79 Kidney Cancer: Histologic Subtypes and Genetic Syndromes
Cancer of the kidney and renal pelvis represents 3.5% of all new cancer cases in the United States. There are approximately 63,000 new cases and almost 14,000 deaths from cancer of the kidney and renal pelvis each year (1). The rate of new cases of kidney cancer has steadily been on the rise, averaging 1.4% per year over the last 10 years, according to the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) database. Out of all primary kidney neoplasms, renal cell carcinoma (RCC) is the most common, comprising nearly 80% to 85% of cases. Transitional cell carcinoma of the renal pelvis is the second most common, comprising approximately 8%. RCC is a heterogeneous group of tumors with distinct pathology, histology, and different clinical presentations. RCC is classified based on morphology, cell of origin, and growth pattern and histochemical and molecular basics (2,3) (Table 13.1).
80CLEAR CELL CARCINOMA
Clear cell carcinoma is the most common histologic subtype of RCC. It arises from the proximal tubule of the kidney. Clear cell carcinomas are mostly solid and less commonly cystic. Clear cell carcinoma is specifically associated with the von Hippel–Lindau (VHL) syndrome.
Papillary carcinoma also arises from the proximal tubule and can be further divided into type 1 and type 2. Papillary carcinoma tends to be bilateral and multifocal. Type 1 usually presents in early stage and type II presents in late stages III and IV.
Chromophobe carcinomas originate from the intercalating cells of the collecting duct and often have a hypodiploid number of chromosomes. They usually present at an earlier stage and have a good prognosis, with a low tendency to progress and metastasize (4).
Oncocytomas are rare and invariably benign in nature. Oncocytes are large nucleated cells with dense eosinophilic cytoplasm. Like chromophobe carcinomas, oncocytomas usually originate from the intercalating cells of the collecting duct. They can coexist with other forms of RCC. Oncocytomas are usually single and unilateral but can be multiple and bilateral, as seen in tuberous sclerosis.
COLLECTING DUCT TUMORS
Collecting duct tumors of Bellini are rare but aggressive in nature. They usually present at a young age in an advanced stage (T3, T4) or as metastatic disease at diagnosis. Renal medullary carcinoma is one of the most aggressive collecting duct tumors. 81This is more often seen in patients with sickle cell trait, and less commonly in those with homozygous sickle cell disease. They usually present with hematuria and resemble transitional carcinoma more than other RCCs.
Sarcomatoid differentiation can occur in all subtypes of RCC but is most commonly seen in clear cell and chromophobe subtypes. Sarcomatoid tumors are aggressive and usually show high nuclear grade (grade 4). Sarcomatoid carcinomas have a higher distant metastatic rate and lower overall survival compared to their nonsarcomatoid counterparts (5).
OTHER TUMORS OF THE KIDNEY
Other rare tumors include unclassified RCCs, lymphomas, translocation carcinomas, and mucinous tubular and spindle cell carcinomas. The latter is a very rare indolent epithelial neoplasm with tightly tubular cells with extracellular mucin and spindle cells. Primary renal cell sarcomas are extremely rare and can present as various subtypes including spindle sarcoma, leiomyosarcoma, and angioliposarcoma and are aggressive in nature (Figure 13.1).
KIDNEY CANCER AND GENETIC AND FAMILIAL PREDISPOSITION
In 1979, Cohen et al. reported a family with 10 members diagnosed with kidney cancers who had a translocation between chromosomes 3 and 8 (t3;8) (6). Recognition of the familial pattern and advances in molecular genomics have led to the discovery of various hereditary cancer syndromes associated with RCC, with 12 genes currently implicated in such syndromes. Identification of key genes in the pathogenesis of hereditary kidney cancer syndrome has allowed insight into the development of sporadic cancers and serves as a framework for developing new targeted therapy. The following are the common hereditary kidney cancer syndromes (7).
Figure 13.1 Some histologic subtypes of kidney cancer. (A) Clear cell carcinoma with sarcomatoid differentiation. (B) Papillary renal cell carcinoma. (C) Collecting duct carcinoma. (D) Chromophobe carcinoma. (E) Mucinous tubular and spindle cell carcinoma.
Source: Courtesy of Dr. Thomas Wheeler.
VON HIPPEL–LINDAU SYNDROME
VHL is an inherited, autosomal dominant syndrome caused by a germline mutation in the VHL gene, a tumor suppressor gene located in chromosome 3p. The two hit hypothesis plays a role in pathogenesis. Inheritance of an ineffective VHL allele from a 83parent or a de novo mutation of one allele and further deactivation of second allele lead to cyst formation and tumorigenesis.
VHL mutations are associated with a wide range of tumors, including hemangioblastomas of the brain (mainly cerebellum and spine), which is the most common type of tumor, retinal angioma, clear cell variant of RCC, pheochromocytoma, endolymphatic tumors of the middle ear, serous cystadenoma, neuroendocrine tumors of the pancreas, and papillary cystadenoma of the epididymis and broad ligament.
The VHL syndrome can be further divided into type 1 and type 2 depending on mutations and the tendency to develop certain tumors. Type 1 patients have a lower risk of pheochromocytoma. Type 2 patients have a higher risk of pheochromocytoma and can be further subclassified into type 2A with high risk of RCC, type 2B with low risk of RCC, and type 2C with only pheochromocytomas without RCC or hemangiomas.
RCC associated with VHL is invariably of the clear cell subtype and tends to be bilateral and multifocal. It usually presents before age 60. VHL gene mutation is also seen in sporadic cases of RCC. VHL gene inactivation leads to upregulation of hypoxia-inducible factors (HIF), which in turn regulates downstream vascular endothelial growth factor (VEGF) that promotes angiogenesis and proliferation. Understanding the VHL gene mutations has opened doors toward targeted treatment of VEGF in the treatment of RCC.
The management of VHL is focused on early diagnosis and appropriate intervention via thorough history taking, familial genetic screening, routine imaging, and timely surgical removal of tumor. RCC less than 3 cm in size have a low rate of metastasis and can be monitored with close surveillance. Tumors more than 3 cm require immediate surgical intervention. Nephron sparing surgery is recommended whenever possible, since tumors are often bilateral. There are ongoing trials of VEGF inhibitors in VHL patients.
HEREDITARY PAPILLARY RENAL CELL CARCINOMA
Hereditary papillary renal cell carcinoma (HPRCC) is a rare autosomal dominant familial cancer syndrome associated with the development of type I papillary renal carcinomas. 84Lesions are bilateral and multifocal like other hereditary RCCs. HPRCC is caused by the HPRC gene, MET proto-oncogene, also known as hepatocyte growth factor receptor, which is located on the long arm of chromosome 7. MET gene mutation is also seen in 10% of sporadic papillary renal carcinomas.
HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CARCINOMA
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial cancer syndrome characterized by development of leiomyomas of the uterus and skin, and RCC. Type II papillary carcinoma is the most common tumor associated with HLRCC, but tumors of collecting ducts and chromophobe carcinomas are also seen. RCCs occur at an early age and are usually bilateral and aggressive in nature. Tumors have a high propensity to metastasize, even when as small as 1 cm in size. Uterine leiomyomas can be severe and present in up to 90% of women with HLRCC before the age of 30. Cutaneous leiomyomas are benign painful pinkish nodules of the skin, which can be disseminated throughout the body. A mutation in the fumarate hydratase gene (FH gene), which converts fumarate to malate in the Krebs cycle, is responsible for HLRCC.
Birt–Hogg–Dubé syndrome (BHD) is an autosomal dominant disorder characterized by benign skin hamartomas, lung cysts and spontaneous pneumothorax, and RCC. BHD syndrome is caused by germline mutations in the folliculin gene (FLCN) located on chromosome 17p11.2, which encodes the protein folliculin. As many as 149 mutations of the FLCN gene have been identified in BHD syndrome. Skin manifestations are the earliest and most frequent manifestation of BHD syndrome. Renal cancer can occur around age 50 and is associated with different histologic subtypes, most commonly chromophobe carcinoma. Renal oncocytosis has been reported in BHD. There is also an association between BHD syndrome and colon polyposis and colorectal carcinoma.
85POLYCYSTIC KIDNEY DISEASE
Polycystic kidney disease (PCKD) is a very common autosomal dominant disorder, occurring in approximately one in every 400 to 1,000 live births. RCCs in PCKD are often bilateral and multifocal, and one third are sarcomatoid type. The risk of RCC in PCKD is found to be equal to that of the general population.
TUBEROUS SCLEROSIS COMPLEX
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the formation of hamartomas in multiple organs including brain, kidney, lung, and skin. TSC is caused by mutations in one of the tumor-suppressor gene products, hamartin (TSC1) or tuberin (TSC2). The clinical manifestations include bilateral, multifocal renal lesions, which typically are angiomyolipomas. Less than 5% of patients with TSC develop RCC. This occurs at a younger age than sporadic tumors, with a female predilection. The most common histologic subtype seen in TSC is clear cell carcinoma.
PTEN HAMARTOMA TUMOR SYNDROME (COWDEN DISEASE)
Cowden disease is a rare autosomal dominant disorder causing formation of hamartomas in skin and various organs. It is associated with increased risk of tumors of breast, endometrium, and thyroid caused by mutation in the phosphatase and tensin homolog (PTEN) gene. Clear cell RCCs have been reported in patients with Cowden disease, and they usually present at a late stage.
OTHER FAMILIAL CANCER SYNDROMES WITH INCREASED RISK OF RCC
Succinate dehydrogenase (SDH) gene associated familial cancer syndrome is one of the Krebs cycle enzyme disorders. It has been reported to increase the risk of RCC in addition to 86hereditary paraganglioma and pheochromocytoma. Various histologic subtypes of RCC are implicated and they are usually aggressive in nature.
BAP1 (BRCA-associated protein 1) mutation in the germline predisposes to familial renal cancer and uveal and cutaneous melanomas. BAP1 is associated with a higher tumor grade and worse overall survival. Clear cell RCCs are most commonly seen.
Chromosome 3 translocation has been identified in a familial RCC as Cohen et al. reported in 1979. Multiple genes including VHL and BAP1 are located on chromosome 3p, and thus translocation and loss of alleles predispose to increased risk of RCC.