Carcinosarcoma of the upper urinary tract with an aggressive angiosarcoma component

ABSTRACT

Carcinosarcomas (CS) are biphasic tumors with malignant epithelial and mesenchymal elements. The sarcomatoid elements of CS can include chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, fibrosarcoma, or liposarcoma. CS of the upper urinary tract are extremely rare but are associated with a poor prognosis. We report a case of a 44-year-old man with a localized right renal pelvis mass treated with a right nephroureterectomy. The pathological examination showed a high-grade urothelial carcinoma of the renal pelvis, stage III (pT3aNxM0). A few days later, he developed lower back pain, hematuria, cough with hemoptoic sputum and progressive dyspnea. Radiological explorations showed multiple bilateral lung nodules and a retroperitoneal mass. A CT-guided biopsy of the retroperitoneal mass revealed a high-grade angiosarcoma. A review of the nephrectomy specimen showed a microscopic focus of angiosarcoma in the urothelial carcinoma. Therefore, the initial diagnosis was changed to CS of the renal pelvis with an angiosarcoma component. The patient developed progressive respiratory failure and died 8 weeks after surgery. An autopsy revealed a large retroperitoneal mass with metastatic nodules to the abdominal wall, diaphragm, small intestine, liver, spleen, and lung. All lesions were angiosarcoma, with no evidence of urothelial carcinoma. This is the first case reported of a patient with CS of the upper urinary tract with an angiosarcoma component with a very aggressive course that caused the immediate appearance of multiple angiosarcoma metastases. We also describe the clinical and molecular characteristics of CS, which will help to contribute to a better understanding of this type of tumor.

Case

In late November 2010, a 44-year-old man, current smoker (30 packs/year), was admitted to our hospital with progressive macroscopic hematuria. An ultrasound scan revealed a mass of 6 × 6.5 × 7.5 cm in the right renal pelvis. Abdominal CT scan confirmed the evidence of a mass in the right kidney, without evidence of distant metastasis. On December 2nd, 2010, a right laparoscopic nephroureterectomy was performed, and pathological examination showed a papillary proliferation of urothelial cells with severe atypia and pleomorphism, infiltration of renal parenchyma without angiolymphatic or perineural invasion and negative surgical margins. The tumor was categorized as high-grade urothelial carcinoma of the renal pelvis, stage III (pT3aNxM0).

During the first days of the post-operative period, the patient had lower back pain that irradiated to the right thigh and rapidly increased in intensity and that was not controlled with non-opiate analgesic. Furthermore, he developed hematuria, cough with hemoptoic sputum and progressive dyspnea. On clinical examination, his Easter Cooperative Oncology Group (ECOG) performance score was 2, with pulmonary rales and intense pain at palpation of the lumbar zone. Laboratory tests showed severe anemia (hemoglobin 7.3 g/dL), elevated acute phase reactants (white blood cell count 23.2 × 109/L, erythrocyte sedimentation rate 82mm/h and C-reactive protein 211mg/L), procalcitonin of 0.24ng/mL (normal range, 0–0.4ng/mL), and lactate dehydrogenase of 394 U/L (normal range, 100–250U/L). Creatinine, hepatic function tests and calcium levels were normal. A chest X-ray showed bilateral nodular lung infiltrates. A magnetic resonance of the spine 5 weeks after surgery revealed focal, nodular lesions at dorsal, lumbar and sacrum, with incipient signs of medullary compression in the dorsal vertebral bodies. In addition, abdominal CT scan showed a polynodular, heterogeneous, necrotic and cystic mass in the retroperitoneal area, from the right diaphragmatic crura, extending toward the retroaortic space and infiltrating the psoas muscle at the 2nd and 3rd lumbar vertebrae. A cystoscopy showed only large clots in the bladder. New pulmonary nodular and alveolar infiltrates progressively appeared. Microbiological studies were negative. A fibrobronchoscopy showed hematic rests in the bronchial tree, with left predominance, without evident endobronchial lesions or signs of active bleeding. The biopsy and cytology were negative for malignancy, and microbiological studies were negative.

A CT-guided biopsy of the retroperitoneal mass revealed a proliferation of anastomosing vascular channels, covered by atypical endothelial cells, with infiltration of striated muscle fascicles of the psoas muscle. Inmunohistochemical studies were positive for CD31 and vimentin and negative for cytokeratins, corresponding to high-grade angiosarcoma. These findings prompted us to perform a detailed review of the nephrectomy specimen, which showed a microscopic focus of sarcomatoid pattern (angiosarcoma) in the urothelial carcinoma. This sarcomatous component was also positive for vimentin and CD31. Therefore, the initial diagnosis was changed to carcinosarcoma (CS) of the renal pelvis with an angiosarcoma component (Fig. 1, left, urothelial carcinoma. Arrow indicates microscopic angiosarcomatous component).

Figure 1.

CS of the upper urinary tract with an angiosarcoma component (Left, urothelial carcinoma; Arrow indicates microscopic angiosarcomatous component.) that caused immediate appearance of distant metastases of angiosarcoma (Right, angiosarcoma lung metastasis).

While hospitalized, the patient suffered severely increasing pain requiring treatment with high-dose morphine, persistent macroscopic hematuria with secondary anemia, and progressive respiratory failure. He died in January 25 2011, 8 weeks after surgery. The postmortem examination revealed a large retroperitoneal mass extending from the nephrectomy area to the right psoas muscle, with infiltration of the wall of the ascending colon and the lumbar paravertebral space, with metastatic nodules to the abdominal wall, diaphragm, small intestine, liver, spleen, and lung. The pathological analysis revealed that all the lesions were angiosarcoma, with no evidence of urothelial carcinoma (Fig. 1, right, angiosarcoma lung metastasis).

Discussion

CS, also called malignant mesodermal/müllerian tumors, metaplastic carcinomas or sarcomatoid carcinomas with or without heterologous differentiation, are biphasic tumors with malignant epithelial and mesenchymal elements.^1,3 The sarcomatoid elements of CS can include chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, fibrosarcoma, rhabdomyosarcoma and, rarely, liposarcoma.² The mesenchymal element of CS lacks epithelial markers and is considered a true heterologous sarcoma, while the mesenchymal element in sarcomatoid carcinoma retains the expression of epithelial markers.^2,8 Recently, it has been suggested that CS simply represent different points on a continuum between epithelial and mesenchymal differentiation.^2-7

CS are extremely rare but aggressive tumors that usually arise in the uterus in women and in the bladder in men. From 1988 to 2003, only 0.09% of high grade bladder cancers were CS, and the age-adjusted incidence was 2 per 10,000,000 persons per year.⁹ CS in the bladder occurs more often in elderly men and is a highly malignant tumor, with a greater risk of death than urothelial carcinoma.¹⁰ CS of the upper urinary tract is even rarer, with only 12 cases reported until 2006,¹¹ compared to 14 cases of CS of the renal pelvis.^12,13 In seven patients with CS of the renal pelvis, the mesenchymal component was osteosarcoma or chondrosarcoma, and all of these patients had a poor prognosis.¹⁴

While the histogenesis of urothelial CS is yet to be well defined, overexpression and polysomy of EGFR, overexpression of p53, gain of chromosomes 3, 7 and 17, and loss of chromosome 9p212 are common genetic alterations in CS of the upper urinary tract, whereas c-kit or HER 2/neu alterations are not involved.¹ Two opposing theories of CS histogenesis have been proposed. The multiclonal theory (convergence hypothesis) regards CS as a collision tumor composed of the derivatives of 2 or more stem cells of separate epithelial and mesenchymal origin, which give rise to the carcinomatous and sarcomatous components, respectively.¹⁵ The monoclonal theory (divergence hypothesis) proposes that both carcinomatous and sarcomatous elements are derived from a single pluripotent stem cell that subsequently diverges along separate epithelial and mesenchymal pathways.^4,16 Findings from several studies lend support to the divergence hypothesis.^17-20 For example, studies examining loss of heterozygosity in patients with CS of the bladder found identical patterns between the epithelial and sarcomatoid components of the tumors,^18-20 although identical patterns were more frequent in genetic alterations related to early events in bladder carcinogenesis rather than those associated with later events.^18,20 In addition, identical TP53 mutations and concordant p53 expression patterns were detected in both the epithelial and sarcomatoid tumor components in 5 of 17 patients with CS of the urinary bladder.¹⁷ In our case, however, TP53 sequencing of exons 5, 7 and 8 in the urothelial carcinoma and in the angiosarcoma tissue failed to detect TP53 mutations, and immunostaining for p53 was positive in a very low percentage of cells in both components.

The recommended optimal treatment for CS is not well established. There is no standard radiotherapy or chemotherapy regimen although response to cisplatin and gemcitabine has been observed in some cases.²¹ Although radical surgery is recommended, local recurrence and/or metastases frequently occur after surgical resection, and in 8 cases of CS of the upper urinary tract, median survival after surgical resection was only 8.2 months.¹

Metastases of CS usually have a mixed histology, with epithelial predominance. Few case reports include a pathologic description of the metastases. One Japanese report described metastases of chondrosarcoma in liver, lung and bone and mixed metastasis in skin.²² Another report described an early local recurrence as a pure high-grade sarcoma of undetermined phenotype.²³ A third reported that both the carcinomatous and sarcomatous elements of the tumor metastasized separately to different organs.²⁴ In a fourth case, the autopsy showed recurrence of a chondrosarcoma component.²⁵

In the case reported here, although angiosarcoma was found only as a microscopic focus in the primary tumor at the nephroureterectomy, it spread rapidly, causing rapid deterioration that precluded the administration of chemotherapy. The patient died 8 weeks after surgery with multiple angiosarcoma metastases, whereas the urothelial component was not present in the postmorten examination. This case report illustrates the importance of a detailed histologic evaluation for the correct diagnosis of CS, especially in patients with an atypical evolution of urothelial carcinoma.

To the best of our knowledge, this is the first case reported of a patient with CS of the upper urinary tract with an angiosarcoma component. Interestingly, the angiosarcoma caused the immediate appearance of distant metastases with rapid evolution, and the patient died soon after the complete resection of the primary tumor. We postulate that this unusual case can contribute to a better understanding of this type of tumor.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.