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History

Daniel Sennert made the first reference suggesting a tumour arising in the kidney in his text Practicae Medicinae, first published in 1613.

Miril published the earliest unequivocal case of renal carcinoma in 1810. He described the case of Françoise Levelly, a 35 year old woman, who presented to Brest Civic Hospital on April 6, 1809, supposedly in the late stages of pregnancy.

Koenig published the first classification of renal tumours based on macroscopic morphology in 1826. Koenig divided the tumors into scirrhous, steatomatous, fungoid and medullary forms.

The Hypernephroma Controversy

Following the classification of the tumour, researchers attempted to identify the tissue of origin for renal carcinoma.

The pathogenesis of renal epithelial tumours has provided one of the most enduring controversies of modern surgical pathology. The debate was initiated by Paul Grawitz when in 1883, he published his observations on the morphology of small, yellow renal tumours. Grawitz concluded that only alveolar tumours were of adrenal origin, whereas papillary tumours were derived from renal tissue.

In 1893, Paul Sudeck challenged the theory postulated by Grawitz by publishing descriptions of renal tumours in which he identified atypical features within renal tubules and noted a gradation of these atypical features between the tubules and neighboring malignant tumour. In 1894, Otto Lubarsch, who supported the theory postulated by Grawitz coined the term hypernephroid tumor, which was amended to hypernephroma by Felix Victor Birch-Hirschfeld to describe these tumours.

Vigorous criticism of Grawitz was provided by Oskar Stoerk in 1908, who considered the adrenal origin of renal tumours to be unproved. Despite the compelling arguments against the theory postulated by Grawitz, the term hypernephroma, with its associated adrenal connotation, persisted in the literature.

Foot and Humphreys, and Foote et al. introduced the term Renal Celled Carcinoma to emphasize a renal tubular origin for these tumours. Their designation was slightly altered by Fetter to the now widely accepted term Renal Cell Carcinoma.

Convincing evidence to settle the debate was offered by Oberling et al. in 1959 who studied the ultrastructure of clear cells from eight renal carcinomas. They found that the tumour cell cytoplasm contained numerous mitochondria and deposits of glycogen and fat. They identified cytoplasmic membranes inserted perpendicularly onto basement membrane with occasional cells containing microvilli along the free borders. They concluded that these features indicated that the tumours arose from the epithelial cells of the renal convoluted tubule, thus finally settling one of the most debated issues in tumour pathology.

Classification

Renal cell carcinoma (RCC) is not a single entity, but rather a collection of different types of tumours, each derived from the various parts of the nephron (epithelium or renal tubules) and possessing distinct genetic characteristics, histological features, and, to some extent, clinical phenotypes.

Classification of the Common Histological Subtypes of Renal Cell Carcinoma

Renal Cell Carcinoma Subtype	Frequency	Genetic Abnormalities	Characteristics
Clear Cell Renal Cell Carcinoma (CCRCC) Generally the cells have a clear cytoplasm, are surrounded by a distinct cell membrane and contain round and uniform nuclei.	60-70%	Alterations of chromosome 3p segments occurs in 70 – 90% of CCRCCs Inactivation of von Hippel-Lindau (VHL) gene by mutation and promoter hypermethylation Gain of chromosome 5q Loss of chromosomes 8p, 9p, and 14q In 2009-2010, five new frequently mutated genes were discovered in CCRCC; KDM6A/UTX, SETD2, KDM5C/JARID1C, and MLL2	CCRCC is derived from the proximal convoluted tubule Most commonly affects male patients in their sixties and seventies Majority of CCRCC arise sporadically Only 2 – 4% of the cases presenting as part of an inherited cancer syndrome
Papillary Renal Cell Carcinoma (PRCC) Type 1 PRCC consist of papillae covered with a single or double layer of small cuboid cells with scanty cytoplasm and Type 2 PRCC consist of papillae covered by large eosinophilic cells arranged in an irregular or pseudostratified manner.	10–15%	Trisomy or tetrasomy of chromosomes 7 and 17 Loss of chromosome Y in men Gain of chromosomes 12, 16, and 20 Rare mutations of Met proto-oncogene	PRCC is derived from the proximal convoluted tubule PRCCs most commonly affect males in their sixties and seventies Less aggressive tumour than clear cell RCC, with 5-year survival rates of 80% to 85%. Majority of tumours occur sporadically, but some may develop in members of families with hereditary PRCC
Chromophobe Renal Cell Carcinoma (ChRCC) ChRCC consists of tumor cells with abundant eosinophilic cytoplasm (pale cells and eosinophilic cells with a perinuclear halo) and show mainly a solid structure.	3–5%	Loss of chromosomes Y, 1, 2, 6, 10, 13, 17, and 21	ChRCC is derived from the cortical collecting duct ChRCC has a much better prognosis than clear cell and papillary RCC, with 5-year survival rate of greater than 90%. Most cases arise sporadically, while some familial cases are associated with Birt-Hogg-Dube (BHD) syndrome

Clinical, Pathological, and Genetic Features of Uncommon RCC Subtypes Included in the 2004 WHO Classification of RCC Pathology

RCC subtype	Clinical features	Cell/Tissue Characteristics	Genetics	Prognosis
Multilocular Cystic RCC	Variant of CCRCC (5% of CCRCC) Mean age 51 years (range 20–76) Male:female = 2–3:1	Clear cytoplasm, small dark nuclei	3p deletion as observed in CCRCC	Favorable No local or distant metastasis after complete surgical removal
Carcinoma of the Collecting Ducts of Bellini	Less than 1% of all renal tumors; arising in the collecting ducts of Bellini Mean age 55 years (range 40-70) Male:female = 2:1	High-grade tumour cells with eosinophilic cytoplasm	Variable results: LOH on chromosomes 1q, 6p, 8p,9p, 13q, 19q32 and 21q; c-erB2 amplification associated with unfavorable outcome	Poor prognosis 1/3 presenting with metastasis 2/3 patients succumb to the disease within 2 years of diagnosis
Medullary Carcinoma	Exceedingly rare; almost exclusively in patients with sickle cell hemoglobinopathies or traits Majority are African-Americans Mean age 19 years (5–69) Male:female = 2:1	Haemorrhage and necrosis, high-grade tumour cells with eosinophilic cytoplasm	Not well defined	Highly aggressive 95% presenting with metastasis Often succumb to the disease within 6 months of diagnosis
Xp11.2 Translocation Carcinoma	Predominantly affecting children and young adults Accounts for 40% of RCCs in this age group Affects adult patients with a striking female predominance	May resemble PRCC Clear and eosinophilic cells	Chromosomal translocation involving TFE3 gene on Xp11.2 resulting in overexpression of the TFE3 protein	Present at advanced stage, but with indolent clinical course in children Adult patients may pursue more aggressive course
Mucinous Tubular Spindle Cell Carcinoma	Mean age 53 years (range 13–82) Affects predominantly female patients (male:female = 1:4) incidental finding in most cases	Tubules, extracellular mucin and spindle cells	Not well defined; Losses involving chromosomes 1, 4, 6, 8, 9, 11, 13, 14, 15, 18, 22 reported; 3p alterations and gain of chromosome 7, and 17 not present	Favourable Majority of patients remain disease free after surgical resection
Post-Neuroblastoma Renal Cell Carcinoma	Mean age of RCC diagnosis is 13.5 years (range 2–35)	Eosinophilic cells with oncocytoid features (same as CCRCC)	Not well defined; Loss of multiple chromosomal loci observed	Similar to other common RCC subtypes