Renal oncocytoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Homa Najafi, M.D.[2] Shanshan Cen, M.D. [3]

Overview

The exact pathogenesis of [disease name] is not fully understood.

OR

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].

OR

[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

OR

[Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

OR

The progression to [disease name] usually involves the [molecular pathway].

OR

The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

Physiology

The normal physiology of [name of process] can be understood as follows:

Pathogenesis

• The exact pathogenesis of [disease name] is not completely understood.

OR

• It is understood that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3].
• [Pathogen name] is usually transmitted via the [transmission route] route to the human host.
• Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.
• [Disease or malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].
• The progression to [disease name] usually involves the [molecular pathway].
• The pathophysiology of [disease/malignancy] depends on the histological subtype.

Genetics

DNA diploidy is seen in 96% of patients with renal oncocytomas.

The development of renal oncocytoma is the result of multiple genetic mutations such as:

• Deletion of chromosome 1
• Deletion of the sex chromosome
• Translocation of chromosome 11q13
• Sporadic or no chromosomal alteration

Associated Conditions

Conditions associated with renal oncocytoma include:

• Familial renal oncocytoma
• Birt-Hogg-Dube syndrome

Note: Birt-Hogg-Dube syndrome is an autosomal dominant syndrome which is presented with different types of dermatologic diseases and renal epithelial tumors such as renal oncocytoma and RCCs.

Gross Pathology

On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Renal oncocytomas are usually tan to brown and well demarcated. A “pseudocapsule” is often seen where the tumor compresses the adjacent renal parenchyma. 1,13,14 Although hemorrhage is typically absent, focal areas can be detected in some tumors. 1,6,7,12–16 Most cases of oncocytoma are confined within the renal parenchyma, and gross evidence of capsular or vascular invasion is rare.1,2,12,16 One distinctive feature of oncocytomas is the presence of a prominent central scar in an otherwise homogenous tumor, seen in 33% to 80% of cases.1,12,17,18 The average size of oncocytomas with central scars is slightly less than that of tumors without scars,18 indicating a limited correlation between tumor size and the presence of central scars. Thus, the diagnosis of oncocytoma cannot be made on the basis of the tumor size or the absence or presence of a central scar.

Renal oncocytomas often have a typical macroscopic appearance, which differs significantly from the typical gross appearance of RCCs. They are solitary, in rare instances multiple, generally well-encapsulated with a thick, well-defined, fibrous capsule.12 The surface on sectioning is usually mahogany-brown and less often tan in color. Large oncocytomas occasionally have a characteristic central stellate fibrous scar, which is composed of loose or dense hyalinized connective tissue containing occasional entrapped tumor cells and represents a sign of slow growth of this renal epithelial neoplasm.13 On the cut section, renal oncocytomas generally have a homogeneous appearance with no hemorrhage or necrosis within the tumor. Cases of histologically typical renal oncocytoma with calcification in the tumor center,14 necrosis,14,15 a liquid center,16 or a large central cyst,17 and numerous cysts18 have been described.

The characteristic gross appearance of oncocytoma includes a tan or mahogany brown cut surface (2, 6–8), generally similar to normal renal parenchyma in color and in contrast to the golden yellow cut surface of clear cell renal cell carcinoma. Although a central scar is quite characteristic of oncocytoma (Figure 1A), it is not specific for oncocytoma and is not present in all tumors (2, 6–8). A central scar can also be found in chromophobe renal cell carcinoma, as well as other slow-growing neoplasms, and substantial hyalinization and fibrosis can also be present within clear cell renal cell Journal of Kidney Cancer and VHL 2017; 4(4): 1–12 2 carcinoma. With the increasing identification of renal masses incidentally via imaging techniques, the size of oncocytoma tumors can also range from small solid nodules without central scar to large masses that would otherwise be concerning for high-stage renal cell carcinoma.

Microscopic Pathology

On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Overview

On gross pathology, tan or mahogany brown, well circumscribed tumor, and central scar are characteristic findings of renal oncocytoma. On microscopic histopathological analysis, oncocytes and large eosinophilic cells are characteristic findings of renal oncocytoma.

Pathogenesis

• Renal oncocytoma is thought to arise from the intercalated cells of collecting ducts of the kidney.

Gross Pathology

• The tumors are tan or mahogany brown, well circumscribed, and contain a central scar. They may achieve a large size (up to 12 cm in diameter).

Microscopic Pathology

• An epithelial tumor composed of oncocytes, large eosinophilic cells having small, round, benign-appearing nuclei with large nucleoli and excessive amounts of mitochondria.

Genetics

• Genes involved in the pathogenesis of renal concocytoma may include mtDNA MTND6 and FLCN.

Renal oncocytomas are usually tan to brown and well demarcated. A “pseudocapsule” is often seen where the tumor compresses the adjacent renal parenchyma. 1,13,14 Although hemorrhage is typically absent, focal areas can be detected in some tumors. 1,6,7,12–16 Most cases of oncocytoma are confined within the renal parenchyma, and gross evidence of capsular or vascular invasion is rare.1,2,12,16 One distinctive feature of oncocytomas is the presence of a prominent central scar in an otherwise homogenous tumor, seen in 33% to 80% of cases.1,12,17,18 The average size of oncocytomas with central scars is slightly less than that of tumors without scars,18 indicating a limited correlation between tumor size and the presence of central scars. Thus, the diagnosis of oncocytoma cannot be made on the basis of the tumor size or the absence or presence of a central scar. MICROSCOPIC FEATURES Microscopic examination of oncocytomas reveals characteristic features of the cellular architecture, cytoplasm, and nucleus. Uniformity in cellular size and color, round to polygonal shape, and abundant fine granular cytoplasm are consistent findings.1,6,13–15,17 Clear cells are not present, but foci of cytoplasmic clearing can be seen within the granular cells, distinctive from the clear cells seen in RCC.1,2,19 The typical nuclei appear small, uniform, and round, contain fine evenly dispersed chromatin, and show no evidence of mitosis.1,2,7,13–15,17,19,20 A minority of cells can have nuclear atypia and there may be focal presence of large nucleoli, moderate to marked pleomorphism, hyperchromasia, and binucleation or multinucleation.1,2,10,15,17,20 The degree of nuclear atypia is not correlated with the tumor size2 and does not affect the benign nature of the tumor. Accordingly, nuclear grading for oncocytomas has been abandoned.1,2 Three cellular architectural patterns are commonly seen (Fig. 1). The first type is described as “organoid,”2,6 with nests of cells surrounded by a reticulin framework of thin blood vessels and strands of delicate fibrous stroma. The nests can be loosely arranged or packed tightly into a sheet-like appearance.1,2,6,15,17 The second pattern is tubulocystic or alveolar, with cells arranged as tubular and cystic structures separated in a loose edematous stroma.1,2,15,17 The third type consists of a mixture of the organoid and tubulocystic patterns. 2,17 Lymphovascular invasion, perinephric extension, and necrosis are usually not present.1,2,15 Because such findings are so uncommon, the impact on patient prognosis is inconclusive. Such tumors are best considered “atypical oncocytomas.” Examination using Hale’s colloidal iron staining is often used to distinguish oncocytomas from CRCC, and the results are either negative or focally positive at perinuclear, perimembranous, or apical regions of the cell (Fig. 2). In CRCC, a correlation has been found between positive Hale’s colloidal iron staining and the presence of cytoplasmic mi-crovesicles.3 The pattern of Hale’s colloidal iron staining seen in oncocytomas also parallels the microvesicular distribution. Despite the well-characterized cytologic features of renal oncocytomas and the obvious benefits of the preoperative diagnosis of a benign tumor, the role of tumor biopsy for definitive diagnosis has been studied only retrospectively on samples taken from surgical specimens21,22 and remains questionable. Moreover, the overall sensitivity of renal biopsy ranges from 40% to 90%,23–25 and many tumors that are read as “nondiagnostic” on biopsy are often found to be malignant after complete surgical extirpation and thorough histologic examination. 24,25 Until the techniques and interpretations of biopsies become more consistent, its utility for the preoperative diagnosis of renal oncocytomas will remain limited. ULTRASTRUCTURE AND IMMUNOHISTOCHEMISTRY The most striking feature on electron microscopic examination is the diffuse distribution of round and uniform mitochondria, with a scarcity of all other cytoplasmic organelles1,13,17,20,26 (Fig. 3). Most mitochondria contain long lamellar cristae arranged in parallel arrays.1,26 Small amounts of microvesicles can usually be identified in the cytoplasm. 20,26 The presence of these microvesicles supports the conclusion that oncocytomas originate from the intercalated cells of the collecting duct, which normally demonstrate numerous apically located microvesicles.27 Immunohistochemical studies have shown that oncocytomas express various cytokeratins typical to epidermal neoplasms. But unlike most RCCs, which diffusely express vimentin, oncocytomas will show only sporadic vimentin expression.28 Immunohistochemical staining for cathepsin H can also distinguish oncocytomas from RCC,29 with negative or weakly positive staining for cathepsin H in RCC and strong and diffuse staining in oncocytomas. GENETIC ALTERATIONS DNA ploidy studies and chromosomal analyses have demonstrated important differences between oncocytomas and RCC. DNA diploidy occurs in up to 96% of oncocytomas.10,16,30 In comparison, more than 60% of RCC tumors demonstrating granular cytoplasm have some ploidy anomaly.16 Oncocytomas average two genetic alterations per tumor and locally advanced RCC averages 4.6.31 The most common abnormalities associated with RCC variants, including loss of heterozygosity of chromosome 3p in nonpapillary RCC, specific trisomies of chromosomes 3q, 7, 8, 12, 16, 17, and 20 in papillary RCC, and the combined loss of heterozygosity at chromosomes 1, 2, 6, 10, 13, 17, and 21 in chromophobe RCC, are not detected in oncocytomas. 31–34 The chromosomal alterations that are associated with oncocytomas can be placed in three categories: loss of chromosome 1 and the sex chromosome, balanced translocations involving chromosome 11q13, and a third group consisting of apparently sporadic, still ill-defined, chromosomal changes or no detectable chromosomal changes. 30,31,35–39 Table I summarizes the most common genetic alterations associated with the various tumor types. Chromosome 1p is thought to harbor a tumor suppressor gene that is involved in the development of oncocytomas.36 Others believe that oncocytomas and CRCC reside on a common “morphologic spectrum”40 on the basis of their loss of chromosome 1. One hypothesis suggests that oncocytomas with loss of chromosome 1 have the potential to progress to CRCC after subsequent loss of chromosomes 2, 6, 10, 13, 17, and 21.37 Others speculate that the two tumors actually arise from a common precursor with the potential to differentiate either in the benign or malignant direction. 40 It is also notable that oncocytomas are marked by alterations in their mitochondrial DNA.39 Mitochondrial proteins are encoded on chromosomes 1, 11, and 20, suggesting that mitochondrial enzymes may have some role in the development of oncocytomas.41 Despite these interesting findings, most oncocytomas fall into the third category of sporadic, ill-defined, genetic aberrations. Clearly, the genetic changes resulting in the pathogenesis of oncocytomas remain largely unknown. Associations between a subset of patients with multifocal renal oncocytomas and heritable syndromes have been described, including familial renal oncocytoma42 and Birt-Hogg-Dube syndrome. 43,44 Birt-Hogg-Dube syndrome is an autosomal dominant syndrome characterized by various dermatologic disorders and the development of renal epithelial tumors, including oncocytomas and RCCs. The clinicopathologic impact of these heritable syndromes is unclear.