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A 23-year-old man presented with right-sided flank pain and hematuria. Abdominal CT scan confirmed the presence of an 8.0 cm renal mass involving the mid pole and pelvis. The nephrectomy specimen revealed an 8.0 cm gray-white, infiltrative mass centered on the medulla. The tumor grossly extended into the renal vein and ureter, but did not invade through the kidney capsule.
Archive Case and Diagnosis:
Histologic sections reveal a high-grade tumor with infiltrative margins. The tumor is arranged in cribriform and reticular glands, some of which have an adenoid cystic pattern. Many of the glands are filled with necrotic debris, and stromal desmoplasia can be marked. Tumor cells have abundant eosinophilic cytoplasm with high-grade cytology including pleomorphic nuclei and prominent nucleoli. Sickled red blood cells are observed within the tumor and surrounding vessels. These findings suggest renal medullary carcinoma.
Confirmatory ancillary tests performed included immunohistochemistry in which tumor cells showed positivity for cytokeratin-7 and rare cells positive for CD10. Tumor cells were negative for high molecular weight cytokeratin (34beta12) and showed loss of INI1.
The patient had a hemoglobin variant screen that showed markedly elevated hemoglobin S. Hemoglobin electrophoresis showed Hemoglobin-AS consistent with sickle cell trait.
Renal medullary carcinoma is a rare and aggressive type of renal cell carcinoma originally described in 1995 by Davis et al. It arises from cells of the collecting duct and may be related to collecting duct carcinoma based on similar morphologic and immunohistochemical features. In fact, renal medullary carcinoma is considered, by some experts to be an aggressive variant of collecting duct carcinoma.
Renal medullary carcinoma is very rare, with less than 100 reported cases. It typically occurs in young patients (age range 5 – 39 years, average age 21 – 24 years). It is much more common in the right kidney than the left and symptoms include flank pain, hematuria, nausea, vomiting, fever, or symptoms related to metastasis. It occurs predominantly in males (>75% of cases) and almost exclusively in African-Americans due to its relationship with sickle cell trait. Almost all reported cases have occurred in the setting of sickle cell trait or sickle cell disease. Most patients have sickle cell trait with Hemoglobin-AS (Hb-AS), however cases have been reported in patients with hemoglobin SC disease (Hb-SC) and even sickle cell disease (Hb-SS). In fact, chronic medullary hypoxia due to hemoglobinopathy with subsequent chronic regenerative proliferation of the damaged epithelium has been implicated in the pathogenesis of renal medullary carcinoma.
Renal medullary carcinoma is a medullary-based tumor with ill-defined borders and a gray-white, firm, rubbery cut surface. It is often discovered at an advanced stage with infiltration into the peri-hilar fat. There are frequently satellite nodules in the adjacent kidney parenchyma, or the tumor may embolize into large vessels.
This high-grade tumor may show a variety of architectural patterns, but most often forms glands. The glands may have a reticular or cribriform pattern. Other patterns such as microcystic, nesting, tubular, sheeting or an adenoid cystic-like pattern can be observed. A papillary or tubulopapillary pattern is not seen. The tumor often has infiltrative borders, desmoplastic stroma, intratumoral neutrophils, geographic necrosis and hemorrhage. The cytology is high grade with enlarged, pleomorphic, hyperchromatic nuclei, prominent nucleoli and may have rhabdoid features with abundant eosinophilic cytoplasm. Cytoplasmic mucin may be observed. Mitoses are frequent, as is lymphovascular invasion. Frequently sickled red blood cells are seen within the tumor or in surrounding blood vessels.
Tumor cells are positive for high molecular weight cytokeratin and may be positive for vimentin, mucicarmine, EMA and CEA. Tumor cells show a characteristic loss of expression of INI1 by negative immunostaining. It may be associated with monosomy 11; and some have described an association with the ABL-BCR translocation, and amplification of ABL and BCR genes.
Renal medullary carcinoma is an aggressive neoplasm with a poor prognosis. Survival is approximately 4 months, as patients usually present with metastatic disease to lymph nodes, adrenal glands, peritoneum, perinodal retroperitoneum, liver, lungs or the inferior vena cava. It is typically resistant to radiotherapy and chemotherapy.
The chief diagnostic differential is with collecting duct carcinoma. Some experts believe that medullary carcinoma is a variant of collecting duct carcinoma. However, collecting duct carcinoma has no association with hemoglobinopathy and shows retained expression of INI1. Collecting duct carcinomas also usually express CK7, HMCK, vimentin and Ulex, while are negative for CK20, RCC, CD10 and p63. Although collecting duct carcinoma has a poor prognosis, it is worse for renal medullary carcinoma.
Urothelial carcinoma involving the renal pelvis is also a diagnostic consideration, as it is a tumor often centered in the medulla or pelvis, can exhibit high-grade cytology and desmoplasia, and may have prominent glandular features. One helpful clue to the diagnosis of urothelial carcinoma is the presence of a mucosal papillary or in situ carcinoma component. The presence of squamous morphology or other patterns of urothelial carcinoma within the specimen may also lead one to the diagnosis of urothelial carcinoma. Urothelial carcinoma is typically positive for CK7, CK20, HMCK, p63, uroplakin III, thrombomodulin, CK5/6, INI1, and Ulex, while are negative for RCC, vimentin and CD10.
Rhabdoid tumor may be in the differential diagnosis in a young patient. Rhabdoid tumors are aggressive tumors composed of cells that resemble rhabdomyoblasts but are not of muscle derivation. Like renal medullary tumors, they are infiltrative, often with satellite lesions, and have high-grade cytology. Rhabdoid tumors typically occur in young children; most patients are less than 1-year-old, and all reported cases are in children under the age of 5 years. The tumor has a trabecular or alveolar pattern of loosely cohesive sheets of cells with well defined cell borders and abundant eosinophilic cytoplasm with perinuclear eosinophilic hyaline globules. These tumors, like medullary renal carcinoma, show loss of INI1 expression. Immunohistochemistry, as well as clinical history, may be helpful in determining the diagnosis. Rhabdoid tumor are positive for keratin, vimentin and EMA while are negative for INI1, smooth muscle actin and desmin.
Unclassified renal cell carcinoma is another differential diagnostic consideration, as it can be a high-grade tumor with variable morphology. Immunohistochemical stains may help elucidate the diagnosis. Unclassified renal cell carcinoma is typically positive for RCC, vimentin, CD10 and INI1 while negative for CK7, HMCK, Ulex and p63.
Metastatic carcinoma should also be considered as part of the differential, particularly given the fact that renal medullary carcinoma frequently presents with metastases, renal satellite nodules and intravascular tumor emboli. Immunohistochemical studies utilizing markers specific to the suspected primary tumor are frequently useful to confirm this impression.