Abstract
Primary angiosarcoma of the kidney is a rare tumor, hence little is known concerning its diagnostic features and therapeutic management. We conducted this survey to present a complete literature review with emphasis on clinicopathological features, diagnosis and therapy. A thorough search was conducted in MEDLINE/PubMed. All relevant studies concerning primary renal angiosarcomas in adults were thoroughly reviewed. Primary renal angiosarcoma is characterized by an overall poor prognosis, is of unknown etiology and occurs most commonly in males between 60 and 70 years old. Presence of distant metastasis at the time of diagnosis is prevalent. Histopathological examination and immunohistochemical studies are the most important diagnostic tools. Treatment options include surgery, chemotherapy, radiotherapy and immunotherapy. Conclusion: Primary renal angiosarcoma is a rare but aggressive malignancy with low response to available therapeutic regimens and dismal survival rates.
Angiosarcoma is an extremely rare and aggressive malignant tumor occurring in fewer than 2% of all soft-tissue sarcomas (1). Primary angiosarcoma arises most commonly from the skin, superficial soft tissue, liver, spleen, bone, and breast (2, 3). An exceedingly infrequent location is the kidney, which accounts for 1% of the total of angiosarcomas diagnosed (4). Primary renal angiosarcoma (PRA) has an overall dismal prognosis, with an estimated average life expectancy of 6 months. It is also referred to as renal hemangiosarcoma and was first described in 1942, with few reported cases since then. Its etiology is still unknown and its predisposing factors remain ill-defined (5, 6). However, case reports show development of PRA in patients with pre-existing renal angiomyolipoma or multicystic kidney disease (7, 8). White males between 60-70 years old are most commonly affected (9). Presenting symptoms in the majority of patients include flank pain, hematuria, anemia and palpable mass (3).
Initial diagnostic approach involves abdominal computed tomography (CT) and magnetic resonance imaging which may reveal a solitary renal mass. Further total body scan, which is indicated for TNM staging, may unveil distant metastatic lesions in the lungs, liver, bone, spleen, abdominal lymph nodes, peritoneum, or soft tissues (3). Histopathologically, it is defined by an angiomatous structure composed of atypical proliferation of endothelial cells, with epithelioid, spindle or histiocytoid characteristics, and anastomotic vascular channels (10). Biopsy and cytological characteristics combined with a positive immunohistochemical staining for CD31, CD34, factor VIII, vimentin, and friend leukemia integration 1 (FLI1) are the gold standard methods for the definitive diagnosis of PRA (6, 10). Prognosis is influenced by the extent of distant metastasis and tumor size (11, 12). The mainstay of treatment of PRA is surgical resection (12). Sequential chemotherapy with/without radiotherapy may be applied but the survival rate remains low (13). Other recent therapeutic approaches such as immunotherapy, molecular targeting therapy and anti-angiogenic agents can be promising, but these need to be further evaluated (3, 14). The aim of this study was to systematically review the literature on PRA and report epidemiological, clinicopathological, diagnostic and therapeutic data for this rare entity.
Epidemiology
Sarcomas, tumors of mesenchymal origin, are generally considered to be rare nosologic entities, accounting for fewer than 1% of all adult solid malignancies. Analyses of the Surveillance, Epidemiology and End Results database from 1973 to 2008 underlined that the sweeping majority of all diagnosed sarcomas were of soft-tissue origin, while the remaining diagnoses were malignant bone tumors (15). Angiosarcomas are an infrequent and aggressive subtype of soft-tissue sarcomas, occurring in fewer than 2% of all soft-tissue sarcoma cases with endothelial cell origin. While cutaneous angiosarcoma of the scalp and face is the most prevalent form, primary angiosarcoma of the kidney involves only 1% of all angiosarcomas, indicating its absolute rarity. The general peak incidence of angiosarcoma is the seventh decade, although any age group can be affected (16). The distribution between sexes is practically identical and this is clearly highlighted by epidemiological research of the National Cancer Data Base of the American College of Surgeons, which revealed that hemangiosarcomas are marginally more common in women, with a sex predilection of 1.08/1.00 (17). Regarding PRA, Omiyale et al., conducting a review of 62 PRA cases, reported the occurrence of the disease in only seven women, suggesting that the tumor predominantly affects men, with a male to female ratio of 7:1. Unambiguous data of this research also pointed out that the vast incidence of the disease occurred in the sixth and seventh decades, while the mean age of diagnosis was 61 years (range=24-95 years). As far as tumor location is concerned, the left kidney was involved in 66.7% of the patients. Familial predisposition was not detected (18-20).
Histopathology and Classification
Histological examination of PRA reveals a mixture of spindle and epithelioid cells, lining anastomosing vascular channels (3, 13, 21). Different morphological features are determined by the degree of cellular atypia, categorizing the tumor from well-differentiated (low grade) to poorly differentiated (high grade) (13). According to the literature, there is no specific and official classification of PRA. However, Singh et al. classified this neoplasm as classic PRA or epithelioid renal angiosarcoma (ERA), depending on the predominance of a spindle or epithelioid pattern of cells, respectively (22, 23). ERA has been described by many case reports as a divergent and infrequent manifestation of PRA, based on the exhibition of fundamental cell morphological and immunohistochemical discrepancies (10, 12, 18, 22, 24, 25). Co-existence of PRA with other renal tumors and pathologies can modify the conventional histological features. Cases of PRA arising in patients with pre-existing angiomyolipoma, schwannoma and multicystic kidney disease have been reported (7, 8, 26). The above manifestations need to be further assessed for the histological delineation and classification of PRA, which is already demanding due to its rarity.
Histopathological analysis, either from the specimen of resected tumor or from samples of preoperative core biopsy, is of great importance in order to confirm suspicion of PRA based on clinical and imaging data. A hemorrhagic or necrotic renal mass with dimension ranging from 3.7 to 30 cm (mean=13 cm) represents the macroscopic traits of PRA, which commonly infiltrates the perirenal fat and perinephric soft tissue (13, 18, 21). Microscopically, conventional smears reveal a histological pattern of anastomosing vascular channels lined by varyingly differentiated endothelial cells that are partly filled by erythrocytes (13). In the poorly differentiated phenotype, endothelial cells create a less obvious vasoformative configuration, becoming atypical and spindle or epithelioid in shape (18). These cells are arranged in multiple layers, occasionally forming intraluminal papillary projections (3, 10). On the other hand, the well-differentiated phenotype includes distinct vascular channels lined by a single layer of neoplastic cells with pleomorphic and hyperchromatic nuclei, immiscible cytoplasm and prominent nucleoli (10). Classic PRA, which concerns the majority of cases, consists predominantly of spindle and elongated cells. In contrast, the predominance of epithelioid mild-moderate pleomorphic and round-polygonal cells is clearly reported in ERA (12, 25).
Distinction between subtypes of PRA based on morphological patterns is also highlighted by immunohistochemical studies. Most tumor cells exhibit positive immunoreactivity for endothelial markers, such as CD31, CD34, vimentin, factor 8-related protein and FLI1 but are negative for cytokeratins 8/18, CD10, S100, renal cell carcinoma (RCC)-marker, melan-A and human melanoma black 45 (HMB-45) (13, 22). For ERA, as well as for CD31, CD34, and FLI-1, tumor cells demonstrate positive staining both for epithelioid low-molecular-weight cytokeratins 8/18, B72.3, epithelial membrane antigen and broad-spectrum cytokeratin AE1/AE3 (12, 25). Expression of Ki-67 corroborates the highly proliferative behavior and aggressiveness of this tumor type (18). The neuroendocrine differentiation of the tumor, proven by the expression of neuroendocrine markers chromogranin A and synaptophysin, has been encountered in only one case (27). This finding should be further investigated for the avoidance of a potential diagnostic misunderstanding.
Diagnostic Approach
PRA shares similar clinical manifestations with other renal tumors, such as RCC. The most prevailing symptom of these tumors is flank pain, which starts when the expanding mass compresses adjacent nerves and muscles. Other common clinical features include hematuria, palpable mass in the flank or abdomen, weight loss, fever and general malaise (28). In addition, fatigue, dizziness, anemia and hemoptysis are frequent symptoms in many patients with PRA (3, 18). Anorexia, flank or costal swelling, ureteric obstruction, cough and spontaneous rupture of the tumor with consequent retroperitoneal hematoma have also been reported (18, 29-31). Benns et al. reported that patients with soft-tissue sarcomas, including PRA, may initially present with deep vein thrombosis (32). The existence of other pathological entities that resemble PRA, either clinically or on imaging studies, demonstrates the critical importance of an appropriate diagnostic approach which sequentially determines the therapeutic management. Considering the absence of guidelines for PRA diagnosis, we reviewed literature evidence for laboratory, imaging and immunohistochemical studies in order to propose a proper and more specific diagnostic pathway.
Laboratory and imaging examinations. Primary symptoms including flank pain, gross hematuria and palpable mass in the abdomen with also non-specific fever, weight loss and hemoptysis, reflect a disease originating from the genitourinary system. Based on limited case reports, initial routine laboratory blood tests mainly show the presence of anemia while remaining blood tests and tumor marker levels, including that of carcinoembryonic antigen (CEA), are within standard limits. Apart from confirmed hematuria, urinalysis is normal (6, 33, 34). Ultrasound, revealing a solid renal mass with heterogeneous echo, cannot reliably differentiate benign from malignant behavior nor histological subtypes of the tumor (30, 35, 36). However, color Doppler ultrasound examination may reveal a centrally avascular and peripherally hypervascular round-shaped tumor, a feature that indicates a malignant condition (36). The ultrasound presentation of normal kidney with perirenal hematoma should not be underestimated. Hematoma may hide a ruptured solid PRA or RCC mass, and thus must be further evaluated on CT (31, 37). Contrast-enhanced CT is compulsory for the staging workup of the tumor, detecting potential lymph node infiltration and metastatic lesions. PRA is commonly depicted as a well-demarcated heterogeneous renal mass with rapid peripheral enhancement on cortico-medullary phase. It is also characterized by fast wash out of the contrast agent followed by delayed central filling on nephrographic or excretory phase (6, 13, 33, 38, 39). Interestingly, in contrast to sarcomas, RCC has the pathological tendency to invade the renal vein or inferior vena cava (40). Coexistence of previous CT characteristics with small lesions in the liver or lungs may be interpreted as metastases from the primary renal tumor.
Concerning metastatic rates, the latest review conducted by Li et al. showed that 38 out of 55 patients (69%) had metastatic disease at the time of diagnosis or shortly afterwards, while 26 out of 55 patients (47%) presented with two or more metastatic sites (19). Although sarcomas usually spread via the vascular system, angiosarcomas can also involve local lymph nodes (20). The liver, lungs and bones are the most common metastatic sites (19). Other secondary lesions can include the peritoneum, chest wall, skin, spleen, soft tissue, abdominal lymph nodes and renal veins (18).
Magnetic resonance imaging signal characteristics include intermediately high intensity on T1-weighted images. The hyperintense peripheral rim indicates the presence of a peripheral capsule. Alternating areas of high and low signal intensity on T2-weighted images are also demonstrated (9, 41). Signal voids in the periphery of the mass with a tangled mesh of tumor vessels correspond to vascular channels (9, 33). A striated presenting pattern on T2-weighted magnetic resonance imaging is a strong imaging finding suggestive of PRA (9). Despite these described PRA features, no pathognomonic radiological signs have been reported. Since there is a considerable overlap between the aforementioned clinical, laboratory and imaging data for PRA, a few subtypes of RCC and retroperitoneal hematoma, the differential diagnosis includes these entities. In the case of no metastatic lesions, anastomosing renal hemangioma and angiomyolipoma should also be considered (13).
Histopathological examination and immunohistochemistry. Definitive PRA diagnosis is made by histopathological and immunohistochemical studies either by preoperative core-needle biopsy or excisional postoperative biopsy. Although fine-needle aspiration is also mentioned, it is not suggested as an initial diagnostic method (42). Fundamental differences in morphological patterns and tissue markers single out PRA either from RCC or renal hemangioma and renal angiomyolipoma. Three subtypes of RCC, including clear-cell, papillary and chromophobe, may exhibit papillary characteristics or sarcomatoid differentiation commonly also encountered in PRA (13). However, the characteristic anastomosing vascular channels lined by a mixture of epithelial and spindle cells with various cell differentiation of PRA are lacking from these tumor types (13, 43, 44). Furthermore, features such as multilayering, hyperchromatic nuclei, atypical mitotic figures, irregular nuclear outline and spindle or polygonal cell appearance reflect the malignant behavior of PRA (10). In contrast, renal angiomyolipoma and hemangioma, lack these features as benign entities (13, 45). Immunoreactivity for certain endothelial markers clearly distinguishes PRA from other renal tumors. RCCs are positive for biomarkers such as CK7, alpha-methylacyl-CoA racemase, carbonic anhydrase IX and transcription factor enhancer 3 (46). Like PRA, positive staining for CD31 and CD34 is also found on renal hemangioma. However, smooth muscle actin is detected in the myxoid supporting stroma cells of hemangioma but not in angiosarcomas (47). Angiomyolipoma diagnosis is confirmed by the presence of positive reactivity for biomarkers such as melanocytic markers (melan-A and HMB-45 antigen) and smooth muscle markers (smooth muscle actin and caldesmon) for which PRA stains negatively (7, 48). Positive staining for CD31, CD34, vimentin, factor 8-related protein and FLI1 and negative for CK8/18, CD10, RCC-marker, S100, melan-A and HMB-45 are encountered only in classic PRA (13, 22).Based on the aforementioned data, we constructed a flow chart of the diagnostic procedure (Figure 1).
Therapeutic Management
Therapeutic approach of PRA is imprecise due to the paucity of literature data and lack of specific treatment guidelines. However, it is broadly accepted that surgical resection of the tumor constitutes the mainstay of treatment (18). This is clearly highlighted by the fact that 55 out of 57 affected patients (97%) with available treatment data in the literature underwent surgery, while one patient died shortly after diagnosis because of rapid disease deterioration (19, 24, 49). Radical nephrectomy was the optimum choice for 54 patients and only one patient underwent nephroureterectomy. Radical nephrectomy includes the removal of the entire kidney along with perirenal fat, while lymph node and adrenal gland dissection is not always required (50). There are insufficient instructions for the appropriate surgical intervention when PRA invades the renal vein or the inferior vena cava because of the extreme rarity of the condition. Based on RCC knowledge, proper surgical management is radical nephrectomy with tumor thrombectomy and lymph node dissection. Complex resection and reconstruction of the inferior vena cava is not always implemented and depends on the degree of venous occlusion (51). As far as adjuvant therapeutic modalities incorporated in surgery are concerned, there are numerous variations reported in the literature. Among 54 patients who underwent nephrectomy in the aforementioned surveys, 31 were only submitted to complete surgical resection.
In addition to surgery, in Li et al.'s study, chemotherapy was selected for 10 patients, radiotherapy in seven and the combination of chemotherapy and radiotherapy in five cases (19). These data are illustrated in Figure 2. Because of the absence of standard chemotherapy agents intended for PRA, a large variety of chemical substances have been administered. Paclitaxel-based chemotherapy, doxorubicin and the combination of ifosfamide with epirubicin, doxorubicin or anthracycline have been reported (2, 5, 52-55). One study reported the use of oxaliplatin with paclitaxel followed by bevacizumab, but unfortunately patients did not respond (34). Carboplatin with etoposide and vincristine was the applied chemotherapy for a patient with a mixed adult Wilms' tumor and PRA. The impressive response may indicate that PRA might be effectively treated using agents reserved for Wilms' tumor (56). There is only one case where the patient was treated with immunotherapy, specifically with recombinant interleukin-2 (14).
Given that 34 out of 49 patients (69%) with available outcome data in the review of Li et al. died because of their tumor and only four out of 49 (8%) were healthy with no evidence of disease, it can be assumed that none of the available treatments are effective and the role of chemotherapy and radiotherapy remains controversial (19). Zenico et al. reported that patients with the best response underwent chemotherapy and radiotherapy and survived for almost 13 months, compared to those who only underwent nephrectomy and survived about 7 months. However, they emphasize that none of these patients presented with metastatic disease at the time of diagnosis (5). Although studies support that radiotherapy in combination with nephrectomy can benefit local control of the disease, others assume that the administration of adjuvant chemotherapy is necessary (18).
Because of the scarcity of standard therapeutic management and the difficulty of performing research on PRA due to the low number of cases, we propose that successful treatment approaches for other types of angiosarcomas might be applied to PRA. Concerning management of localized angiosarcoma, the only clearly curative method is surgical resection. However, according to retrospective data, adjuvant radiation might improve local disease control and survival rates, particularly in those with microscopically positive surgical margins. There are no data supporting the notion that adjuvant chemotherapy improves overall survival and recurrence-free rates, however neoadjuvant chemotherapy may play a pivotal role in patients with unresectable disease in creating a surgical opportunity. Further research is crucial in order to clarify the potential benefits of adjuvant radiation and chemotherapy in localized disease (57).
Regarding management of metastatic disease, no standard chemotherapy agents have been established. There are several cytotoxic and targeted therapy options that potentially could prove to be efficient but metastatic angiosarcoma remains incurable and lethal (57). Anthracycline-based regimens, such as doxorubicin, are traditionally the treatment of choice for advanced soft-tissue sarcomas, thus allowing its utilization for angiosarcomas (58). Young et al. reported the combination of doxorubicin and ifosfamide to be associated with better progression-free and overall survival in angiosarcoma compared to single-agent anthracycline (59). Tap et al. demonstrated that doxorubicin combined with olaratumab, a recombinant human monoclonal antibody against platelet-derived growth factor receptor alpha, may possess first-line activity for metastatic angiosarcoma because of the significant enhancement in median overall survival noted (60). Pegylated liposomal doxorubicin is an appealing option, particularly in patients with angiosarcoma who cannot tolerate classic doxorubicin. Its physical characteristics allow its precise deposition into the tumor, leading to reduced toxicity (57, 61).
Taxanes represent a supreme option due to angiosarcoma's high sensitivity. Paclitaxel monotherapy is considered to be first- or second-line therapy for metastatic angiosarcoma. Singe-agent gemcitabine or gemcitabine–docetaxel combination is also feasible second-line regimens for soft-tissue sarcomas (57). It is obvious that both anthracycline- and taxane-based chemotherapy are active against angiosarcomas, but the ideal selection remains ambiguous. Penel et al. reported that the choice is determined by previous anthracycline exposure and underlying co-morbidities. However, more head-to-head randomized controlled trials are required to prove a drug's superiority (62).
As far as more unconventional agents are concerned, tyrosine kinase inhibitors constitute an alternative treatment. There are limited clinical trials or case reports available proving the efficacy of sorafenib, pazopanib, sunitinib and regorafenib. More thorough data on tyrosine kinase inhibitor usage in angiosarcoma treatment are required (57). The beneficial application of propranolol, a nonspecific inhibitor of β-1 and β-2 adrenergic receptors, in many patients with angiosarcoma is interpreted to be the result of high levels of adrenergic receptors expressed in the tumor which substantially inhibit its expansion. Promising results on patient responses have been reported, but only when propranolol was combined with other cytotoxic agents, hence further studies are needed for the evaluation of this drug (63). Immunotherapy might be a future option and studies have examined the activity of pembrolizumab, a monoclonal antibody to programmed cell death protein 1 (PD1), against soft-tissue and bone sarcomas with auspicious results (57) Ongoing trials are investigating the effectiveness of other immunotherapy agents in angiosarcoma and its feasible incorporation in future regimens (57). Due to overexpression of vascular endothelial growth factor and its receptors in angiosarcomas, the monoclonal antibody bevacizumab has been examined in a phase II study as a treatment option for angiosarcoma (64). The results were remarkable, with several patients showing partial response and stable disease (65). In contrast, Ray-Coquard et al. reported no advantage of adding bevacizumab to paclitaxel for advanced angiosarcoma (66). This may be explained both by the small sample size of the study, thus the statistical inability to draw strong conclusions, and the fact that some angiosarcomas expressed members of the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway, leading to possible resistance to bevacizumab (67). Further evaluation of bevacizumab as a single agent or in combination with a chemotherapeutic agent is obviously warranted and biomarkers are required in order to determine the patients most likely to respond (68).
In conclusion, PRA is a rare but aggressive malignancy with low responses to available therapeutic regimens and dismal survival rates. Based on general therapeutic management of angiosarcomas, surgical resection, with or without radiotherapy, remains the mainstay of treatment for localized disease. Although surgery constitutes the optimal option for every PRA case, standard effective treatment for metastatic PRA is still unclear and challenging (57). Finally, experience from large centers indicates that combined modality therapy is associated with significantly improved overall and recurrence-free survival. However, larger clinical trials are required (69). Further investigation focusing on both tumor molecular pathophysiology and expression of specific pathways is considered crucial in order to better design future systemic therapies and establish treatment guidelines.
Footnotes
Authors' Contributions
Aikaterini Mastoraki, Pantelis Vassiliu, Emmanouil Pikoulis and Theodore Liakakos designed the study; Aikaterini Mastoraki, Dimitrios Schizas, Timoleon Giannakas and Panagiotis Podromos Papadopoulos collected relevant clinical data; Dimitrios Schizas, Leon Naar, Chrysovalantis Vergadis and Ioannis Anastasiou analyzed the data and wrote the article.
Conflicts of Interest
The Authors declare that no conflicts of interest exist.
- Received January 3, 2020.
- Revision received January 20, 2020.
- Accepted January 21, 2020.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved