ]
Mitelman database t(2;10)(p23;q22) [CaseList]     t(2;10)(p23;q22) [Transloc - MCList]   VCL/ALK Fusion - MCList]
arrayMap arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
Disease databaseKidney: ALK-rearranged renal cell carcinoma
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed

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