H. Lee Moffitt Cancer Center & Research Institute

Virginia S. King. Costa del Sol. Watercolor, 18" x 24".   The Mainz Classification of Renal Cell Tumors José I. Diaz, MD, Linda B. Mora, MD, and Ardeshir Hakam, MD

Introduction

A wide variety of benign and malignant neoplasms have been described in the kidney. The tumors typically encountered in adults are rare in children. Conversely, the tumors seen in children are rare in adults. In this article, we review the pathobiology of the most common renal tumors in adults. These are the tumors derived from the renal tubular epithelium, all of which are included in the Mainz classification of renal cell tumors.

Etiology and Epidemiology of Renal Cell Tumors

Renal cell carcinoma (RCC) is extremely rare in the first two decades of life, rare in patients below 40 years of age, and most prevalent in patients over age 60. The number of new cases of renal cell carcinoma in the United States in 1996 was projected to be 30,600 with an estimated 12,000 deaths.¹

Most of the carcinogens that cause renal cancer are unknown. Smoking, obesity, long-term use of phenacetin and acetaminophen, presence of kidney stones, and exposure to cadmium, thorotrast, petroleum products, and other industrial chemicals are important risk factors for developing renal cancer. Von Hippel-Lindau disease is associated with RCC in one third to one half of patients.² RCC occurs earlier in patients with von Hippel-Lindau disease. In addition, it is multiple or bilateral and metastasizes more frequently. Whether polycystic kidney disease is associated with RCC remains controversial; however, acquired renal cystic disease, which typically occurs in patients with chronic renal failure on hemodialysis, is strongly associated with RCC. There have been a few reports of RCC clustering in families without von Hippel-Lindau disease.² The relationship between benign renal adenomas and RCC is controversial and will be discussed later.

The Mainz Classification

RCC was originally named hypernephroma because it was believed that the tumors originated from adrenal rests due to the histologic resemblance to the adrenal. In 1960, Oberling et al³ demonstrated its origin from the proximal renal tubule based on the ultrastructural features. The tumor was renamed renal cell adenocarcinoma or renal cell carcinoma. For many years, RCC was considered a single pathologic entity and was subdivided into clear, granular, and mixed cell variants based on the cytoplasmic features of the tumor cells. The term papillary renal cell carcinoma was used to designate a subset of granular cell type RCC with exclusive or predominant papillary architecture. While significant variability in clinical behavior was observed in RCC, the old classification failed to provide good clinicopathologic correlation.

In 1976, Klein and Valensi⁴ reported a subtype of renal neoplasms with granular cell features, the so-called renal oncocytoma, which appeared to have an excellent prognosis. Nine years later, Thoenes and colleagues⁵ described another subtype of RCC with clear cell features, which closely resembled the renal tumors experimentally induced in rats.⁶ This tumor was named chromophobe renal cell carcinoma. Shortly after, a new renal tumor was described that appeared to originate from the collecting ducts.⁷ This also had granular cell features and was named collecting duct carcinoma. Overlapping of granular and clear cell features among tumors with marked clinical, pathologic, and phenotypic differences promoted the need for a new classification. In 1986, Thoenes and colleagues⁸ from the Gutenberg University in Germany proposed a new classification for renal tumors of tubular epithelial origin known as the Mainz classification. This classification was still based on conventional histopathologic criteria and included all the new entities described earlier.

The Mainz classification is now widely accepted because several cytogenetic studies^9-12 have confirmed characteristic genetic alterations on each tumor type. Today, RCC is no longer considered a single pathologic entity. The term RCC embraces a group of renal cancers, all of which are derived from the renal tubular epithelium but each with distinct clinical, pathologic, phenotypic, and genotypic features. The Mainz classification of renal cell neoplasms is presented in Table 1 with the relative frequency of each tumor. The most characteristic histopathologic and cytogenic features are presented in Table 2.

Renal Adenoma

Small renal epithelial neoplasms are commonly and incidentally found during autopsies. Many investigators believe that these lesions lack the ability to progress to RCC and are benign. However, since the same lesions are not uncommonly associated with concomitant RCC, other investigators claim that some of these neoplasms might progress to RCC. Methods to distinguish the benign adenomas from the potentially malignant tumors remain controversial.¹³

In 1950, Bell¹⁴ conducted an autopsy study and reported that metastases were exceptional when renal tumors were less than 3 cm in size. He suggested that these lesions should be considered benign adenomas. With the advent of computed tomography scans, an increasing number of small tumors (1 cm or even less) that had already metastasized were reported.¹⁵ Therefore, tumor size is no longer considered a reliable criterion. At the present time, most urologic pathologists agree that there are no reliable criteria to distinguish benign renal adenomas from RCC. Microscopically, histopathologic features of both greatly overlap, and almost any histologic pattern described in RCC can be encountered in benign adenomas. Although it is acknowledged that many of these small renal neoplasms are probably benign, they should be considered potentially malignant, regardless of their size, until reliable diagnostic criteria become available. Tumors with clear cells should never be accepted as benign adenomas. The ideal candidate for a benign renal adenoma is a small and superficial tumor with tubular, papillary, or mixed architecture and without clear cells or nuclear anaplasia.

Renal Oncocytoma

Renal oncocytoma is uncommon but not rare (5% of the tumors derived from tubular epithelium). While most tumors are incidentally found, they can present as a palpable mass or with hematuria. Oncocytomas may resemble RCC clinically and pathologically, and this resemblance may lead to radical nephrectomy. However, conservative surgery is considered an adequate treatment since true oncocytomas are always benign.¹⁶

Renal oncocytoma has a characteristic mahogany appearance and often has a central white fibrous scar (Fig 1). Although rare, necrosis may occur, resembling RCC. Hemorrhage is common. Bilaterally or multicentricity are common. Occasionally, oncocytomas are predominantly cystic.

Fig 1. — Renal oncocytoma. The mahogany appearance of the tumor contrast with the white fibrous scar in the center of the mast.

The histologic features are very characteristic. Strongly eosinophilic tumor cells forming islands and tubules dominate throughout the tumor. Tumor cells exhibit large and finely granular cytoplasm, uniform round nuclei, clumped chromatin and small nucleoli (Fig 2). Bizarre, enlarged nuclei may be scattered throughout the tumor, but mitoses are rare. Oncocytomas sometimes extend into the perinephric fat or into venous sinuses without affecting the prognosis. These two features are never observed grossly. The differential diagnosis with eosinophilic chromophobe RCC would be difficult without Hale’s colloidal iron stain, which is negative in oncocytomas, or without electron microscopy (EM), which in oncocytomas shows numerous mitochondria filling the cytoplasm of the tumors cells (Fig 3).

Fig 2.— Renal oncocytoma. Eosinophilic tumor cells with large granular cytoplasm form small aggregates and tubules. Note the lack of mitotic activity and cytologic atypia (hematoxylin-eosin, x 600).		Fig 3. — Renal oncocytoma. The ultrastructural micrograph shows numerous mitochondria filling the cytoplasm of the tumor cell.

Clear Cell Renal Cell Carcinoma

Clinically, this is the most common renal neoplasm seen in adults (70% of tumors derived from tubular epithelium). This tumor can be as small as 1 cm or less and discovered incidentally, or it can be as bulky as several kilograms. Most often it presents with pain, as a palpable mass or with hematuria, but a wide variety of paraneoplastic syndromes have been described. Clear cell RCC might be clinically silent for years and may present with symptoms of metastasis.

The gross appearance is characteristic. The tumor is solid, lobulated, and yellow, with variegation due to necrosis and hemorrhage (Fig 4). The tumor might be well circumscribed, or it might invade the perirenal fat or the renal vein. Cystic degeneration is common, but some tumors are predominantly cystic (15%).¹⁸ The so-called cystic RCC is more often multilocular and with clear cells, but it can be un