Histopathology of Renal Cell Carcinoma

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According to the classification defined by the World Health Organization (WHO) in 2016, there are many histopathologic subtypes of Renal Cell Carcinoma (RCC).

Renal pathology has become an almost standard diagnostic step in the diagnosis of renal tumors with recent advances in technology. Standardized pathological subtypes of tumors and increased incidence of renal cell carcinoma (RCC) contributed to the  better understanding of histologic subtypes.

The most commonly seen and main 3 histopathologic subtypes of Renal Cell Carcinoma (RCC) are clear cell carcinoma (ccRCC), papillary cell carcinoma (pRCC – type I and II) and chromophobe renal cell carcinoma (chRCC). Cytogenetic and genetic analyzes with pathological evaluation are required for definitive identification of all these subtypes. [1]

Furthermore, clinicians can be more consistent in predicting the natural course and prognosis of the Renal Cell Carcinoma (RCC), thanks to subclassifications made by molecular genetics and immunohistochemical studies.

Most renal tumors are incidentalomas. This means that many tumors are diagnosed during the diagnostic studies which are ordered for other health issues. Therefore, it is extremely important to determine both the risk factors and the most common symptoms of Renal Cell Carcinomas (RCC). First, as in bladder cancer, smoking is the most important risk factor. Then, obesity, renal failure and hemodialysis are among the risk factors. [2, 3]

In order to make histological diagnosis of renal cell carcinoma, nuclear grade, sarcomatoid features, invasion of collecting system and peri-renal fat tissue should be evaluated.

At the same time, pT and pN values used in the classification of renal cell carcinoma are extremely important. [4]

In this article, subtypes in the histopathological classification of renal cell carcinoma will be discussed, together with their details.

1. Clear Cell Renal Carcinoma (ccRCC)

Clear cell carcinoma (ccRCC) is the most common histological subtype.This subtype is presented in approximately 75% of all malignant kidney cancer tumors. [5, 6]

This subtype most commonly derived from the proximal tubule epithelium. And in many cases the cells have a clear cytoplasm and large prominent nuclei.

a. Association with von Hippel Lindau (VHL)

Clear cell carcinomas (ccRCC) are known to be associated with von Hippel Lindau (VHL) disease. The presence and evaluation of this genetic abnormality has led to significant improvements in the treatment of clear cell carcinomas (ccRCC). von Hippel Lindau has a prevalence of 1 in every 36,000 people in the United States.

Because the relationship with von Hippel Lindau (VHL) disease, clinical manifestations of clear cell carcinoma (ccRCC) include pheochromocytomas, retinal angiomas, and central nervous system hemangioblastomas.

b. Morphology

In general, clear cell carcinomas have well circumscribed boundaries and lack of capsules.

When examined morphologically, the appearance has a golden-yellow color. Besides, it is mostly present with hemorrhage and necrosis.

c. Genetic

Overall, in the genetic examination, loss of chromosome 3p and also the mutation in the von Hippel-Lindau (VHL) gene which is located at the chromosome 3p25 is generally found. Also, additional tumor suppressor genes near the von Hippel-Lindau (VHL) gene are frequently deleted such as ETD2, BAP1, and PBRM1. [7]

The chromosome 3p25-26 encodes the von Hippel Lindau protein which make complex with the hypoxia inducible factor (HIF-1).

Hypoxia inducible factor (HIF-1). controls the production of many proteins, including vascular endothelial growth factor (VEGF), which are normally under control, but whose production increases greatly in stress situations such as hypoxia and hunger.

The von Hippel Lindau (VHL) protein degrades this complex called hypoxia inducible factor (HIF-1). [8]

d. Prognosis

Clear cell carcinoma (ccRCC) has a worse prognosis than other main subtypes which are papillary (pRCC) and chromophobe cell carcinoma (chRCC). [9]

However, multilocular cystic renal cell carcinoma, which is one of the subtypes of clear cell carcinoma (ccRCC) defined in WHO classification, has an indolent clinical course. Although von Hippel Lindau (VHL) mutations also have been identified in this subtype, conversion to malignancy is extremely rare. In the diagnosis of multilocular cystic renal cell carcinoma hallmarks are small nests and clear cells in the cyst wall.

e. Survival rates

5-year cancer-specific survival rates calculated for clear cell carcinoma from patients treated between 1987 and 1998.

These can be listed as 91%, 74%, 67% and 32% according to TNM I, II, III and IV. [10]

2. Papillary Cell Renal Carcinoma (pRCC)

Papillary cell carcinoma (pRCC) is the second most commonly diagnosed histopathologic subtypes of Renal Cell Carcinoma (RCC). Just like clear cell carcinoma (ccRCC), well-defined genetic abnormalities associated with this subtype have also been identified. Approximately 10% to 15% of all renal masses are papillary cell carcinoma (pRCC), but only a few are associated with familial syndromes.

a. Histopathology

This subtype originates from convoluted distal tubules in the kidney. As the name implies, papillary carcinoma consists of single or pseudostratified cells. These cells encircle a fibrovascular core and this is the characteristic microscopic view of the tumor.

These tumors are recognized pathologically with the foamy macrophages and psammoma bodies that accumulate in the papillae.

b. Subtypes

This subtype is divided into 2 in itself; these are type I and type II. [1]

Type I and Type II papillary cell carcinomas (pRCC) have been shown to have clinically and biologically different behaviors.

Type I tumors are more common. Microscopy of these tumors shows small cells characterized by scanty basophilic cytoplasm and low nuclear grade. On the contrary, in type II tumors, large cells with eosinophilic cytoplasm and high nuclear grade are seen. [11]

Growth in exophytic spheric pattern, pseudo-necrotic changes and pseudocapsule are classic features of type I papillary cell carcinoma (pRCC).

These tumors are generally fragile. A contrast-enhanced CT scan shows a hypodense central area. Around this area, viable tumor tissue is presented as serpiginous contrast-enhancing margin. [12]

c. Genetic

According to genetic studies, type I is associated with MET mutations which are the activating germline mutations and type II is associated with activation of NFR2-ARE pathway with at least 3 mutations. [13]

d. Morphology

In morphological examination, papillary cell carcinomas (pRCC) are well circumscribed and have a pseudocapsule. These tumors have a soft structure and are usually yellow or brown in color.

e. Prognosis

Compared to the other two main types, clear cell (ccRCC) and chromophobe cell carcinoma (chRCC), these tumors have significantly higher rates in the sense that they are limited to the kidney. This means that papillary cell carcinomas (pRCC) are in pT1-2N0M0 stage almost without exception. Therefore, these tumors have higher 5-year cancer-specific survival rates. [14]

When the comparison between type I and type II is evaluated, it is seen that type I papillary cell carcinoma (pRCC) has a better survival rate and prognosis than type II. [1, 14]

3. Chromophobe Renal Cell Cancer (chRCC)

These histopathologic subtypes of renal cell carcinoma, first described in 1985, account for approximately 5% of all kidney tumors. [15]
Chromophobe renal cell carcinoma (chRCC) has a much better prognosis than both papillary cell (pRCC) and clear cell carcinoma (ccRCC). To date, this subtype has not yet been reported to metastasize.

Chromophobe cell carcinoma originates from intercalated cells of the collecting duct epithelium.

a. Histopathology

Chromophobe renal cell carcinoma (chRCC) is characterized by large plant-like eosinophilic to pale cells with abundant cytoplasm. Nuclear properties of this subtype include perinuclear halos, binucleation and raisinoid nucleus.

In general, this renal cell carcinoma subtype is a homogeneous, well demarcated, hard and non-capsulated mass.

b. Grading

Since chromophobe renal carcinoma has innate nuclei atypia, it cannot be graded. Although alternative grading systems have been produced, they have not yet been validated yet. [1]

c. Subtypes

Eosinophilic variant, a subtype of chromophobe cell carcinoma (chRCC), is very difficult to differentiate from another renal tumor called oncocytoma. However, oncocytoma is a benign kidney tumor. The clinical course and treatment of these two tumors is also very different.

d. Differential diagnosis of chromophobe cell carcinoma and oncocytoma

In the differential diagnosis of these two masses, staining for Hale’s colloidal iron is preferred. Chromophobe renal cell carcinoma (chRCC) shows diffuse reticular staining pattern, whereas oncocytoma shows only patch staining pattern. [16]

Immunohistochemical studies may also be helpful in differential diagnosis. Chromophobe renal cell carcinoma (chRCC) is positive for CK7 and C-kit and negative for pax-2. Conversely, oncocytomas are negative for CK7 and c-kit and positive for pax-2.

e. Genetic

Loss of chromosome Y, 1, 2, 6, 10, 13, 17, 21 and also hipodiploidy are typical findings in the genetic analysis of this cancer. [17,18]

A familial genetic disorder, called Birt-Hogg-Dube syndrome, is associated with chromophobe renal cell carcinoma (chRCC). This syndrome is characterized by chromosome 17p11.2 deletion and is accompanied with skin lesions, renal tumors and spontaneous pneumothorax. [19]

Approximately half of the tumors of Birt-Hogg-Dube syndrome patients have both features of chromophobe cell carcinoma (chRCC) and oncocytoma. Such tumors are also referred to as hybrid oncocytic tumors.

f. Prognosis

The prognosis of this renal cell carcinoma subtype is relatively better. The tumor has a high five-year recurrence free survival (RFS) rate, and its 10-year cancer specific survival (CSS) rates are also promising. [20]

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4. Collecting Duct Carcinoma

These histopathologic subtypes of renal cell carcinoma were first described in 1986. Just like chromophobe renal cell carcinoma (chRCC), collecting duct carcinoma (CDC) also originates from collecting duct cells located in the medulla.

However, patients with this tumor are highly symptomatic and diagnosed in the late stages. Approximately one-third of patients had cancer metastasis when diagnosed. These tumors are more likely to occur in men than women. (2: 1)

a. Histopathology

Collecting duct carcinoma (CDC) is characterized by infiltrative and irregular tubules and papillae. These papillae and tubules present with desmoplastic stromal reactions of different sizes.

Collecting duct carcinomas (CDC) do not have a specific staining pattern but are characterized by extremely high nuclear grades and multiple mitotic figures.

This histopathologic subtype is positive for CEA, peanut lectin agglutinin and Ulex europaeus agglutinin. In some tumors, cyto-keratin 34BE12 and CK7 may also be positive.

b. Genetic

Unlike other renal cell carcinoma subtypes, collecting duct carcinomas (CDC) do not have specific and clear genetic karyotypes.

Although some individual tumors have trisomy or loss of heterozygosity mutations of some chromosomes, no definite consensus has been established. [21]

5. Renal Medullary Carcinoma

Renal medullary carcinoma was first described in 1995 as a different variant of renal tumors. [22]
These histopathologic subtypes of Renal Cell Carcinoma are originates from the renal collecting ducts. Therefore, it is considered to be more aggressive than collecting duct carcinoma (CDC). It is a tumor usually seen in young people of the African American race. The mean age of presentation is defined as 19 years. This tumor also has male predominance. (2:1)

a. Clinical manifestations

Almost all reported renal medullary cancers are associated with sickle cell anemia, while some have been associated with sickle cell trait. Patients usually present to the urology clinic with symptoms of hematuria, flank pain, abdominal pain, and weight loss. Unfortunately, approximately 95% of patients have metastatic disease when diagnosed. The prognosis is extremely poor and the average life expectancy after diagnosis is 18 weeks. [23]

b. Histopathology

Infiltrative, poorly differentiated cancer cells are characteristic in the pathology of medullary cell carcinoma. These tumor cells have a distinct desmoplastic response. Sickled red blood cells are usually detected inside the tumor. In immunohistochemical staining, this tumor has a lot of similarities with collecting duct carcinoma (CDC).

c. Genetic

Like collecting duct carcinoma (CDC), it is a tumor that is difficult to characterize by genetic analysis. Although some studies have shown significant alterations in the number of genes, the genetic profile has not yet been clearly identified.

For more information about the histopathological subtypes of Kidney Cancer, you can read:

6. Mucinous Tubular and Spindle-Cell Carcinoma

Mucinous tubular and spindle-cell carcinoma is one of the new histopathologic subtypes of renal cell carcinoma that was recently added to the WHO classification.

This cancer is thought to originate from the loop of Henle. In the present classification, this tumor is named according 3 components of it as tubules, spindle cells, and mucinous stroma.

a. Clinical manifestations

The mean age of presentation of patients with this tumor is 53 years. Mucinous Tubular and Spindle-Cell Carcinoma shows a female predominance. Although it is generally known as a non-aggressively progressing tumor, several cases with metastasis and nodal involvement have also been reported.

b. Histopathology

Microscopically, it is seen that this cancer is composed of tightly packed elongated tubules. In some of them, a spindle-cell appearance in the bubbly mucinous stroma can also be seen.

The nuclei of cancer cells of these masses generally have a low grade and uniform appearance. Foam cells and psammoma bodies are also frequently observed.

In immunohistochemical studies, Mucinous Tubular and Spindle-Cell Carcinomas are positive for CK7, racemase, and RCC antigen.

c. Genetic

Genetic analyzes of these tumors show trisomy on chromosomes 7 and 17, also deletion mutations on chromosomes 1, 4, 6, 8 and 13. Although these mutations have been shown to be characteristic, the entire genetic analysis of the tumor has not yet been fully performed. [24]

7. Renal Translocation Carcinomas

These histopathological subtypes of Renal Cell Carcinoma were included in the literature with the 2004 with WHO classification. It is the most recent distinct renal cell carcinoma subtype described. These tumors are often defined as clear cell variants. Because these cancer cells tend to form papillae that have been lined with clear cells. While this appearance resembles classic clear cell carcinoma (cRCC), renal translocations carcinomas are considered as variant.

a. Clinical manifestations

Generally, the majority of patients are diagnosed at a young age. Hematuria, flank pain, an abdominal mass, or fever are the most common reasons for admission to the urology clinic.

b. Histopathology and immunohistochemistry

In the histopathologic and morphologic examinations of these tumor show very large masses. [25]

Genetic analysis is associated with changes in the Xp11.2 gene. These alterations may include both translocation and fusion mutations. The microphthalmia transcription factor subfamily in the Xp11.2 gene, which contains E3 and EB transcription factors, affected by such alterations. As a result of these genetic mutations, over-produced proteins can also be demonstrated by immunohistochemical examinations.

c. Prognosis

Although these tumors are extremely rare, they have a serious aggressive progression. Especially in adults, prognosis is extremely poor. Therefore, the diagnosis should be clear and accurate. [26]

8. Other Subtypes

Many new histopathologic subtypes of Renal Cell Carcinoma are emerging with the developing technology and increasing scientific studies, apart from these subtypes which mentioned above.

These tumors are often associated with end-stage renal disease and have a hybrid histopathology. [27]


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