Since the first edition of the World Health Organization Classification of Renal Tumors was introduced in 1981, the past three decades have witnessed a series of tremendous evolutions and advances in diagnostic terminology nomenclature, tissue classification, grading, and tumor staging of renal tumors, particularly renal cell carcinoma. The International Society of Urologic Pathology convened its fourth consensus meeting in Vancouver, Canada in March 2012, focusing on four aspects of renal tumor progress, including (1) classification of adult renal tumors; (2) histologic grading of renal cell carcinoma and other prognostic factors; (3) handling and staging of renal cell carcinoma specimens and (4) immunohistochemical diagnosis of renal tumors and molecular prognostic markers.
I. Classification of adult renal tumors
Compared with the 2004 WHO renal tumor classification, the new classification includes five new renal cell carcinoma subtypes, three tentative renal cell carcinoma subtypes, and amendments to the nomenclature and classification categories of certain known types of renal tumors.
1. New renal cell carcinoma subtypes
The five new renal cell carcinoma subtypes include (1) tubular cystic renal cell carcinoma; (2) renal cell carcinoma associated with acquired cystic kidney disease; (3) clear cell (tubular) papillary renal cell carcinoma; (4) MiTF family translocation renal cell carcinoma, including Xp11 translocation renal cell carcinoma and t(6;11) renal cell carcinoma; and (5) renal cell carcinoma associated with hereditary smooth muscle tumor disease renal cell carcinoma syndrome .
2.Tentative renal cell carcinoma subtypes
The three tentative renal cell carcinoma subtypes include (1) thyroid follicle-like renal cell carcinoma; (2) mesenchymal lymphoma kinase translocation renal cell carcinoma and (3) succinate dehydrogenase B deficiency-related renal cell carcinoma.
3. Diagnostic terminology and classification of already renal tumor types
(1) Renaming multifoveal cystic renal cell carcinoma as low-grade malignant potential multifoveal cystic renal tumor is mainly based on the fact that the majority of patients with multifoveal cystic renal cell carcinoma diagnosed according to the strict criteria of WHO classification have a very good prognosis, with little recurrence or metastasis in the case of complete tumor resection. (2) Papillary cell carcinoma is generally classified into type I and type II according to nuclear grade, and eosinophilic papillary renal cell carcinoma as a morphological subtype of papillary renal cell carcinoma is classified as a non-specific type of papillary renal cell carcinoma. (3) Heterogeneous eosinophil/suspected chromophobe renal tumor is classified as a subtype of suspected chromophobe renal cell carcinoma. (4) The diagnosis of collecting duct carcinoma requires the following diagnostic criteria: lesion involving at least part of the renal medulla; significant tubule formation; presence of a pro-connective tissue proliferation interstitial reaction; high-grade cytologic features; infiltrative growth; and absence of concomitant other types of renal cell carcinoma or uroepithelial carcinoma. (5) Vascular smooth muscle lipomas with epithelioid morphologic features were further classified as “epithelioid vascular smooth muscle lipoma with atypia” and “epithelioid vascular smooth muscle lipoma without atypia”. There was no specific consensus on the prognostic classification of epithelioid angiomyolipoma; although nearly 64% of the experts present believed that epithelioid smooth muscle lipoma should be classified into low-risk, intermediate-risk, and high-risk groups based on existing criteria, rather than simply benign and malignant. (6) Cystic nephroma and mixed epithelial mesenchymal tumor are two different histological types of the same disease entity, which belong to the category of mixed mesenchymal epithelial tumor. (7) Synovial sarcoma of kidney is classified as renal mesenchymal tumor.
Grading system and other prognostic parameters of renal cell carcinoma
Regarding the grading system and prognostic parameters of renal cell carcinoma, the consensus conference mainly discussed the histological phenotype, sarcomatoid/rhabdoid differentiation, tumor necrosis, grading, and the role of microvascular infiltration as potential prognostic factors of renal cell carcinoma.
1. Histologic phenotype of tumors
The major histomorphological phenotypes of renal cell carcinoma have obvious prognostic significance. Papillary renal cell carcinoma is classified into type I and type II according to the size of the nucleus with prognostic significance. Clear cell papillary renal cell carcinoma has a significantly better clinical outcome compared to clear cell renal cell carcinoma and papillary renal cell carcinoma.
2.Sarcomatoid differentiation
The morphological features proposed for the diagnosis of sarcomatoid differentiation include long spindle-shaped atypical sarcomatoid cells and atypical sarcomatoid cells without spindle cell morphology. Sarcomatoid renal cell carcinoma can originate from a variety of different histologic types of renal cell carcinoma, with the highest incidence of sarcomatoid differentiation occurring in collecting duct carcinoma (25-29%). In addition, treatment modalities may differ for sarcomatoid carcinoma with clear cell renal cell carcinoma and sarcomatoid carcinoma with a non-clear cell renal cell component, primarily in response to treatment with receptor tyrosine kinase inhibitors. Therefore, the consensus conference recommended that the histologic type of the cancerous component needs to be reported at the time of diagnosis of sarcomatoid carcinoma. Finally, for pure sarcomatoid carcinoma, most experts present agreed to report it as grade 4 unclassified renal cell carcinoma with sarcomatoid differentiation.
3.Rhabdomyosiform differentiation
Transverse myeloid differentiation of renal cell carcinoma refers to tumor cells morphologically similar to transverse myoblasts, but with different ultrastructural and immunophenotypic features. The presence or absence of rhabdoid differentiation and the histological subtype of renal cell carcinoma associated with it should be indicated in the report without reporting the proportion of rhabdoid differentiated areas.
4. Tumor necrosis
Nearly 30% of renal cell carcinomas can show varying degrees of tumor necrosis, which can range from large necrosis visible to the naked eye to small focal necrosis visible only to the microscope. There is substantial evidence that the presence of tumor necrosis is associated with a poor prognosis in clear cell renal cell carcinoma; however, this is not true for all types of renal cell carcinoma; for example, in papillary renal cell carcinoma, the tumor can often undergo spontaneous degenerative necrosis. It is recommended that the presence of tumor necrosis be noted in routine reports of clear cell renal cell carcinoma; and that tumor necrosis, both visually and microscopically, be evaluated. In addition, the proportion of necrotic components needs to be indicated.
5.Tumor grading
The Fuhrman grading system is not applicable to many non-clear cell renal cell carcinomas and does not reflect well the relationship between tumor grading and prognosis. The new grading standard is called the ISUP grading system. ISUP grade 1: tumor cells with no nucleoli or inconspicuous nucleoli at 400x; ISUP grade 2: tumor cells with clear nucleoli at 400x, but inconspicuous or indistinct nucleoli at 100x; ISUP grade 3: tumor cells with clear nucleoli at 100x; ISUP grade 4 : Tumor cells show sarcomatoid or rhabdoid differentiation; or contain tumor giant cells; or show markedly pleomorphic nuclei with clusters of chromatin. This grading system is applicable to clear cell renal cell carcinoma and papillary renal cell carcinoma. The grading of suspicious cell renal cell carcinoma is not required at this time.
6.Microvascular infiltration
Renal cell carcinoma is a tumor with highly vascularized mesenchyme, so intravascular tumor infiltration is relatively common.
III. Specimen processing and staging of renal cell carcinoma
Staging is the most important prognostic factor that determines the clinical outcome of renal cell carcinoma patients; it depends on the size of the tumor, the presence of infiltration of adjacent structures, the presence of intraventricular cancer thrombus and the status of lymph nodes and distant metastases. Correct handling of kidney tumor resection specimens is the basis for accurate staging of tumors.
1. Specimen incision and processing
There are two main methods to mark the margins, one is to selectively mark only the margins suspected of tumor involvement, and the other is to mark the entire outer surface of the specimen. Selective marking of partial nephrectomy specimens requires marking of the parenchymal margins, as well as marking if the specimen contains a portion of perirenal fat. For radical nephrectomy specimens, the specimen is dissected along the long axis of the specimen at the hilum (collecting system) through the venous system to fully expose the relationship between the tumor and the renal sinus and to observe the relationship between the tumor and the renal pelvis, sinus fat and vascular system.
2.Measurement of tumor
According to the TNM staging system in 2010, the accurate measurement of the maximum tumor diameter has an important prognostic significance. Before measuring the tumor diameter, a serial incision of the tumor is required to carefully find the largest surface of the tumor and record the maximum diameter. The size of the renal vein or vena cava thrombus need not be measured or included in the tumor size. Small satellite tumor foci are also not included in the assessment of the primary tumor size.
3. Number of tumors to be sampled
The sampling of renal tumors requires sampling of the interface between the tumor and adjacent structures (e.g., perinephric fat, renal sinuses, renal veins, adjacent renal parenchyma) and areas that generally show different color characteristics. The basic guideline for the number of tumors to be retrieved was agreed upon by consensus discussion, which was at least 1 tissue block per 25 px of tumor and at least 3 tissue blocks per tumor.
4. Evaluation of perirenal fatty infiltration
Broadly speaking, the features that identify perirenal fatty infiltrates include irregular tumor contours, poorly defined borders with adipose tissue, or multifocal irregular tumor nodules within the fat. The best way to assess perirenal fatty infiltration is to perform a multisection examination of the vertical interface between the tumor and the perirenal fat, and if infiltration is present, the area should be extensively sampled and confirmed microscopically. In contrast, microscopic diagnosis of perirenal fatty infiltration is determined by either direct contact of the tumor with the fat or by diffusion into the fat through an irregular tongue-like structure that may or may not be accompanied by a pro-fibroproliferative interstitial reaction.
5. Evaluation of renal sinus infiltration
Renal sinus fatty infiltration is one of the common modes of extrarenal spread of renal cell carcinoma. Tumor involvement of any tissue structure within the renal sinus (including fat, lax connective tissue, and endothelial cell-lined lumen) is considered to be present with renal sinus involvement.
6. Renal vein sampling with positive renal vein cut margins and vena cava infiltration
Positive renal vein margins were considered only if there was tumor cell adhesion on the true vascular margins and confirmed microscopically. Vena cava tumor infiltration is a pT3c stage tumor, defined as a tumor that has largely spread into the vena cava above the diaphragm or infiltrated into the vena cava wall. At least 2 or more sections are required to examine the vena cava wall tissue and possible infiltration.
7.Sectioning of uninvolved renal parenchyma
The main purpose is to assess the presence of non-neoplastic renal disease, including glomerular disease, tubulointerstitial disease and vascular disease.
8. Adrenal involvement
Tumor involvement of the adrenal glands has a significantly worse prognosis compared to perirenal fat. When the adrenal gland is involved by tumor, an important issue is to distinguish between direct infiltration (pT4) or hematogenous metastasis (M1), which mainly depends on the gross presentation of the tumor and microscopic evaluation, and hematogenous metastasis is commonly intravascular cancer thrombus.
IV. Biomarkers for diagnosis and prognosis of renal tumors
Comprehensive sampling and careful histological observation can provide accurate diagnosis and staging of most renal tumors. Immunohistochemical staining is mainly used for the staging of rare types of renal tumors, the differential diagnosis between epithelial and non-epithelial tumors, and primary renal tumors and rare metastatic tumors. Common markers used for the diagnosis and staging of renal tumors include keratin (CK), vimentin, epithelial membrane antigen (EMA), methyl racemase (AMACR), carbonic anhydrase IX (CAIX), PAX2, PAX8, renal cell carcinoma marker (RCC maker), CD10, E-cadherin, kidney-specific adhesion protein (KSC), parvalbumin, claudin-7, claudin-8, S100A1, CD82, CD117, TFE3, TFEB, thrombomodulin, P63, and S100P. The most frequently used marker for the diagnosis and differential diagnosis of renal cell carcinoma is CK7, followed by CD10, while PAX2 and PAX8 were identified as the best markers to confirm the origin of renal tumors in the differential diagnosis of primary renal tumors versus metastatic tumors. For the molecular diagnosis of renal tumors, questionnaires showed that fluorescence in situ hybridization (FISH) was the most frequently used study, while VHL mutation and heterozygous deletion analysis were less frequently used.