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Pathology, therapy and prognosis of papillary renal carcinoma
Diana Silva Fernandes*,1 & José Manuel Lopes1
ABSTRACT Papillary renal cell carcinoma (pRCC) accounts for approximately 10% of renal parenchymal tumors. There are two pRCC subtypes reported in several studies, but at present, there is limited molecular evidence to validate this pRCC subtyping in the daily routine. The utility of subtyping pRCC is based on reports describing that pRCC subtype is an independent predictor of outcome, with type 1 tumors showing significantly better survival than type 2 tumors. In this article, we summarize the relevant knowledge on pRCC regarding tumor features: clinical presentation, histopathology, electron microscopy, immunohistochemistry, cytogenetics, genetic/molecular and prognosis. We present an overview of the currently available pRCC treatment options and some of the new promising agents. Epidemiology Kidney cancer is the 13th most common malignancy worldwide, with approximately 271,000 new cases diagnosed in 2008 and approximately 116,000 people died from the disease [1] . In 2012, the incidence of kidney cancer was approximately 328,204, with 114,100 of these cases in Europe, 4331 in Central America, 14,994 in South America and 63,124 in North America [2] . Overall, a higher incidence of cases was reported in men (209,106 vs 119,098 in women) [2] . Similar to the results of 2008, in 2012, the incidence of kidney cancer varied geographically, with it being highest in Europe, North America and Australia, and lowest in India, Africa and China [1,2] . The mortality rates from kidney cancer in the EU peaked at 4.8/100,000 in 1990–1994 and declined to 4.1/100,000 (-13%) in 2000–2004 [3] . In women in the EU, the corresponding values were 2.1/100,000 and 1.8/100,000 [3] . In Portugal, the mortality rates in women declined by 14% during 1990–2004 [3] . Renal cell carcinoma (RCC) represents approximately 90% of all malignancies of the kidney that occur in adults in both sexes [4] . The incidence is low in Africa and Asia, but high in Latin America. The Czech Republic had the highest observed incidence of 20 and ten annual new cases per 100,000 of the population in men and women, respectively [4] . The lowest rates recorded were less that one new case per 100,000, showing a tenfold variation in the risk of the disease [4] . RCC is extremely rare in the pediatric population and accounts for approximately 6% of malignant pediatric tumors (10 years [1] . Previously, pRCC was reported to be the most common histological subtype found in dialysis patients with ACDK, but recent reports establish ACDK as the major Box 1. Lifestyle risk factors for papillary renal cell carcinoma. Associated risk factors ●● Cigarette smoking ●● ACDK Nonassociated risk factors ●● Obesity Controversial risk factors ●● Hypertension ●● Animal products intake
●● Fat intake ACDK: Acquired cystic disease-associated renal cell carcinoma. Data taken from [1,8,12–16].
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histological subtype, accounting for 44% of tumors compared with 11% in pRCC [1,8,14] . Genetic syndromes Table 1 summarizes the genetic syndromes associated with pRCC. In 1994, hereditary papillary renal cancer was reported to be a rare autosomal-dominant inherited syndrome with very high penetrance (30 families described so far), meaning that there is a high probability of a person developing pRCC by 80 years of age [18–20,22,31] . An early-onset form has recently been reported in which the disease appears in the second and third decade [31] . Diagnosis of this condition is based on the detection of germline mutations of the c-MET gene; c-MET mutations were reported to play a role in 13% of patients with pRCC and no family history of renal tumors (Table 1) [17–18,21,32] . Mutations of c-MET were also reported in a subset of tumors from patients with sporadic type 1 pRCC [6] . Hereditary leiomyomatosis RCC (HLRCC) occurs at a mean age of 36–39 years, although the youngest age at diagnosis of pRCC in a FH gene mutation carrier was reported in an 11-year-old patient [25,26] . Among the 89 cases reported in the literature, six (7%) were found in individuals younger than 20 years of age [27] . Two distinct FH mutations occurring in heterozygotes (2bpdel, codon 181 and R300X) were reported in HLRCC families affected by renal cancer and uterine leiomyosarcoma [23] . The renal tumors associated with HLRCC tend to be hypovascular, solitary and may metastasize early [19] . Biallelic inactivation of SDH was reported as a pathway in the pathogenesis of pRCC [33] . Based on the study of a small series, Malinoc et al. estimated that 10% of individuals with the SDHC gene mutation develop RCC (both clear and papillary types) [33] . Pathological features ●●Macroscopic, microscopic & ultrastructural
features Box 2 summarizes the macroscopic, microscopic
and ultrastructural features of pRCC. In 1997, two consensus conferences – one in Heidelberg, Germany, and one in Rochester, MN, USA – recognized the existence of benign papillary neoplasms of the renal tubular epithelium that are incidental findings as being much more common than clinically recognized pRCC [35] . At the Rochester conference, it was recognized that there are no reliable histological differences between
future science group
Pathology, therapy & prognosis of papillary renal carcinoma
Review
Table 1. Genetic syndromes associated with papillary renal cell carcinoma. Syndrome
Gene/location
HPRCC HLRCC
MET, 7q31.3; frequently exons 17, MET 18 and 19; occasionally exon 16 FH, 1q42–44 FH
Gene product pRCC
PTEN-HTS
PTEN, 10q23
PTEN
Type 1: multiple, bilateral and multifocal Type 2: unilateral, solitary and aggressive; metastasis (∼20.0% HLRCC families) Unifocal
Other tumors/lesions
BHD
FLCN (BHD), 17p11
Folliculin
Multiple and bilateral
HPTJT
CDC73 (HRPT2), 1q21–31
Parafibromin
Bilateral
FPTC
Unknown gene, 1q21
Unknown
Multifocal
Breast, pancreas, lung, skin and stomach tumors Uterine and cutaneous leiomyoma/ leiomyosarcoma Cerebellar dysplastic gangliocytoma, breast, thyroid (nonmedullary) and endometrial tumors, hamartomatous intestinal polyps, lipomas and fibromas Fibrofolliculoma, trichodiscoma, acrochordon and colon and kidney tumors Renal hamartoma, nephroblastoma and uterine, parathyroid, fibro-osseous mandibular and maxillary tumors Renal adenoma and oncocytoma, papillary thyroid cancer and nodular thyroid disease
BHD: Birt–Hogg–Dubé syndrome; FPTC: Familial papillary thyroid cancer; HLRCC: Hereditary leiomyomatosis renal cell carcinoma; HPRCC: Hereditary papillary renal cell carcinoma; HRPT2: Hyperparathyroidism 2 (with jaw tumor); HPTJT: Hyperparathyroidism–jaw tumor syndrome; pRCC: Papillary renal cell carcinoma; PTEN-HTS: PTEN hamartoma tumor syndrome. Data taken from [17–30].
these small tumors and many clinically detected pRCCs, and renal papillary adenoma was defined on the basis of size less than 5 mm, whereas larger tumors were classified as pRCCs [35] . Traditionally, tumors have been classified as pRCCs if papillary structures comprise at least 50%, but a variety of other architectural patterns, such as tubular, trabecular and solid, have been reported [17,38] . Kovacs suggested that more than 75% of the tumor being composed of papillary structures may be a better criterion for discriminating pRCCs from non-pRCCs showing 3p deletions [38] . The presence of solid variants of pRCCs that are composed of poorly formed papillae have been reported, and this group comprises at most
Pathology, therapy and prognosis of papillary renal carcinoma
Diana Silva Fernandes*,1 & José Manuel Lopes1
ABSTRACT Papillary renal cell carcinoma (pRCC) accounts for approximately 10% of renal parenchymal tumors. There are two pRCC subtypes reported in several studies, but at present, there is limited molecular evidence to validate this pRCC subtyping in the daily routine. The utility of subtyping pRCC is based on reports describing that pRCC subtype is an independent predictor of outcome, with type 1 tumors showing significantly better survival than type 2 tumors. In this article, we summarize the relevant knowledge on pRCC regarding tumor features: clinical presentation, histopathology, electron microscopy, immunohistochemistry, cytogenetics, genetic/molecular and prognosis. We present an overview of the currently available pRCC treatment options and some of the new promising agents. Epidemiology Kidney cancer is the 13th most common malignancy worldwide, with approximately 271,000 new cases diagnosed in 2008 and approximately 116,000 people died from the disease [1] . In 2012, the incidence of kidney cancer was approximately 328,204, with 114,100 of these cases in Europe, 4331 in Central America, 14,994 in South America and 63,124 in North America [2] . Overall, a higher incidence of cases was reported in men (209,106 vs 119,098 in women) [2] . Similar to the results of 2008, in 2012, the incidence of kidney cancer varied geographically, with it being highest in Europe, North America and Australia, and lowest in India, Africa and China [1,2] . The mortality rates from kidney cancer in the EU peaked at 4.8/100,000 in 1990–1994 and declined to 4.1/100,000 (-13%) in 2000–2004 [3] . In women in the EU, the corresponding values were 2.1/100,000 and 1.8/100,000 [3] . In Portugal, the mortality rates in women declined by 14% during 1990–2004 [3] . Renal cell carcinoma (RCC) represents approximately 90% of all malignancies of the kidney that occur in adults in both sexes [4] . The incidence is low in Africa and Asia, but high in Latin America. The Czech Republic had the highest observed incidence of 20 and ten annual new cases per 100,000 of the population in men and women, respectively [4] . The lowest rates recorded were less that one new case per 100,000, showing a tenfold variation in the risk of the disease [4] . RCC is extremely rare in the pediatric population and accounts for approximately 6% of malignant pediatric tumors (10 years [1] . Previously, pRCC was reported to be the most common histological subtype found in dialysis patients with ACDK, but recent reports establish ACDK as the major Box 1. Lifestyle risk factors for papillary renal cell carcinoma. Associated risk factors ●● Cigarette smoking ●● ACDK Nonassociated risk factors ●● Obesity Controversial risk factors ●● Hypertension ●● Animal products intake
●● Fat intake ACDK: Acquired cystic disease-associated renal cell carcinoma. Data taken from [1,8,12–16].
122
Future Oncol. (2015) 11(1)
histological subtype, accounting for 44% of tumors compared with 11% in pRCC [1,8,14] . Genetic syndromes Table 1 summarizes the genetic syndromes associated with pRCC. In 1994, hereditary papillary renal cancer was reported to be a rare autosomal-dominant inherited syndrome with very high penetrance (30 families described so far), meaning that there is a high probability of a person developing pRCC by 80 years of age [18–20,22,31] . An early-onset form has recently been reported in which the disease appears in the second and third decade [31] . Diagnosis of this condition is based on the detection of germline mutations of the c-MET gene; c-MET mutations were reported to play a role in 13% of patients with pRCC and no family history of renal tumors (Table 1) [17–18,21,32] . Mutations of c-MET were also reported in a subset of tumors from patients with sporadic type 1 pRCC [6] . Hereditary leiomyomatosis RCC (HLRCC) occurs at a mean age of 36–39 years, although the youngest age at diagnosis of pRCC in a FH gene mutation carrier was reported in an 11-year-old patient [25,26] . Among the 89 cases reported in the literature, six (7%) were found in individuals younger than 20 years of age [27] . Two distinct FH mutations occurring in heterozygotes (2bpdel, codon 181 and R300X) were reported in HLRCC families affected by renal cancer and uterine leiomyosarcoma [23] . The renal tumors associated with HLRCC tend to be hypovascular, solitary and may metastasize early [19] . Biallelic inactivation of SDH was reported as a pathway in the pathogenesis of pRCC [33] . Based on the study of a small series, Malinoc et al. estimated that 10% of individuals with the SDHC gene mutation develop RCC (both clear and papillary types) [33] . Pathological features ●●Macroscopic, microscopic & ultrastructural
features Box 2 summarizes the macroscopic, microscopic
and ultrastructural features of pRCC. In 1997, two consensus conferences – one in Heidelberg, Germany, and one in Rochester, MN, USA – recognized the existence of benign papillary neoplasms of the renal tubular epithelium that are incidental findings as being much more common than clinically recognized pRCC [35] . At the Rochester conference, it was recognized that there are no reliable histological differences between
future science group
Pathology, therapy & prognosis of papillary renal carcinoma
Review
Table 1. Genetic syndromes associated with papillary renal cell carcinoma. Syndrome
Gene/location
HPRCC HLRCC
MET, 7q31.3; frequently exons 17, MET 18 and 19; occasionally exon 16 FH, 1q42–44 FH
Gene product pRCC
PTEN-HTS
PTEN, 10q23
PTEN
Type 1: multiple, bilateral and multifocal Type 2: unilateral, solitary and aggressive; metastasis (∼20.0% HLRCC families) Unifocal
Other tumors/lesions
BHD
FLCN (BHD), 17p11
Folliculin
Multiple and bilateral
HPTJT
CDC73 (HRPT2), 1q21–31
Parafibromin
Bilateral
FPTC
Unknown gene, 1q21
Unknown
Multifocal
Breast, pancreas, lung, skin and stomach tumors Uterine and cutaneous leiomyoma/ leiomyosarcoma Cerebellar dysplastic gangliocytoma, breast, thyroid (nonmedullary) and endometrial tumors, hamartomatous intestinal polyps, lipomas and fibromas Fibrofolliculoma, trichodiscoma, acrochordon and colon and kidney tumors Renal hamartoma, nephroblastoma and uterine, parathyroid, fibro-osseous mandibular and maxillary tumors Renal adenoma and oncocytoma, papillary thyroid cancer and nodular thyroid disease
BHD: Birt–Hogg–Dubé syndrome; FPTC: Familial papillary thyroid cancer; HLRCC: Hereditary leiomyomatosis renal cell carcinoma; HPRCC: Hereditary papillary renal cell carcinoma; HRPT2: Hyperparathyroidism 2 (with jaw tumor); HPTJT: Hyperparathyroidism–jaw tumor syndrome; pRCC: Papillary renal cell carcinoma; PTEN-HTS: PTEN hamartoma tumor syndrome. Data taken from [17–30].
these small tumors and many clinically detected pRCCs, and renal papillary adenoma was defined on the basis of size less than 5 mm, whereas larger tumors were classified as pRCCs [35] . Traditionally, tumors have been classified as pRCCs if papillary structures comprise at least 50%, but a variety of other architectural patterns, such as tubular, trabecular and solid, have been reported [17,38] . Kovacs suggested that more than 75% of the tumor being composed of papillary structures may be a better criterion for discriminating pRCCs from non-pRCCs showing 3p deletions [38] . The presence of solid variants of pRCCs that are composed of poorly formed papillae have been reported, and this group comprises at most
