Tumors of the Urinary Tract

Macroscopic Appearances.

Clear cell renal cell carcinomas are typically globular masses which may arise anywhere in the renal cortex ( Fig. 12A.9 ) and often protrude beyond the normal contour of the kidney. However, they occasionally grow inward or are diffusely infiltrative. The cut surface is usually variegated ( Fig. 12A.10 ), composed of soft bright yellow parenchyma with areas of grayish edematous stroma, hemorrhage, necrosis, and cysts. The cysts are filled with clear straw-colored fluid or with hemorrhage. Clear cell renal cell carcinoma may invade the renal venous system, occasionally filling the renal vein and extending into the vena cava or even the right atrium. Approximately 5% of clear cell renal cell carcinomas have areas of sarcomatoid change. These tend to appear grossly as firm solid whitish tissue ( Fig. 12A.11 ).

Rarely cystic masses ( Fig. 12A.12 ) grossly resembling cystic nephroma and meeting the criteria listed in Box 12A.4 contain aggregates of clear epithelial cells within their septa. These cells almost always have small dark-staining nuclei and are histologically identical to nuclear grade 1 clear cell renal cell carcinoma. Because there is little or no evidence of malignant behavior by such tumors, they should be diagnosed as multilocular cystic renal neoplasm of low malignant potential .

Histologic Appearances.

Clear cell renal cell carcinomas typically have a network of small blood vessels which invest alveolar clusters of carcinoma cells ( Fig. 12A.13 ). These blood vessels are very delicate and of a uniform small caliber. This vascular pattern is of great help in diagnosis since it is particular to clear cell renal cell carcinoma and not found in other types of renal cell carcinoma.

While a solid sheet of alveoli is a common pattern of growth, the alveoli often have small central lumens which contain freshly extravasated erythrocytes. Commonly, some of the lumens are larger, forming microscopic cysts of variable size ( Fig. 12A.14 ). Among renal cell carcinomas, clear cell renal cell carcinoma is the one most prone to the formation of small and large cysts—a helpful diagnostic clue.

The cytoplasmic volume of clear cell renal cell carcinoma is variable over a range from moderate to voluminous. However, it is typical that the cells in one area of a tumor are similar in size. This zonal pattern of cellular sizes contrasts with the mosaic pattern characteristic of chromophobe renal cell carcinoma. The clarity of the cytoplasm is caused by the abundant lipid and glycogen which dissolve in tissue processing.

One should think twice before diagnosing a tumor with obvious papillary architecture as clear cell renal cell carcinoma. If they occur at all, psammoma bodies and foamy macrophages, which are common in papillary renal cell carcinoma, are extremely rare in clear cell renal cell carcinoma. Mucin is at most rare in clear cell renal cell carcinoma, and some would categorize tumors containing mucin as renal cell carcinoma, unclassified.

Differential Diagnosis.

The diagnosis of the typical clear cell renal cell carcinoma is usually straightforward. Sarcomatoid change occurs in approxmimately 5% of clear cell renal cell carcinomas and may cause difficulty because it very closely mimics a sarcoma. This problem is well known however, and because of the rarity of renal sarcomas, they should be diagnosed with caution. Extensive sampling may be helpful since these tumors frequently have foci, albeit sometimes small, of typical renal cell carcinoma which make the correct diagnosis obvious. Immunohistochemistry for epithelial markers usually demonstrates epithelial features in cells that appear sarcomatous in sections stained with hematoxylin and eosin.

In adults, urothelial carcinomas of the renal pelvis may be confused with renal cell carcinomas, especially when tumors are large and extensively infiltrate the kidney. Microscopically, the diagnosis may be difficult, particularly when the pelvic tumor is predominantly sarcomatoid. Extensive sampling may be necessary to find small areas of typical urothelial carcinoma, even in situ, or renal cell carcinoma.

Clinically occult renal cell carcinomas presenting at distant sites with unknown primaries or recurring years after an apparently successful nephrectomy may pose special diagnostic problems. Positive immunohistochemistry for PAX8 can help to indicate renal origin. Also the coexpression of cytokeratin and vimentin, which occurs in a majority of clear cell renal cell carcinomas, is unusual among carcinomas and should be taken as suggestive of a renal primary when found in a metastasis of unknown origin. Solitary metastasis to the contralateral adrenal can resemble primary adrenal cortical carcinoma. In such cases, immunohistochemical staining for epithelial membrane antigen and cytokeratins can be helpful since renal cell carcinomas almost always stain for epithelial membrane antigen or cytokeratin, or both, while adrenal cortical carcinomas do not contain epithelial membrane antigen and stain for cytokeratin only weakly. Further immunohistochemistry for inhibin and melan-A can also be helpful. Metastasis to the thyroid can mimic clear cell carcinoma of the thyroid ; thyroglobulin, or TTF-1, immunohistochemistry can be helpful in making the distinction. Metastases to the ovary can be confused with primary ovarian clear cell adenocarcinoma. Capillary hemangioblastoma of the central nervous system may closely resemble clear cell renal cell carcinoma in sections stained with hematoxylin and eosin and poses a particular problem because both neoplasms are associated with von Hippel-Lindau disease. This problem can usually be resolved by staining for epithelial membrane antigen, since capillary hemangioblastomas fail to stain, while renal cell carcinomas usually do.

Macroscopic Appearances.

Papillary renal cell carcinomas usually are well-circumscribed, globular tumors with pale tan or brown parenchyma. In about two-thirds of cases, hemorrhage and necrosis are prominent, which may cause the tumor to appear hypovascular radiographically. Many of these carcinomas are large. Often the cut surface is friable or granular, a reflection of the papillae seen microscopically. The larger tumors are often surrounded by a rim of dense fibrous tissue. In about one-third of cases, there are calcifications.

Histologic Appearances.

The architecture is predominantly papillary or tubulopapillary in more than 90% of papillary renal cell carcinomas. Tight packing of papillae imparts the appearance of a solid growth pattern in some tumors. The papillae usually have delicate fibrovascular cores covered by a single layer of cells. The form of the papillae varies, ranging from complex branching to long parallel arrays. The cores are sometimes expanded by foamy macrophages ( Fig. 12A.15 ) or edema fluid. Psammoma bodies occasionally are present. Rarely the papillary cores are wide and collagenous. The tubular architecture consists of small tubules lined by a single layer of cells identical to those covering papillae.

There are two types of papillary renal cell carcinoma, which Delahunt and Eble have designated type 1 and type 2. Type 1 is more common than type 2. In type 1, the cells usually are small, with inconspicuous pale cytoplasm ( Fig. 12A.16 ). The nuclei are typically uniform, nearly spherical, and small, with nearly or completely invisible nucleoli. In type 2, the cells are usually larger and often have abundant eosinophilic cytoplasm. The nuclei are arranged in a pseudostratified pattern, are large, spherical, and often have prominent nucleoli ( Fig. 12A.17 ). The two types differ in their genetic aberations and in their prognoses.

Nuclear grading is recommended for papillary renal cell carcinomas.

Differential Diagnosis.

In children and adolescents, papillary renal cell carcinomas must be distinguished from Wilms tumors with epithelial predominance. Beckwith emphasized the similarity of some Wilms tumors to typical renal cell carcinoma. Thorough sampling of such tumors usually will reveal blastema or differentiated stroma (e.g., skeletal muscle) and the diagnosis of Wilms tumor will be made with relative ease. The appearance of the nuclei—elongate with tapered ends in the epithelium of Wilms tumor and spheroidal in renal cell carcinoma—also may be helpful. The diagnosis of papillary renal cell carcinoma in a young person should be made only after epithelial predominant Wilms tumor has been excluded.

Macroscopic Appearances.

The tumors range widely in size and invasion of perirenal fat and extension into the renal vein and vena cava occur frequently. The tumors are predominantly solid but about 50% have at least a minor cystic component.

Histologic Appearances.

Papillary architecture is present in more than 50% of tumors, but tubular architecture is common and about 20% are mixtures of papillary and tubular architectures. A cystic component is present in about half ( Fig. 12A.18 ). The cytoplasm is typically abundant and eosinophilic, but foci of clear cytoplasm can be present. The nuclei are large and typically contain large eosinophilic nucleoli surrounded by haloes ( Fig. 12A.19 ). Mitotic figures usually are present, ranging from two to six per high-power field (hpf).

Differential Diagnosis.

Hereditary leiomyomatosis and renal cell carcinoma syndrome carcinomas can have areas resembling papillary renal cell carcinoma, type 2, tubulocystic carcinoma, collecting duct carcinoma, or renal oncocytoma. Immunohistochemistry can usually resolve questions of differential diagnosis: In hereditary leiomyomatosis and renal cell carcinoma–associated carcinomas immunohistochemistry for fumarate hydratase gives a negative result in the neoplastic cells, while nonneoplastic cells serve as positive internal controls. S-(2-succino)-cysteine was detected immunohistochemically in all hereditary leiomyomatosis and renal cell carcinoma renal tumors and seldom was detectable in type 2 papillary renal cell carcinomas and other tumors with histologic appearances overlapping them. Of course, a clinical history of cutaneous leiomyomas or early onset of uterine leiomyomas also is helpful.

Macroscopic Appearances.

Chromophobe renal cell carcinomas are usually well-circumscribed globular solid tan or brown tumors ( Fig. 12A.20 ). Formalin fixation may change their color to a pale off-white. Large cysts are not typical of chromophobe renal cell carcinoma.

Histologic Appearances.

Chromophobe renal cell carcinoma is characterized by the presence of cells with large numbers of minute intracytoplasmic vesicles which impart a pale, reticular or flocculent appearance to the cytoplasm in hematoxylin and eosin ( Fig. 12A.21 ). The vesicles are demonstrable by electron microscopy ( Fig. 12A.22 ). The Hale colloidal iron stain colors the cytoplasm blue ( Fig. 12A.23 ). The initial descriptions emphasized the well-defined thick cytoplasmic membranes and lightly staining flocculent cytoplasm of what is now called the typical variant of chromophobe renal cell carcinoma. The typical variant also has thick-walled blood vessels. The cells range widely in size and small and large cells are mixed together in a mosaic pattern. Later, the eosinophilic variant of chromophobe cell renal cell carcinoma was recognized. This variant shares the ultrastructural and colloidal iron staining features of the typical variant but, in hematoxylin and eosin-stained slides, closely resembles renal oncocytoma ( Fig. 12A.24 ). It is prudent to perform a colloidal iron stain on any tumor in which the differential diagnosis includes renal oncocytoma and chromophobe cell renal cell carcinoma.

Differential Diagnosis.

The vasculature, mosaic pattern of variability of cell size, and cytoplasmic characteristics make the classical form of chromophobe renal cell carcinoma distinctive; and diagnosis can usually be easily achieved in routine sections. The eosinophilic variant is more problematic because of its close resemblance to oncocytoma. In sections stained with hematoxylin and eosin, perinuclear haloes, wrinkled irregular nuclei, and microcystic architecture lend support to the diagnosis of the eosinophilic variant of chromophobe renal cell carcinoma. However, histochemical staining with the Hale colloidal iron reaction is helpful and a diffuse cytoplasmic positive reaction supports the diagnosis of chromophobe renal cell carcinoma, while a diffusely negative reaction supports oncocytoma. Immunohistochemistry for cytokeratin 7 usually shows a strong diffusely positive reaction in chromophobe renal cell carcinomas. Chromophobe renal cell carcinomas are typically negative for vimentin.

Macroscopic Appearances.

While the collecting ducts are present in the cortex and the medulla, the gross pathologic finding of a tumor arising in the inner medulla ( Fig. 12A.26 ), where most other parts of the renal tubular system are absent, can be an important aid to the diagnosis. Unfortunately precise localization to the medulla is only possible with small tumors and many tumors are too large at the time of resection for the specific site of origin within the kidney to be recognizable. The tumors are usually centered in the medulla, often with extensions into the cortex or hilar tissues. Infiltrative borders and white or grey cut surfaces with central necrosis are typical. A connection with the renal pelvis is common.

Histologic Appearances.

These are distinctive carcinomas with features of adenocarcinoma and urothelial carcinoma. Microscopic examination shows highly irregular ductlike structures, nests, and cords of cells in an abundant loose, slightly basophilic stroma ( Fig. 12A.27 ). The carcinoma cells lining the lumens have small or moderate amounts of cytoplasm and nuclei which are pleomorphic and have thick nuclear membranes. An especially useful feature, rarely found in renal cell carcinoma and not found in urothelial carcinoma, is the hobnail appearance sometimes seen in the cells lining duct lumens ( Fig. 12A.28 ). Rhabdoid morphology is common in these carcinomas. Atypical epithelium in the medullary tubules adjacent to the carcinoma has been seen in some cases.

Differential Diagnosis.

Awareness of collecting duct carcinoma and appreciation of the differences between the microscopic features described earlier and those of other renal cancers should establish the diagnosis in most cases. Untangling collecting duct carcinoma from renal medullary carcinoma can be challenging. If there is evidence of sickle cell mutation, then medullary carcinoma is strongly favored. A positive immunohistochemical reaction for POU5F1 (OCT3/4) also weighs heavily in favor of medullary carcinoma rather than collecting duct carcinoma, as does loss of SMARCB1. High-grade urothelial carcinoma is an important consideration in the differential diagnosis. Immunohistochemistry can be helpful with this. A positive reaction for PAX8 combined with negative reactions for p63 and GATA3 supports a diagnosis of collecting duct carcinoma, while a negative reaction for PAX8 combined with positive reactions for p63 and GATA3 weighs in favor of a diagnosis of urothelial carcinoma. Borderline cases should be diagnosed as renal cell carcinoma, unclassified.

Macroscopic Appearances.

Translocation carcinomas usually are solid tan-yellow tumors; foci of hemorrhage and necrosis are common.

Histologic Appearances.

Xp11.2 translocation carcinomas often have large areas of papillary architecture in which the papillae are covered by cells with abundant clear or pale cytoplasm ( Fig. 12A.29 ). However, they also have an alveolar or nested architecture and cells with eosinophilic cytoplasm are common. Psammoma bodies are common and may be quite numerous. There are subtle variations in morphology among carcinomas with the different Xp11 translocations.

T translocation carcinomas consist of nests and microscopic cysts composed of polygonal cells with pale or eosinophilic cytoplasm. Papillae are uncommon. A distinctive component consists of cells with small amounts of cytoplasm and denser chromatin arranged around nodules of hyaline material in large acini. At low magnification, these resemble rosettes.

Translocation carcinomas with gene fusions involving TFE3 typically show a positive intranuclear reaction with antibodies to TFE3. Carcinomas with gene fusions involving TFEB typically show positive intranuclear reactions with antibodies to TFEB. Xp11 translocation carcinomas characteristically fail to mark or mark weakly with antibodies to epithelial markers, such as epithelial membrane antigen and cytokeratins. T carcinomas are frequently positive for HMB45 and melan-A and contain extracellular eosinophilic nodules which react with antibodies to collagen IV. Cathepsin K is another marker for these carcinomas.

Macroscopic Appearances.

The sizes of these carcinomas have ranged widely, with a mean diameter of 50 mm. The tumors are mainly solid, with cystic change in a minority. The cut surfaces of these well-circumscribed tumors have been described as tan to red.

Histologic Appearances.

At low magnification, succinate dehydrogenase-deficient renal cell carcinomas give an impression of growth in sheets punctuated by small cysts. Higher magnification shows the cells to be arranged in small alveoli invested by delicate blood vessels. Some of the alveoli expand to form lumina of variable size filled with pale eosinophilic fluid. The neoplastic cells have eosinophilic cytoplasm which usually has a pale flocculent appearance but occasionally is dense and brightly eosinophilic. A distinctive and diagnostically helpful feature is the nearly constant presence of intracytoplasmic inclusions or vacuoles ( Fig. 12A.30 ). Electron microscopy shows that the cytoplasmic inclusions are abnormally enlarged mitochondria. Nonneoplastic tubules and glomeruli are frequently entrapped within the tumor. Sarcomatoid change is found in approximately 10% of tumors and coagulative necrosis in somewhat fewer.

Differential Diagnosis.

Regardless of which of the genes is mutated, immunohistochemistry for SDHB is negative in the neoplastic cells, while other types of cells staining positively serve as internal controls. A substantial number of tumors which resembled succinate dehydrogenase-deficient renal cell carcinomas have been tested immunohistochemically and found to have normal contents of SDHB. As might be expected, clear cell renal cell carcinomas in which the cytoplasm is richly filled with lipid and glycogen frequently give weakly positive reactions with antibody to SDHB.

Macroscopic Appearances.

Mucinous tubular and spindle cell carcinomas have ranged in size from 22 mm to 130 mm in diameter. The cut surfaces are solid and tan brown to pinkish. Some authors have variously described the cut surfaces as gray to white, tan, and yellow to pinkish. Foci of hemorrhage or necrosis has been found in a few of the tumors. One small tumor appeared to be centered on the renal medulla. All but one of the tumors have been well circumscribed and contained within the renal capsule.

Histologic Appearances.

Mucinous tubular and spindle cell carcinomas have a distinctive histologic appearance, consisting of cuboidal cells arranged in long cords and tubules and making abrupt transitions to spindle cell morphology ( Fig. 12A.31 ). These epithelial structures are arrayed against a background of lightly basophilic mucinous or myxoid material. The nuclei usually are spherical or oval, have a few small chromatin clumps and small nucleoli. Mitotic figures are uncommon. The spindle cell component may form sheets. The mucinous background material may focally dominate with the epithelial elements forming small cords in lakes of mucinous material. The mucinous background material has little affinity for mucicarmine but reacts strongly with Alcian blue. Plasma cells, mast cells, and clusters of foamy histiocytes are sometimes present. Sarcomatoid change has been reported. The immunohistochemical results obtained in different series have varied. Positive reactions with antibodies to vimentin and epithelial membrane antigen have been the most frequent findings. Reaction with the cytokeratin cocktail AE1/3 was positive in 10 of 14 tumors in two studies. Expression of racemase (P504S) is common. The lectin Ulex europaeus , which binds to collecting duct epithelium, has consistently failed to bind to the cells of mucinous tubular and spindle cell carcinoma.

Macroscopic Appearances.

Tubulocystic carcinoma is usually solitary and well circumscribed. The tumors have ranged from 0.5 to 17 cm in diameter (mean 4 cm) and typically have a white to gray spongy cut surface ( Fig. 12A.32A ).

Histologic Appearances.

Tubulocystic carcinoma consists of cysts of variable size separated mainly by delicate fibrous septa. Foci of solid growth occasionally are present and usually small. The cysts are lined by cuboidal cells which frequently have a hobnail appearance (see Fig. 12A.32B ). The nuclei usually are nearly spherical and nuclear pleomorphism is slight. Often prominent nucleoli are visible in most of the nuclei. Occasional cases have poorly differentiated foci. The cytoplasm is eosinophilic or weakly amphophilic. Immunohistochemistry is usually positive for cytokeratins 8, 18, and 19; CD-10; racemase (P504S); and parvalbumin while cytokeratin 7 positivity is usually focal.

Tumors that have a cystic growth pattern feature in the differential diagnosis for tubulocystic carcinoma. The lining cells of cystic nephroma often have a hobnail appearance but seldom have prominent nucleoli. Multilocular cystic renal cell neoplasm of low malignant potential is composed of clear cells, rather than cells with eosinophilic or amphophilic cytoplasm and the nuclei rarely if ever contain prominent nucleoli.

While some authors have suggested a linkage between tubulocystic carcinoma and papillary renal cell carcinoma, tubulocystic carcinomas lack trisomy 7 and 17.

Macroscopic Appearances.

Clear cell papillary renal cell carcinoma are usually small at presentation, with reported sizes ranging up to 8.5 cm in maximum diameter. The majority of tumors are cystic, with the cysts often containing serosanguinous fluid. There is often a thick fibrous pseudocapsule and sometimes the largest cysts are at the periphery of the tumor adjacent to the pseudocapsule.

Histologic Appearances.

An acinar or glandular architecture usually predominates in these tumors. Papillae are present in approximately 80% of cases, although they often constitute only a minor component. The papillae usually differ in architecture from those of papillary renal cell carcinoma types 1 and 2, and from the papillae of translocation carcinomas. The papillae are less complex, the cores are thicker, and the stroma within them often is cellular ( Fig. 12A.33A ). Additionally, sometimes stubby secondary papillae branch from the primary papillae. This architecture is distinctive, and when present, is strong evidence that the tumor is a clear cell papillary renal cell carcinoma. Nests of cells with clear cytoplasm and delicate vasculature closely resembling ordinary clear cell renal cell carcinoma are common and in a needle biopsy could easily be diagnosed as ordinary clear cell renal cell carcinoma. The cytoplasm is abundant and usually very clear (see Fig. 12A.33B ). On papillae, it is sometimes so voluminous that the apical cytoplasm of the cells on one papilla touches that of the cells on an opposite papilla, creating a broad clear band between the wide cores. Uncommonly the cytoplasm is weakly eosinophilic. The nuclei of the epithelial cells show little pleomorphism and mitotic figures are difficult to find. It is common for the nuclei to be high in the cytoplasm, away from the basement membrane. Psammoma bodies and foamy macrophages are not found in these tumors. The stroma of the papillary stalks and between the epithelial elements is more abundant and more cellular that is expected in an ordinary clear cell renal cell carcinoma and this can be a helpful clue to the nature of the tumor. The stromal cells are mostly nondescript spindle cells but sometimes show smooth muscle differentiation.

The epithelial elements usually show an immunophenotypic profile which distinguishes them from papillary renal cell carcinoma and clear cell renal cell carcinoma. A diffuse and strongly positive reaction with antibody to cytokeratin 7 is typical, while reactions for alpha methyacyl-CoA racemase and CD10 are consistently negative, with the exception that CD10 can be positive in the cells lining cysts. Less helpful but occasionally useful are the positive reactions for carbonic anhydrase IX and vimentin and negative reactions for TFE3 which are typical of clear cell papillary renal cell carcinoma. While genetic studies on these tumors are limited, it is becoming clear that they have neither the gains of chromosomes 7 and 17 typical of papillary renal cell carcinomas nor the mutations in VHL or losses in chromosome 3p25 which are characteristic of clear cell renal cell carcinomas.

Macroscopic Appearances.

These tumors are usually well-circumscribed soft brown tumors and, when large, show pseudoencapsulation often with dystrophic calcification.

Histologic Appearances.

Microscopically there are a variety of architectural patterns ranging from solid and acinar to cystic and papillary ( Fig. 12A.34 ). The presence of irregular lumina gives the tumor a cribriform appearance. In many of the smaller lesions the tumor appeared to arise in a cyst. The cells typically have abundant eosinophilic cytoplasm with nearly spherical nuclei and a single large nucleolus. Occasional cells have vacuolated cytoplasm and focally clear cells are present. Oxalate crystals are present in the majority of tumors but may be few and difficult to find.

Genetic analysis of acquired cystic disease–associated renal cell carcinoma shows gains of chromosomes 7 and 17. FISH analysis has also shown gains of chromosomes 1, 2, 3, 6, 16, and Y in several cases, with additional gains of chromosomes 1, 5, 11, 12, and X being occasionally seen. Mutations of the VHL gene have not been identified in these tumors.