Kidney Tumors Cancer

KIDNEY TUMORS: DEFINITION-CLASSIFICATION, HISTOPATHOLOGICAL EVALUATION

Kidney cancers make up 2.5% of malignancies seen in adults. Like other types of cancer, these tumors can be hereditary or sporadic in nature, with approximately 4% of cases being hereditary .

Renal cancers were first classified by Grawitz in 1883. Grawitz believed these tumors originated from ectopic adrenal tissue and named them “hypernephromas.” Later on, the classification of renal tumors was based on cytomorphological features and possible cellular origin. Thoenes and colleagues grouped tumors into two main categories based on cellular structure and tissue architecture: benign and malignant .

Accordingly, renal tumors are classified as clear cell, granular cell, chromophobe, sarcomatoid/pleomorphic cell cancers, and oncocytomas.

Recent studies have started to classify renal tumors histopathologically based on underlying genetic abnormalities.

In 1997, the UICC histological classification reached its final form through a consensus meeting of European and American working groups. According to this classification, renal tumors are divided into two main categories: malignant and benign .

Malignant Tumors

• Conventional (clear cell) carcinoma
• Papillary renal carcinoma
• Chromophobe renal carcinoma
• Collecting duct carcinoma
• Unclassified renal cell carcinoma

Benign Tumors

• Oncocytoma
• Papillary adenoma
• Metanephric adenoma

Conventional (Clear Cell) Renal Carcinoma:

This group of neoplasms accounts for 70-80% of renal tumors .

The tumors mainly consist of cells with clear cytoplasm, but nests of cells with eosinophilic cytoplasm are also common. The tumor architecture often contains both solid and cystic features, with widespread branching observed in tumor-associated vascular structures. Sarcomatoid changes are seen in about 5% of these tumors . It is believed that this tumor originates from the epithelial cells of the proximal renal tubule .

Hereditary Clear Cell Renal Carcinoma:

Conventional renal cell carcinoma can develop as part of a hereditary tumor syndrome in individuals with von Hippel-Lindau (VHL) disease, which results from mutation-loss in the von Hippel-Lindau gene (chromosome 3p25) .

Examination of tumor samples from patients with hereditary clear cell renal carcinoma has revealed mutations in the VHL gene. These findings indicate that abnormalities in chromosome 3p, particularly those in the VHL gene, are genetic abnormalities that occur early in clear cell renal carcinomas.

Sporadic Clear Cell Renal Carcinoma:

Studies have shown that mutations in the VHL gene are early genetic abnormalities in sporadic conventional renal cell carcinoma as well. Research by Gnarra et al. on 98 localized and advanced sporadic conventional renal cell carcinoma cases found that almost all tumors (98%) had heterozygous loss (LOH) in the VHL gene, meaning that one allele of this tumor suppressor gene was lost .

The remaining allele was found to be mutated in 57% of cases. Cytogenetic analyses showed that 87% of cases had a loss of the 3p13-ter segment (where the VHL gene is located) .

The fact that loss of chromosome 3p or monosomy 3 is the only detectable abnormality in 80% of tumors measuring less than 1 cm suggests that these genetic changes are associated with early stages of tumor development. LOH of chromosome 3p is the primary genetic abnormality that occurs in 81-98% of cases .

Another mechanism that inactivates the VHL gene is hypermethylation. When CpG-rich DNA regions in 5′ promoter regulatory regions (CpG islands) are methylated, “downstream” genes (genes under the control of the promoter region) become inactive. This occurs in the VHL gene in 11-19% of sporadic conventional renal carcinoma cases .

It is very common for one allele of the VHL gene to be lost in tumor cells, with the other being inactivated by hypermethylation. Some studies suggest that one or more genes on chromosome 3p besides the VHL gene may also be important. Indeed, LOH related to chromosome 3 is generally concentrated in three regions: 3p13-14, 3p21, and 3p25-26 (VHL). Foster and colleagues found LOH in at least one of these three regions in 64% of non-papillary renal carcinomas .

In 50% of these cases, LOH was detected in the 3p13-14 region. Another study found LOH in 87% of cases in the 3p12-21.1 region, suggesting that there may be other tumor suppressor genes on chromosome 3p .

Other important genetic abnormalities related to clear cell renal carcinoma include translocation in the Fragile Histidine Triad (FHIT) gene , increased expression of the TGF-α gene due to VHL gene loss , overexpression of TGF-β in 60% of cases , overexpression of the myc oncogene , duplication of the 5q22-ter chromosome region (in advanced tumors) , trisomy of chromosome 5q , p53 gene mutations, and LOH in chromosomes 17p, 14q, 8p, 11p, and 13q .

Papillary Renal Cell Carcinoma:

This is the second most common type of kidney cancer originating from proximal renal tubular cells, accounting for 10-15% of all renal cancers .

Morphologically and cytogenetically, it differs from conventional (clear cell) and chromophobe cell carcinomas. Due to the staining of cells during histological examination, it is also referred to as chromophil or, due to the tumor’s architectural structure, as tubular papillary renal carcinoma. The microscopic architecture of the tumor can be papillary, tubular, tubular papillary, or solid. If 75% of the tumor tissue exhibits papillary or tubular papillary characteristics, it is called papillary renal cell carcinoma .

The cytoplasmic and nuclear staining of papillary tumors can also exhibit different characteristics. They are divided into three groups: eosinophilic, basophilic, and duophilic. Basophilic tumors consist of small cells with dark cytoplasm and low-grade nuclei. Eosinophilic tumors have large cells with a broad eosinophilic cytoplasm and a large nucleus. Duophilic tumors are a mix of these two types . Recently, it has been proposed to classify papillary renal cell carcinomas as Type I (basophilic) and Type II (eosinophilic) .

In general, basophilic type tumors are seen twice as frequently as eosinophilic ones. However, in patients with chronic renal failure, the frequency of eosinophilic papillary type renal cell carcinoma is higher compared to the normal population .

Clinically, papillary renal cell carcinomas are 5-8 times more common in men than in women .

The prognosis of papillary renal cell carcinomas is better compared to clear cell renal carcinomas, with higher overall survival expectations. The projected 5-year survival rate for stage I papillary renal cell carcinoma is 87-100%, compared to 65-75% for clear cell carcinoma at the same stage .

Hereditary Papillary Renal Cell Carcinoma:

The hereditary form of basophilic (Type I) papillary renal cell carcinoma was described by Zbar et al. .

Recently, the gene responsible for this hereditary tumor has been identified as the c-met gene located on chromosome 7p31.1-34. “Missense” mutations in the region with tyrosine kinase activity have been found in family members carrying the disease. In addition, trisomy 7 and 17 and Y chromosome losses are common genetic abnormalities in hereditary papillary renal cell carcinoma .

Sporadic Papillary Renal Cell Carcinoma:

Trisomy 7, 17, and loss of the Y chromosome are observed in approximately 80% of sporadic cases. Similar genetic changes are also present in papillary adenomas. Additionally, mutations in the c-met gene have been found in some sporadic papillary renal cell carcinomas . Trisomy or tetrasomy 7 and trisomy 17 are observed in papillary renal cell carcinomas at rates of 45-100% and 64-100%, respectively .

However, no p53 mutation has been detected in papillary tumors. This suggests that other genes on chromosome 17 may play a role. Thrash-Bingham et al. found LOH in chromosomes 9p, 11q, 14q, and 21q and 6p at rates ranging from 33% to 43% in papillary renal cell carcinomas using microsatellite markers .

Y chromosome loss occurs in 80-90% of cases .

Chromosome 3p abnormalities do not appear significant for papillary renal cell carcinomas. Similarly, VHL gene mutations have not been detected .

Chromophobe Renal Cell Carcinoma:

First described in 1985, chromophobe renal cell carcinoma is composed of large polygonal cells with pale reticular cytoplasm and prominent cell membranes, showing a compact growth pattern .

The glycogen content in the cytoplasm of these cells is lower compared to clear cell carcinomas. Additionally, the cytoplasm does not stain with routine histological dyes. However, widespread and strong cytoplasmic staining is seen with Hale’s colloidal iron stain, which is typical for chromophobe renal cell carcinomas .

However, this tumor may also consist of cells referred to as eosinophilic chromophobe cells, which contain numerous mitochondria and have few cytoplasmic vesicles .

Chromophobe renal cell carcinomas account for approximately 5% of all renal tumors .

The overall survival expectancy for these tumors is higher compared to clear cell carcinomas of the same nuclear grade (e.g., 92% versus 62% for grade II/IV). Additionally, most chromophobe renal cell carcinomas are stage I tumors (86%) or are detected incidentally (53%) .

Cytogenetically, these tumors exhibit multiple chromosome losses. Losses of chromosomes 1, 2, 6, 10, 13, and 17 are defined changes in these tumors .

LOH of chromosome 3p is found in 25% of cases, and VHL gene mutations are quite rare .

p53 gene mutations are detected in 30% of these tumors. Furthermore, losses of alleles from chromosome 17p are observed in 78% of these tumors .

In addition to all these genetic changes, alterations in the genetic structure of mitochondrial DNA have also been reported in some chromophobe renal cell carcinomas .

Collecting Duct (Bellini Duct) Carcinoma:

They make up only 0.4-2.6% of renal tumors . Tumors are generally located in the medulla or central part of the kidney. They have a white-gray cut surface and exhibit tubular papillary growth, including microcystic and solid patterns. Microscopically, they show high-grade cytological atypia, stromal desmoplasia, and dysplastic changes in the surrounding medullary renal tubules, with mucin in the cytoplasm staining darkly with histological dyes. The biological behavior of the tumor is more aggressive than other renal carcinomas, with frequent clinical conditions such as invasion of perinephric adipose tissue and/or renal pelvis, spread to adrenal glands, and lymph node metastases .

These tumors are thought to originate from medullary collecting ducts. The most common genetic changes are monosomy in chromosomes 18 and 21 and loss of the Y chromosome .

An increase in the number of chromosomes 7, 12, 17, and 20, along with LOH observed in 57-69% of cases in chromosome 1q, particularly in the 1q32 region .

LOH frequencies in chromosomes 8p, 6p, 21q, and 13q are reported to be 40-50% in these tumors. A recent study using microdissection techniques has shown LOH in chromosome 3p in 55% of cases .

Overall, c-erbB-2 oncogene amplification is observed in 45% of patients. Expression of this oncogene indicates poor prognostic features. All patients with amplification in the oncogene died from the disease within one year, whereas the average survival time was 42 months for patients without this amplification .

With this feature, collecting duct carcinoma shows similarity to transitional cell carcinoma.

Renal medullary carcinoma, first described by Davis et al. in 1995, is a variant of collecting duct carcinoma, characterized by its occurrence only in black individuals who are carriers of or have sickle cell anemia .

Renal medullary carcinomas typically range in size from 4 to 12 cm, with the main mass located within the medulla. Unlike other renal cell carcinomas and Wilms’ tumors, they exhibit an infiltrative growth pattern within the tissue. Satellite lesions in the renal cortex and renal pelvis soft tissue, as well as venous and lymphatic invasion, are frequently observed. Lesions have a reticular, yolk sac-like, or adenoid cystic appearance, consisting of poorly differentiated areas mixed with highly desmoplastic stroma. Clinically, these tumors present as advanced-stage disease in individuals aged 20-30, exhibiting aggressive biological behavior. The average survival time after diagnosis is 3.5 to 4 months. They do not respond to chemotherapy or immunotherapy.

Renal Oncocytoma:

These lesions, which make up 3-5% of all renal tumors, are thought to originate from distal renal tubules .

Histological examination shows that these tumors characteristically consist of clusters of eosinophilic cells. They can also contain solid, trabecular, and tubular cystic patterns. Macroscopically, the tumor is well-circumscribed and appears beige-brown. Necrosis is rare, but a typical central scar area may be present. The cell nuclei are round with smooth contours. Approximately half of the tumors have prominent nucleoli in the cells. Focal nuclear pleomorphism is not uncommon. One typical feature of oncocytomas is the abundance of cytoplasmic mitochondria .

With these characteristics, oncocytomas can be confused with other renal tumors with eosinophilic (granular) cytoplasm (such as chromophobe, clear cell, and papillary renal cell carcinomas). Renal oncocytomas are generally considered benign tumors. In a recent study, none of the 93 tumors found in 80 patients showed recurrence, metastasis, or disease-related death .

Oncocytomas form a cytogenetically heterogeneous group. They can generally be examined in three main groups. The first group includes tumors with numerical chromosome anomalies involving chromosomes Y and 1, the second group consists of tumors with translocations involving a breakpoint at 11q13, and finally, tumors with other genetic abnormalities (such as chromosomal monosomies, trisomies 1, 7, 12, 14, LOH in chromosomes 17p, 17q, 10q, and 3p). Oncocytomas do not show p53 gene mutations, and LOH in chromosome 3p is rarely observed.

Papillary Adenoma:

The most common renal tumor, accounting for the majority of cortical adenomas, is seen in 20% of patients .

Tumors can consist of small blue (basophilic) or sometimes larger eosinophilic cells. They typically form solid tubular papillary structures. The lesions are often less than 5 mm in diameter. The morphological structure of the tumors is similar to low-grade papillary renal carcinomas, and there is no cytological criterion to unequivocally distinguish between these two lesions. Trisomy or tetrasomy of chromosome 7 and Y chromosome loss are characteristic of papillary adenomas .

The histological and genetic similarities between papillary adenomas and papillary renal cell carcinomas suggest that both tumors represent different stages of a continuing disease process.

Metanephric Adenoma:

Renal metanephric adenoma is a recently described tumor thought to be benign. The cells constituting the tumor are highly mature and differentiated. These rare tumors consist of uniform, small epithelial cells forming tubular or tubular papillary structures. Rosette-like structures can be observed without marked necrosis or cellular atypia. Nuclei are oval with smooth borders, and mitosis is not observed. Macroscopically, tumors are well-defined, nodular, tan-pink in color, and approximately 0.6 to 8 cm in diameter. This tumor is suggested to be a benign form of Wilms’ tumor .

Cytogenetic studies have not shown any chromosomal abnormalities. To date, only one case has been reported with trisomy 7, 17, and Y chromosome loss .

In conclusion, genetic changes occurring in the early stages of tumor development show characteristics according to histological types. By taking advantage of this situation, it seems possible to diagnose renal tumors at the molecular level.