Unclassified/Translocation
There are scant data available for unclassified and translocation
RCC. Although no prospective trials have been
conducted in this setting, there are case reports that document
the activity of VEGF-targeted agents. For patients
with Xp11.2 translocation, one study reported 15 patients
with had received VEGF-directed therapies. Three patients
(20%) achieved a partial response. The median PFS was
7.1 months and medians OS was 14.1 months.56 The Juvenile
RCC network reported a series of 11 patients who
received sunitinib in the first-line setting with a median
PFS of 8.2 months.57
Conclusion
With no clear standard of care FDA approved agents, nonclear
cell RCC represents a significant and long ongoing
unmet medical need. Patients should be encouraged to
participate in clinical trials whenever
possible, though given the heterogeneity
of this disease, investigators should
not make the mistake of combining numerous
non-clear cell RCCs in prospective
trial designs. Instead, each non-clear
cell histology has its unique characteristics
and should be studied individually.
In general, the current treatment of
choice for non-clear cell RCC is a vascular
endothelial growth factor (VEGF) receptor
inhibitor followed by a mammalian
target of-rapamycin (mTOR) inhibitor
at the time of progression. Immunotherapy
with checkpoint inhibitors
is not yet FDA approved for nonclear
cell RCC; however, there are ongoing
studies that show promising results,
“As the landscape of treatment
for clear cell RCC has
shifted to immunotherapy
due to the CheckMate 214
trial that suggested an OS
advantage with the combination
of nivolumab/
ipilimumab over sunitinib
in the first-line setting, there
is biological rationale to
extrapolate the activity of
immunotherapy in non-clear
cell RCC.”
notably in papillary RCC with sarcomatoid and rhabdoid
features. Combinations with a PD-1 inhibition with
CTLA-4 inhibitors, or ido-1 inhibitors are noteworthy and
currently in study. As we gain a better understanding of
the biology through the discovery of molecular and genomic
testing, collaborative efforts will be essential for
the therapeutic development of targeted pathways and
agents to further advance this orphan disease.
References
1. National Cancer Institute’s Surveillance, Epidemiology, and End Result
(SEER) Program data
2. Welch HG, Skinner JS, Schroeck FR, et al. Regional Variation of Computed
Tomographic Imaging in the United States and the Risk of
Nephrectomy. JAMA Intern Med. 2018Feb 1;178(2):221-227.
3. Zeegers MPA, Tan FES, Dorant E, van den Brandt PA. The impact of
characteristics of cigarette smoking on urinary tract cancer risk : a metaanalysis
of epidemiologic studies. Cancer. 2000;89:630–639.
4. Inoue M, Iwasaki M, Otani T, Sasazuki S, Noda M, Tsugane S. Diabetes
mellitus and the risk of cancer: results from a large-scale populationbased
cohort study in Japan. Arch Intern Med. 2009;166:1871–1877.
5. Setiawan VW, Kolonel LN, Henderson BE. Menstrual and reproductive
factors and risk of renal cell cancer in the Multiethnic Cohort. Cancer
Epidemiol Biomerkers Prev. 2009;18:337–340.
6. Chiu WA, Caldwell JC, Keshava N, Scott CS. Key scientific issues in the
health risk assessment of trichloroethylene. Environ Health Perspect.
2006;114:1445–1449.
24 Kidney Cancer Journal
7. Chow WH, Dong LM, Devesa SS et al. Nat Rev Urol. 2010; May 7(5):
245-257.
8. Cook MB, et al. Sex disparities in cancer incidence by period and
age. Cancer Epidemiol Biomarkers Prev. 2009;18:1174–1182.
9. Curado MP, et al., editors. IARC Scientific Publications No. 160. Lyon:
IARC; 2007. Cancer Incidence in Five Continents, Vol. IX.
10. Eble JN, Sauter G, Epstein JI, et al. Pathology and Genetics of Tumours
of the Urinary System and Male Genital Organs. Lyon, France; IARC Press;
2004.
11. Sankin A, Hakimi AA, Hsieh JJ, et al. Metastatic Non-Clear Cell Renal
Cell Carcinoma: An Evidence Based Review of Current Treatment Strategies.
Frontiers in Oncology. 2015; 5:67.
12. Liaw BC, Mehrazin R, Baker C, et al. Management of Atypical Renal
Cell Carcinomas. Curr.Treat.Options in Oncol. (2017) 18:61.
13. The Cancer Genome Atlas Research Network Comprehensive molecular
characterization of papillary renal-cell carcinoma. New England
Journal of Medicine. 2016; 374: 135-145.
14. Albiges I, Guegan J, Le Formal A, et al. MET is a potential target
across papillary renal cell carcinomas: result from a large molecular
study of pRCC with CGH array and matching gene expression array.
Clin Cancer Res. 2014;20(13):3411-21.
15. Srigley JR, Delahunt B, Ebel JN, et al. ISUP Renal Tumor Panel. The
International Society of Urological Pathology (ISUP) Vancouver Classification
of Renal Neoplasia. American Journal of Surgical
Pathology. 2013; 37(10):1469-1489.
16. Durinck S, Stawiski EW, JimenezAP et al. Spectrum
of diverse genomic alterations define nonclear
cell renal carcinoma subtypes. Nature genetics.
13-27(2015).
17. Klatte T, Pantuck AJ, Said JW et al. Cytogenetic
and molecular tumor profiling for type 1 and type
2 papillary renal cell carcinoma. Clin Cancer Res.
2009; 15:1162.
18. Wei MH, Toure O, Glenn GM, et al. Novel mutations
in FH and expansion of the spectrum of
phenotypes expressed in families with hereditary
leiomyomatosis and renal cell cancer. Journal of
Medical Genetics. 2006; 43: 18-27.
19. Isaacs JS, Jung YJ, Mole DR et al. HIF overexpression
correlates with biallelic loss of fumarate
hydratase in renal cancer: novel role of fumarate in
regulation of HIF stability. Cancer Cell. 2005;8(2):
143-53.
20. Davis CF, Ricketts CJ, Wang M, et al. The somatic
genomic landscape of chromophobe renal
cell carcinoma. Cancer Cell. 2014; 26(3): 319-330.
21. Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene
lead to kidney tumor, lung wall defects, and benign tumors of the hair
follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell. 2002;
2: 157-164.
22. Habib SL, Al-Obaidi NY, Nowacki M, et al. Is mTOR inhibitor good
enough for treatment all tumor in TSC patients? J Cancer. 2016;7(12):
1621-31.
23. Motzer RJ, Bacik J, Mariani T, et al. Treatment outcome and survival
associated with metastatic renal cell carcinoma of non-clear cell histology.
Journal of Clinical Oncolology. 2002; 20:2376-2381.
24. Gupta R, Billis A, Shah RB, et al. Carcinoma of the collecting ducts
of Bellini and renal medullary carcinoma: clinicopathologic analysis of
52 cases of rare aggressive subtypes of renal cell carcinoma with a focus
on their interrelationship. The American Journal of Surgical Pathology.
2012; 36(9):1265-78.
25. Calderaro J, Moroch J, Pierron G, et al. SMARCB1/INI1 inactivation
in renal medullary carcinoma. Histopathology. 2012; 61(3):428-435.
26. Rao P, Tannir NM, Tamboli P, et al. Expression of OCT3/4 in renal
medullary carcinoma represents a potential diagnostic pitfall. Am J Surg
Pathol. 2012; 36(4):583-588.
27. Medendorp K, van Groningen JJ, Vreede L, et al. The renal cell carcinoma
associated oncogenic fusion protein PRCCTFE3 provokes p21
WF1/CIP1-mediated cell cycle delay. Exp Cell Res. 2009;315:23992409.
28. Mir MC, Trilla E, de Torres IM, et al. Altered transcription factor E3
expression in unclassified adult renal cell carcinoma indicates adverse
pathological features and poor outcome. BJU Int. 2011: 108:e71-6.
29. Zisman A, Chao DH, Pantuck AJ, et al. Unclassified renal cell carcinoma:
clinical features and prognostic impact of a new histological subtype.
The Journal of Urology. 2002; 168(3):950-5.
30. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib
for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN