Renal Cell Carcinoma: Diagnosis Based on Metastatic Manifestations

Abstract

Renal cell carcinomas are notorious for their tendency to metastasize early, often before the primary tumor has become apparent. Frequently, the initial complaint is referable to a distant metastatic lesion. Metastatic lesions have been found in almost every organ or tissue of the body. When a patient with a clinically asymptomatic renal cell carcinoma has signs and symptoms referable to a localized lesion, the final diagnosis depends on histologic and cytologic evaluation of a biopsy specimen. In this article, we describe a patient who had a pulsating transcalvarial occipital suboccipital mass as the initial manifestation of an occult renal cell carcinoma. Initial manifestations by site of metastasis described in the literature are reviewed, and the differential diagnosis of primary clear cell tumor versus metastatic lesions from a renal cell carcinoma, according to their pathologic features, is discussed. Renal cell carcinomas are notorious for their tendency to metastasize early, often before the primary tumor has become apparent. Frequently, the initial complaint is referable to a distant metastatic lesion. Metastatic lesions have been found in almost every organ or tissue of the body. When a patient with a clinically asymptomatic renal cell carcinoma has signs and symptoms referable to a localized lesion, the final diagnosis depends on histologic and cytologic evaluation of a biopsy specimen. In this article, we describe a patient who had a pulsating transcalvarial occipital suboccipital mass as the initial manifestation of an occult renal cell carcinoma. Initial manifestations by site of metastasis described in the literature are reviewed, and the differential diagnosis of primary clear cell tumor versus metastatic lesions from a renal cell carcinoma, according to their pathologic features, is discussed. Renal cell carcinoma is one of the great mimics in medicine. Approximately 25% of patients have metastatic disease at initial assessment, and such involvement may actually initiate the diagnosis. We describe a patient who had an occipital mass as the initial manifestation of an occult renal cell carcinoma. A 72-year-old woman was referred to Mayo Clinic Rochester for evaluation of an enlarging occipital mass. The patient had first noted this mass about 1 year earlier. The mass was not associated with pain, but the patient could feel it pulsate when lying on her back. She denied having any other associated symptoms. On physical examination, the patient looked well, and findings were normal except for a large (10 by 5-cm) pulsatile occipital mass over which a bruit was auscultated. Results of routine laboratory tests were normal, including erythrocyte sedimentation rate, complete blood cell count, chemistry group, urinalysis, chest radiography, electrocardiography, and mammography. Computed tomography of the head demonstrated a 3- by 4- by 5-cm mass centered in the midline occipital region (Fig. 1). Enhancement was noted after a contrast agent was administered intravenously. No other lesions were identified in the head. The differential diagnosis included a hemangioma, chondroid tumor, and plasmacytoma. Metastatic disease was thought to be a less likely possibility. Cerebral angiography revealed that the large exophytic mass centered in the calvaria was densely vascular with intracranial and extracranial extension (Fig. 2). Because the possibility of some parenchymal invasion infratentorially could not be excluded, magnetic resonance imaging, including angiographic sequences, was requested. This showed that the mass abutted the parasagittal cerebellar hemispheres and, to a lesser extent, the occipital lobes. Again, the possibility of subtle parenchymal invasion in these areas of abutment could not be excluded (Fig. 3).Fig. 3Gadolinium-enhanced axial T1-weighted magnetic resonance images, showing vascular mass abutting parasagittal cerebellar hemispheres and, to a lesser extent, occipital lobes. Subtle parenchymal invasion cannot be excluded. Tumor involves proximal transverse sinus (arrow) and invades torcular Herophili (parentheses).View Large Image Figure ViewerDownload (PPT) A needle biopsy was performed, and metastatic clear cell carcinoma was identified (Fig. 4). Thus, computed tomography of the abdomen was performed; it showed an 8-cm enhancing mass within the middle and lower portions of the right kidney with the typical imaging characteristics of a renal cell carcinoma. Two low-density regions within the periphery of the right lobe of the liver were suggestive of metastasis. The patient was treated with whole-brain irradiation and a boost to the occipital tumor. The tumor response was modest, and a very prominent mass remained in the occiput. The patient, however, felt well 15 months after completion of palliative radiation therapy. ve radiation therapy. Clinical Aspects.– The clinical manifestation of renal cell carcinoma is diverse and often mimics that of other conditions. The unusual and often deceptive initial features involve many areas and, thus, are of interest to a wide variety of physicians in clinical medicine. The original classic triad of flank pain, hematuria, and palpable mass occurs in only about 10% of patients.1Simons JW Marshall FF Kidney and ureter.in: Abeloff MD Armitage JO Lichter AS Niederhuber JE Clinical Oncology. Churchill Livingstone, New York1995: 1407Google Scholar In fact, the fortuitous detection of an asymptomatic renal cell carcinoma during the course ofvarious diagnostic studies is common-rates range between 25 and 30% of all cases,1Simons JW Marshall FF Kidney and ureter.in: Abeloff MD Armitage JO Lichter AS Niederhuber JE Clinical Oncology. Churchill Livingstone, New York1995: 1407Google Scholar but 25% of patients with renal cell carcinoma have distant metastatic lesions at the time of initial assessment.2Peterson RO Urologie Pathology. Lippincott, Philadelphia1986: 91Google Scholar Approximately 30% of patients have a paraneoplastic syndrome produced by ectopic secretion of various hormones or hormonelike substances (parathyroid hormone, prostaglandins, erythropoietin, prolactin, renin, insulin, glucagon, gonadotropins, and glucocorticoids). The various symptoms caused by these substances can make the diagnosis difficult; their presence, however, is not necessarily indicative of metastatic disease.3Dayal HH Wilkinson GS Epidemiology of renal cell cancer.Semin Urol. 1989; 7: 139-143PubMed Google Scholar Patients who have an asymptomatic renal cell carcinoma but who have signs and symptoms referable to a site of metastasis (as in our patient) have a diagnostically challenging subset of stage IV disease. A wide spectrum of metastatic sites (brain, eye, sinuses, oral cavity, salivary glands, thyroid gland, larynx, breast, heart, lungs, soft tissue, skin, bones, joints, testes, penis, prostate, and vagina) with an equally diverse spectrum of clinical manifestations has been reported.2Peterson RO Urologie Pathology. Lippincott, Philadelphia1986: 91Google Scholar Usually, the single clinically dominant metastatic site reflects widely disseminated disease. The literature as far back as 65 years has frequent references to renal cell carcinoma initially manifesting as metastasis in unusual sites (Table 1).Table 1Reports of Renal Cell Carcinoma Initially Manifesting in Unusual SitesSite of metastasisClinical manifestationReferenceBrainNeurologic signs suggesting brain tumor or intracerebral hemorrhage4Hodgson TJ Howell SJ Kean DM Case report: metastatic renal cell carcinoma presenting as intracerebral haemorrhage.Clin Radiol. 1994; 49: 213-214Abstract Full Text PDF PubMed Scopus (3) Google Scholar, 5Gay PC Litchy WJ Cascino TL Brain metastasis in hypernephroma.JNeurooncol. 1987; 5: 51-56Crossref PubMed Scopus (65) Google Scholar, 6Chute R Ireland Jr, EF Houghton JD Solitary distant métastases from unsuspected renal carcinomas.J Urol. 1958; 80: 420-424PubMed Google Scholar, 7Melicow MM Uson AC Nonurologic symptoms in patients with renal cancer.JAMA. 1960; 172: 145-151Crossref Scopus (31) Google ScholarHypopituitarism8Horikoshi T Mitsuka S Kimura R Fukamachi A Nukui H Renal cell carcinoma metastatic to the hypophysis-case report.Neurol Med Chir (Tokyo). 1988; 28: 78-82Crossref PubMed Scopus (12) Google Scholar, 9Weiss RE Corvalan AH Dillon RW Metastatic renal cell carcinoma presenting as impotence.J Urol. 1993; 149: 821-822PubMed Google Scholar, 10McCormick PC Post KD Kandji AD Hays AP Metastatic carcinoma to the pituitary gland.Br J Neurosurg. 1989; 3: 71-79Crossref PubMed Scopus (166) Google ScholarCranial-extracerebral regionFrontal mass11Sunita Kapila K Singhal RM Verma K Fine needle aspiration diagnosis of an unusual presentation of metastatic renal cell carcinoma [letter].ActaCytol. 1991; 35: 260-261Google ScholarOccipital mass7Melicow MM Uson AC Nonurologic symptoms in patients with renal cancer.JAMA. 1960; 172: 145-151Crossref Scopus (31) Google Scholar, 12Molina M Ortega G de Paco M Seller G Solitary cranial metastasis as an initial manifestation of renal carcinoma [letter].Rev Clin Esp. 1991; 189: 196-197PubMed Google ScholarTrigeminal neuralgia, facial asymmetry13Vleeming R Dabhoiwala NF Bosch DA Ten years survival after recurrent intracranial métastases from a renal cell carcinoma.BrJ Neurosurg. 1994; 8: 229-231Crossref PubMed Scopus (2) Google ScholarPulsatile tinnitus, hearing loss14Vaughan WC Snyderman NL Head and neck manifestations of renal cell carcinoma.J Ark Med Soc. 1986; 83: 117-119PubMed Google ScholarHeadache—subdural bleed15Rothschild MA Maxeiner H Spontaneous subdural hemorrhage of natural cause in metastatic renal cell carcinoma.Beitr Gerichtl Med. 1990; 48: 223-227PubMed Google ScholarGarcin's syndrome16Mubaidin SI Sunna JB Beiruti MA Shennak MM Ayoub MS Renal cell carcinoma presenting as Garcin's syndrome.J Neurol Neurosurg Psychiatry. 1990; 53: 613-614Crossref PubMed Scopus (12) Google ScholarEpidural areaCord compression17Weigensberg IJ Metastatic renal carcinoma: unusual and deceptive presenting features.South Med J. 1972; 65: 611-616Crossref PubMed Scopus (18) Google ScholarCauda equinaCauda equina syndrome18Chauban R Cauda equina syndrome [letter].BrJHospMed. 1994; 51: 193Google ScholarEyeDecreased vision19Portnoy SL Arffa RC Johnson BL Terner IS Metastatic renal cell carcinoma of the iris manifesting as an intrastromal iris cyst [letter].Am J Ophthalmol. 1991; 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Hematogenous dissemination is by far the most important mechanism of metastasis. The route is renal vein to vena cava to right atrium to lung. Massive invasion of the renal vein or vena cava by a neoplastic thrombus is a distinguishing characteristic of renal cell carcinoma. Two other venous routes have some preferential localizations. The spermatic (or ovarian) vein allows reverse metastasis in the pelvic organs (ureter, urinary bladder, ovary, vagina, and penis), and the vertebral veins (or plexus of Batson), with their low pressure and inversion of flow, lead to preferential localization in the vertebral column, thyroid, and central nervous system. A palpable, pulsating mass with an audible bruit should alert the clinician to include renal cell carcinoma in the differential diagnosis. In a review of the literature, we found reports of two other patients whose initial manifestation of renal cell carcinoma was an occipital mass.7Melicow MM Uson AC Nonurologic symptoms in patients with renal cancer.JAMA. 1960; 172: 145-151Crossref Scopus (31) Google Scholar, 8Horikoshi T Mitsuka S Kimura R Fukamachi A Nukui H Renal cell carcinoma metastatic to the hypophysis-case report.Neurol Med Chir (Tokyo). 1988; 28: 78-82Crossref PubMed Scopus (12) Google Scholar, 9Weiss RE Corvalan AH Dillon RW Metastatic renal cell carcinoma presenting as impotence.J Urol. 1993; 149: 821-822PubMed Google Scholar, 10McCormick PC Post KD Kandji AD Hays AP Metastatic carcinoma to the pituitary gland.Br J Neurosurg. 1989; 3: 71-79Crossref PubMed Scopus (166) Google Scholar, 11Sunita Kapila K Singhal RM Verma K Fine needle aspiration diagnosis of an unusual presentation of metastatic renal cell carcinoma [letter].ActaCytol. 1991; 35: 260-261Google Scholar, 12Molina M Ortega G de Paco M Seller G Solitary cranial metastasis as an initial manifestation of renal carcinoma [letter].Rev Clin Esp. 1991; 189: 196-197PubMed Google Scholar A similar case in which the patient had a huge frontal mass also has been reported.11Sunita Kapila K Singhal RM Verma K Fine needle aspiration diagnosis of an unusual presentation of metastatic renal cell carcinoma [letter].ActaCytol. 1991; 35: 260-261Google Scholar Tissue Diagnosis.– The tissue diagnosis is often equally challenging. When the clear cell variant of renal cell carcinoma metastasizes in the setting of a known primary renal cell carcinoma, the pathologic diagnosis of metastatic renal cell carcinoma is not particularly difficult. When renal cell carcinoma manifests as metastatic disease (as occurs in approximately 10% of cases), however, the diagnostic possibilities must include clear cell tumors both primary and metastatic to the organ of involvement. In our patient, the occipital lobe of the brain was partially involved by metastatic renal cell carcinoma (Fig. 4). Primary brain tumors with clear cell features include mainly hemangioblastomas and rarely gliomas such as oligodendroglioma and meningiomas.63a The most common tumors to metastasize to the brain include, in decreasing order of frequency, metastatic neoplasms from the lung, breast, skin (melanoma), and kidney.63Burger PC Scheithauer BW Vogel FS Surgical Pathology of the Nervous System and Its Coverings. 3rd ed. Churchill Livingstone, New York1991: 373-386Google Scholar, 64Aronson SM Garcia JH Aronson BE Metastatic neoplasms of the brain: their frequency in relation to age.Cancer. 1964; 17: 558-563Crossref PubMed Scopus (93) Google Scholar Like most tumors metastatic to the brain, meta static renal cell carcinomas usually form a fairly delimited nodular mass surrounded by reactive brain parenchyma. They also contain some degree of fibrosis. These features are in contrast to those of primary brain tumors, which usually have less distinct borders, exhibit an infiltrative pattern with an admixture of reactive glial cells, and have a generally sparse degree of collagen production.65Bitoh S Hasegawa H Ohtsuki H Obashi J Fujiwara M Sakurai M Cerebral neoplasms initially presenting with massive intracerebral hemorrhage.Surg Neurol. 1984; 22: 57-62Abstract Full Text PDF PubMed Scopus (77) Google Scholar Histologically, renal cell carcinomas are characterized by their trabecular growth pattern in which the tumor cells infiltrate in somewhat ill-defined nests that are demarcated by thin strands of fibrous tissue. This nesting growth pattern can be highlighted by the cytochemical stain for reticulin. The tumors are usually vascular. Cytologically, the tumor cells are characterized by oval, centrally placed nuclei with conspicuous nucleoli. Cytoplasm is moderately abundant and can be either clear or eosinophilic (granular). The clear cell type of tumor (so-called hypernephroma) is the most common histologic variant of renal cell carcinoma and accounts for roughly 70% of all primary carcinomas. This variant derives its clear cytoplasmic color from its rich lipid and glycogen content. In general, almost all common tumor types, regardless of cell type or origin, have been reported in the literature as having clear cell variants. These clear cell features, by definition, must reflect a metabolic state that facilitates accumulation of intracytoplasmic macromolecules (lipid and carbohydrate), which are lost to varying degrees during the processing necessary to stain a tissue section for microscopic analysis. Despite this loss, tumor antigen expression, as determined with immunoperoxidase techniques, frequently allows identification of the specific cell type.66Drier JK Swanson PE Cherwitz DL Wick MR S100 protein immunoreactivity in poorly differentiated carcinomas: immunohistochemical comparison with malignant melanoma.Arch Pathol Lab Med. 1987; 111: 447-452PubMed Google Scholar For example, so-called myoepithelial and glycogen-rich carcinomas of the breast usually have clear cell changes;67Chen PC Chen CK Nicastri ND Wait RB Myoepithelial carcinoma of the breast with distant metastasis and accompanied by adenomyoepitheliomas.Histopathology. 1994; 24: 543-548Crossref PubMed Scopus (65) Google Scholar however, the tumor cells of myoepithelial carcinomas stain not only for cytokeratin but also for S-100 protein and muscle-specific actin, an indication of the myoepithelial nature of these tumors.68Hull MT Warfel KA Glycogen-rich clear cell carcinomas of the breast: a clinicopathologic and ultrastructural study.Am J Surg Pathol. 1986; 10: 553-559Crossref PubMed Scopus (49) Google Scholar Rarely, melanomas can be predominantly clear cell in nature (balloon cell type). Disease metastatic from these tumors, however, typically exhibits more cytologic atypia than routinely seen in metastatic renal cell carcinoma, and it stains positively for the melanocytic markers S-100 protein and HMB-45.69Kao GF Helwig EB Graham JH Balloon cell malignant melanoma of the skin: a clinicopathologic study of 34 cases with histochemical, immunohistochemical, and ultrastructural observations.Cancer. 1992; 69: 2942-2952Crossref PubMed Scopus (94) Google Scholar It is extremely rare for sarcomas of soft tissue and bone to manifest as disease metastatic to the brain. With some degree of frequency, sarcomas have been reported to metastasize to brain parenchyma in patients who have undergone extensive chemotherapy for primary sarcomas.63b Clear cell sarcomas are a distinct histologic entity of soft tissue tumors that contain tumor cells with clear cytoplasm.70Mukai M Torikata C Iri H Mikata A Kawai T Hanaoka H et al.Histogenesis of clear cell sarcoma of tendons and aponeuroses: an electron-microscopic, biochemical, enzyme histochemical, and immunohistochemical study.Am J Pathol. 1984; 114: 264-272PubMed Google Scholar These tumors also have been classified as melanoma of soft parts and react with antibodies to S-100 protein.71Enzinger FM Weiss SW Soft Tissue Tumors. 2nd ed. Mosby, St. Louis1988: 945-951Google Scholar Metastasis of this tumor to an organ system other than the lungs or lymph nodes would be extremely rare. The clinical features in these instances should readily point to the most appropriate diagnosis. As previously noted, primary brain tumors with clear cell features include mainly hemangioblastomas. Like renal cell carcinoma, hemangioblastoma is a vascular neoplasm. Its cell of origin is unknown. Most originate in the cerebellum, usually in a hemisphere. Supratentorial tumors are uncommon, but when present are typically associated with von Hippel-Lindau disease. Hemangioblastomas are formed by a mixture of endothelial cells with accompanying pericytes and stromal cells. If the stromal cells predominate and grow in a lobular fashion, their morphologic appearance is strikingly similar to that of renal cell carcinoma. The cells have clear cytoplasm with distinct cellular borders. Complicating the clinicopathologic picture is the fact that patients with von Hippel-Lindau disease are at increased risk for hemangioblastoma and renal cell carcinoma. Distinguishing features between hemangioblastoma and metastatic renal cell carcinoma include a predominance of lipid over glycogen in the cytoplasm (in comparison with the abundant glycogen present in the cytoplasm of renal cell carcinomas). Consequently, periodic acid-Schiff stain usually is strongly positive in renal cell carcinoma and weakly positive or negative in hemangioblastomas. With immunoperoxidase techniques, hemangioblastomas will not react with monoclonal antibodies to such epithelial markers as keratin and epithelial membrane antigen. Renal cell carcinomas are often keratinpositive and frequently are epithelial membrane antigenpositive. Consequently, immunophenotypic analysis of a clear cell tumor in the brain usually distinguishes hemangioblastoma from metastatic carcinoma. Occasionally, primary glial and meningeal tumors of the brain can exhibit areas of epithelioid and clear cell differentiation. Tumors differentiating along the lines of oligodendrogliomas and meningiomas can have local areas of tumor cells that can mimic metastatic renal cell carcinoma in that they exhibit distinct cell borders, oval nuclei, and clear cytoplasm. Immunophenotypic analysis of glial tumors should readily distinguish between a primary glial neoplasm of the brain and a metastatic lesion. Reaction with antibodies to the glial fibrillary acidic protein and S-100 protein enables the pathologist to differentiate between a glioma and metastatic renal cell carcinoma. In addition, meningiomas should contain areas in which the cells exhibit a “whorled” growth pattern not seen in renal cell carcinomas. In general, clinical and radiologic features can often highlight differences between metastatic renal cell carcinoma and primary brain tumors; thus, treatment of extracted tissue with special stains is unnecessary. Our patient had a pulsating transcalvarial occipital suboccipital mass as the initial manifestation of an occult renal cell carcinoma. In a review of 128 articles (a complete list of references is available from the authors on request), we found metastasis described at about 50 different sites. Thus, a diverse spectrum of clinical symptoms can be the initial manifestation of an occult renal cell carcinoma. When renal cell carcinoma manifests as metastatic disease, the tissue diagnosis can be challenging. The differential diagnosis of primary clear cell tumors versus disease metastatic from a renal cell carcinoma is established according to their histologic and cytologic features.