Original Contribution
Human Immunodeficiency Virus–Associated Renal Cell Carcinoma: A Transatlantic Case Series Elizabeth M. Gaughan1 Bruce J. Dezube1 David Aboulafia2 Mark Bower3 Justin Stebbing4 Thomas Powles5 Liron Pantanowitz6 1Department of Medicine (Hematology-Oncology Division),
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 2Department of Medicine, Division of Hematology and Oncology, Virginia Mason Medical Center, University of Washington, Seattle 3School of Medicine, Chelsea and Westminster Hospital, Department of Oncology 4School of Medicine, Charing Cross Hospital, Department of Medical Oncology, Imperial College, London, UK 5Department of Medical Oncology, St Bartholomew’s Hospital, West Smithfield, London, UK 6Department of Pathology, Baystate Medical Center, Tufts School of Medicine, Springfield, MA
Clinical Genitourinary Cancer, Vol. 6, No. 2, 86-90, 2008 Keywords: Hematuria, Highly active antiretroviral therapy, Interleukin-2, Immunosuppression DOI: 10.3816/CGC.2008.n.013 Submitted: Jan 15, 2008; Revised: Mar 17, 2008; Accepted: Mar 24, 2008 Address for correspondence: Bruce J. Dezube, MD Department of Medicine (Hematology-Oncology Division) MASCO 414, Beth Israel Deaconess Medical Center 330 Brookline Ave, Boston, MA 02215 Fax: 617-632-9296; e-mail:
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Abstract Objective: The spectrum of diseases associated with human immunodeficiency virus (HIV) infection has changed dramatically following the introduction of highly active antiretroviral therapy (HAART). Non–AIDSdefining cancers, including renal cell carcinoma (RCC), are being recognized increasingly in this population. Our aim was to describe the risk factors, clinical findings, pathology, and response to therapy of RCC in patients infected with HIV. Patients and Methods: We identified 9 men with HIV infection who developed RCC. Data regarding their HIV status, RCC risk factors, clinical presentation, and pathology were collected. A detailed retrospective chart review focusing on the course of their malignancy, response to therapy, and outcome was performed. Results: Renal cell carcinoma was diagnosed in patients with a median age of 48 years, and most had a history of tobacco use. No association between HIV-related immunosuppression (mean CD4 count, 301 cells/mm3) and the development, clinical presentation, pathology, or behavior of RCC was identified. Long-term survival correlated with early nephrectomy, and the use of interleukin-2 therapy for advanced RCC was not additive. A total of 5 patients died, 1 from a pulmonary embolism and 4 from disseminated RCC. Conclusion: Renal cell carcinoma should be included in the expanding array of non–AIDS-defining malignancies that develop during the course of HIV infection. Acknowledging the inherent limitations of our small study, these data show that the clinical presentation and behavior of RCC in patients with HIV appear similar to that of the HIV-negative population and that chronic immunosuppression plays a lesser role than age and exposure to risk factors in this setting.
Introduction The use of highly active antiretroviral therapy (HAART) has resulted in a large number of older individuals living with chronic human immunodeficiency virus (HIV) infection.1 Although this population has seen a substantial decline in AIDS-defining malignancies (eg, non-Hodgkin lymphoma and Kaposi’s sarcoma), an increase in several other non–AIDS-defining malignancies has been noted.2 Epidemiologic studies have identified higher rates of several carcinomas (lung, skin, conjunctiva, anal, and liver), hematologic malignancies (Hodgkin lymphoma, leukemia, and plasma cell neoplasia) and other neoplasms (melanoma, leiomyosarcoma) in patients with HIV living in the HAART era.2 In the case of non–AIDS-defining malignancies, HIV-induced immunosuppression appears to play a lesser role than lifestyle habits (eg, smoking) and viral co-infection (eg, human papillomavirus, Epstein-Barr virus, and hepatitis C virus) compared with those of AIDS-defining malignancies, in which immunosuppression is a key player in disease pathogenesis. To date, a link between HIV infection and the development of renal cell carcinoma (RCC) has been reported in a limited number of publications.3-6 Analysis of linked population-based AIDS and cancer registry data (1978-1996)
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Table 1 Characteristics of 9 HIV-Positive Men with Renal Cell Carcinoma CD4 Count HIV Viral Load (Cells/mm3) (Copies/mL)
RCC Risk Factors
Comorbidity
HAART at Diagnosis
< 75
Tobacco, hypertension, CRI
Alcohol abuse, gastritis, dyspnea, colon polyps
No
234
< 75
Tobacco
Herpes zoster
Yes
Tobacco
None
Yes
Case
Age (Years)
Race
1*
53/59
B
731
2
37
B
3
56
W
< 200
< 75
4
74
W
200
> 100,000
Tobacco
Prostate cancer
Yes
16,855
Tobacco
Stage IVA high-grade T-cell NHL
No
5
35
W
288
6
51
W
250
< 75
Tobacco
Kaposi’s sarcoma
Yes
Tobacco
NHL
Yes
7
40
W
261
8071
8
45
W
480
8300
None
Kaposi’s sarcoma
No
62
< 75
None
Mycobacterium tuberculosis
No
9
41
W
*Case
1 had RCC of the right kidney, diagnosed at age 53, and underwent resection. He had RCC of the left kidney, diagnosed at age 59, and underwent partial left nephrectomy. Abbreviations: B = black; CRI = chronic renal insufficiency; HAART = highly active antiretroviral therapy; NHL = non-Hodgkin lymphoma; RCC = renal cell carcinoma; W = white
from many geographically diverse areas in the United States, including 302,834 adults with HIV/AIDS, identified 100 people with HIV-associated RCC and demonstrated a relative risk of approximately 1.5 in this group compared with the general population.7 A metaanalysis of several studies involving 444,172 individuals with HIV/AIDS reported an increased incidence of RCC (standardized incidence ratio [SIR], 2.0) in patients with HIV compared with the general population.8 A retrospective case review conducted at a single medical center in the United States reported the prevalence of RCC in patients infected with HIV to be 8.5 times greater than in their non–HIV-infected population.5 Two similar studies have been reported from Africa. One study from Nigeria found that almost 10% of their patients with RCC in a 10-year period (1988-1998) had concurrent HIV infection.3 More recently, an epidemiologic study from Uganda reported an increased risk of the development of RCC in patients with HIV infection (SIR, 16.0).4 To date, there have been no studies investigating the specific risk factors, including immunosuppression, which might be responsible for the development and/or increased prevalence of RCC in persons positive for HIV. Moreover, the clinical manifestations, natural history, pathology, and management concerns of RCC in this setting have not been characterized. We present 9 cases of men infected with HIV who developed RCC and report on their associated risk factors, clinical findings, pathology, and response to therapy.
Patients and Methods Cases of HIV-associated RCC were identified from the personal archives of the authors. Patient medical records in each case were reviewed, and the following data elements were recorded: (1) patient demographics (age, sex, and race); (2) HIV status (CD4+ T-lymphocyte cell count and HIV viral load at diagnosis of RCC); (3) HIV-related conditions (AIDS-defining illness and opportunistic infections); (4) other medical comorbidity; (5) RCC risk factors (family history, genetic syndromes, smoking, hypertension, chronic renal insufficiency, dialysis); (6) HIV antiretroviral treatment at the time of RCC diagnosis; (7) clinical presentation of RCC; (8) tumor
pathology (Fuhrman grade); (9) extent of cancer (TNM stage); (10) RCC management; and (11) final outcome (alive or dead). Accrued data were analyzed using descriptive statistics.
Results A total of 9 patients with confirmed HIV infection and an established histopathologic diagnosis of RCC were identified (Table 1). All patients were male and had a median age of 48 years (range, 35-74 years). They were all known to have had HIV infection before their RCC diagnosis, and all had a moderate degree of immunosuppression (median CD4+ cell count < 300 cells/mm3; range, 62-731 cells/mm3) when they presented with their renal malignancies. Five (56%) of the patients were receiving HAART at the time of their RCC diagnosis. Four (44%) of the patients had a history of an AIDS-defining malignancy, and 2 patients had previous infections (tuberculosis and herpes zoster), before development of RCC. There was no history of opportunistic infections in any of our patients in the series. Seven (78%) of the patients had ≥ 1 known risk factor for the development of RCC, all of which had a history of tobacco use. One patient had both hypertension and chronic renal insufficiency (creatinine 2.5 mg/dL, glomerular filtration rate, 31 mL/min) before his diagnosis of RCC. None of the patients offered a history consistent with a genetic predisposition or cancer syndrome associated with RCC. The clinical presentation and pathologic findings of our study patients are summarized in Table 2. Six (67%) patients presented with ≥ 1 element of the classic clinical triad of RCC—flank pain, hematuria, and a palpable mass.9 All of the patients who presented with metastatic disease exhibited ≥ 1 symptom of the aforementioned triad. The most common sites of metastasis in our series were ipsilateral adrenal gland (Figure 1), retroperitoneal, and para-aortic lymph nodes, lung, and bone. Renal cell carcinoma was discovered incidentally on imaging performed for another reason (eg, lymphoma staging) in 3 patients. In each of these cases, the patients had T1 disease at diagnosis. Pathologic analysis showed that 6 of the patients
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Table 2 Pathologic Findings and Outcome of HIV-Associated Renal Cell Carcinoma Case
Presentation
Pathology
TNM Stage
Fuhrman Grade
Therapy
Outcome
1
1-Hematuria 2-Renal cysts
1-Papillary 2-Papillary
1-T1 N0 M0 2-T2 N0 M0
1-II 2-II
1-Surgery 2-Surgery
1-Alive 2-Alive
2
Flank pain, increased creatinine
Papillary
T3a N2 M1
IV
Analgesics
Died
3
Flank pain
Collecting duct
T3a N0 M1
IV
Surgery; radiation; IL-2
Died
4
Incidental
Clear cell
T1b N0 M0
II
Surgery
Died
5
Incidental
Clear cell
T1 N0 M0
II
Surgery
Alive
6
Incidental
Clear cell
T1 N0 M0
NR
Surgery
Alive
7
Hematuria
Clear cell
T2 N1 M1
IV
Surgery; IFN-AIL-2
Died
8
Hematuria
Clear cell
T3a N0 M0
III
Surgery
Alive
9
Hematuria
Clear cell
Tx N0 M1
IV
IFN-A
Died
Abbreviations: IFN = interferon; IL = interleukin; NR = not reported; TNM = tumor-node-metastasis
had clear (conventional)-cell RCC, 2 had papillary RCC (Figure 2), and 1 had a collecting (Bellini) duct carcinoma. The median tumor grade (Fuhrman grading system) was II-IV (range, II-IV/IV). All but 1 case (case 1) had unilateral renal involvement. In case 1, the patient had papillary RCC of each kidney, occurring 6 years apart. The treatment received and outcomes are summarized in Table 2. Seven (78%) patients underwent surgical resection, involving a partial or complete nephrectomy, including the 4 individuals who presented with early-stage (T1) disease. Long-term survival was associated with early surgical resection of RCC at the time of tumor presentation. Although case 4 presented with early-stage disease, the patient died from a pulmonary embolism after surgery. Patients with stage IV RCC died. Patients who presented with metastases underwent a variety of interventions, including surgery and administration of immunomodulating agents. Two patients with disseminated RCC received interleukin (IL)-2 therapy without response. HAART was continued during chemotherapy in all cases and implemented in 1 patient (case 7). No adverse drug toxicities to HAART were documented.
Discussion The present study reports the findings in 9 men with RCC positive for HIV. Albeit a relatively small number of cases, this study represents the largest published series to date that provides clinicopathologic and outcome details of HIV-associated RCC. Renal cell carcinoma, the most common form of kidney cancer arising from the renal tubule in adults, appears to be slightly increased in the HIV-infected population.5 The average age for the development of RCC in the general (HIV-negative) population is in the sixth or seventh decade, with a male preponderance.9 In our study, patients were slightly younger at presentation, as half of our patients were diagnosed with RCC before the sixth decade. The single-hospital study from the United States conducted by other investigators reported that the average age of RCC diagnosis in their HIV-infected patients was similarly 15 years younger than the general average.5 Marked immunosuppression was not a characteristic finding in our series. Therefore, it seems unlikely that immunodeficiency alone
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plays a major role in the development of HIV-associated RCC. We did not observe a definitive link between the degree of HIV-associated immunosuppression and the time to onset of RCC from HIV diagnosis, aggressive tumor behavior, adverse response to therapy, or prognosis. Both HIV infection and HAART medications can result in nephropathy and diabetes, both of which are potential risk factors for RCC. This possible association requires further investigation. Tobacco use is a well-documented risk factor for the development of RCC and, as illustrated in our case series, patients infected with HIV are more likely to use tobacco than the general population.10 Of the risk factors known to be associated with RCC development, we identified 7 patients who had used tobacco and 1 patient with both hypertension and chronic renal insufficiency. There was no personal or family history of genetic syndromes associated with RCC (eg, tuberous sclerosis or von Hippel–Lindau syndrome), acquired renal cystic disease, or dialysis dependence identified in our series. The clinical presentation of RCC is not pathognomonic. Even the classic clinical triad of hematuria, flank pain, and abdominal mass is rarely identified. Although many of our patients did have ≥ 1 of these clinical symptoms, no patient presented with the complete triad at diagnosis. Several (44%) of the men included in our study did manifest with hematuria. Therefore, it is prudent for a patient with HIV presenting with hematuria to always be thoroughly evaluated for a possible underlying genitourinary malignancy. Renal cell carcinoma is well known to cause paraneoplastic syndromes, including anemia, hepatic dysfunction, hypercalcemia, cachexia, and erythrocytosis. Such abnormalities might be difficult to attribute to RCC in patients with HIV infection, especially when they have several other comorbidities or side effects of HAART therapy. Nevertheless, there was no reported paraneoplastic syndrome in our cases. With the widespread use of radiographic imaging to work up other conditions, it is likely that more renal tumors will be discovered incidentally. As in our small series, patients with the incidental detection of RCC are likely to have earlier-stage RCC at diagnosis and, if appropriately treated, might have better outcomes. The challenge, however, is to determine which solitary renal masses found on incidental imaging represent RCC. The differential diagnosis for a
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Elizabeth M. Gaughan et al
Figure 2 Typical Histopathologic Image of Papillary Renal
Figure 1 Computed Tomography Scan of Case 2 at
Cell Carcinoma Resected in Case 1
Initial Presentation
The image shows a 4.8 × 6.4 × 6–cm mass originating from the upper pole of the left kidney, with invasion into the adjacent adrenal gland (arrows). In addition, the patient had left upper quadrant lymphadenopathy, thickening of the left hemidiaphragm, and a mass of the right adrenal gland.
solitary renal mass in a patient with HIV is broad. Previous reports have shown solitary renal masses to be due to malignant conditions, including lymphoma (non-Hodgkin and Hodgkin lymphoma), primary leiomyosarcoma, and angiosarcoma, as well as benign tumors, most notably oncocytoma.11-16 One study (reported in 1990), detected renal lymphomas in 2% of autopsies on AIDS patients.13 Infection (eg, tuberculosis) is always a consideration. Unfortunately, there are currently no definitive clinical or radiographic findings that can reliably distinguish RCC from these other benign and malignant causes of solitary renal masses. It is recommended, therefore, that all such lesions be surgically excised in patients who can tolerate surgery. Renal cell carcinoma encompasses several different histologic tumor subtypes, all with unique natural history and treatment considerations. Clear-cell carcinoma is by far the most common type, followed by papillary, chromophobe, and collecting duct carcinoma. The frequency of these subtypes is reflected in the proportion of tumors identified in our series. The 2 prognostic factors of importance with regard to RCC are nuclear (Fuhrman) grade and stage. The median Fuhrman grade in our patients was II/IV. Most of our patients presented with RCC of stage T2 or below (ie, tumors were < 7 cm in largest dimension and limited to the kidney). In the Surveillance Epidemiology and End Results data, 5-year survival rates for localized, regional and distant RCC are 90%, 61%, and 10%, respectively, which are consistent with our observation.17 Nephrectomy is potentially curative for RCC in patients with T1-T3 disease; therefore, it is the treatment of choice. Up to one third of patients, however, who undergo resection will have recurrent disease.8 In patients with HIV, surgical candidacy might be limited by opportunistic infections and poor performance status. Seven patients in our series had surgical resection, and 1 died from a pulmonary embolism after his radical nephrectomy. Advances in surgical technique and experience have permitted nephron-sparing surgery and laparo-
Hematoxylin and eosin stain, high-power magnification.
scopic surgery for some patients.18 One patient in our series (case 1) underwent partial nephrectomy with good long-term results. Renal cell carcinoma, specifically clear-cell type, is notoriously resistant to radiation therapy and chemotherapy. Immunotherapy with interferon (IFN)-α and IL-2 has been the backbone of systemic therapy for this disease, until recently, when the US FDA approved the tyrosine kinase inhibitors sorafenib and sunitinib and the mammalian target of rapamycin inhibitor temsirolimus for use in metastatic RCC.19-21 Also in a phase III clinical trial, the combination of bevacizumab with IFN-α as first-line treatment in patients with metastatic RCC resulted in a significant improvement in progression-free survival compared with IFN-α alone.22 Interleukin-2 works by activating an immune response against the cancer and can lead to long-term remission. However, IL-2 has significant toxicity. Interleukin-2 has also been used in patients with HIV (without RCC) to expand their CD4+ T-lymphocyte counts, without loss of virologic control.23 It might, therefore, provide a treatment option for patients with HIV with advanced RCC. Clearly, further studies with larger patient numbers are needed. HAART was continued for all patients who were on such therapy at the time of their RCC diagnosis and was started on 1 patient before systemic therapy. Because of the importance of compliance and drug levels of HAART in patients with HIV to prevent resistance, introducing new targeted therapies with the potential to affect HAART metabolism is always a treatment consideration.
Conclusion As patients with HIV are living longer with controlled HIV viremia, they are more likely to be diagnosed with neoplasms such as RCC. We present the findings in 9 men with HIV who had concomitant RCC to add to the growing list of non–AIDS-defin-
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HIV-Associated Renal Carcinoma ing cancers. Acknowledging the inherent limitations of our small study, our data suggest that such patients are liable to present at a slightly younger age and with only mild immunosuppression. Our patients followed an expected course for their RCC disease. Patients diagnosed with early-stage RCC did well after surgical resection, while those who were symptomatic with advanced renal cancer at diagnosis did poorly. Further observation and investigation are warranted to better understand the natural history and appropriate treatment of RCC in the HIV-infected population. The role of immunomodulatory and molecular targeted therapy is promising.
References 1. Uhlenkott M, Barash S, Khale E, et al. Causes of death in the era of highly active antiretroviral therapy (HAART): a retrospective analysis of a hybrid hematology-oncology practice and the Seattle/King County Adult/adolescent spectrum of HIV-related diseases (ASD) project. Am J Med Sci. In press. 2. Pantanowitz L, Schlecht HP, Dezube BJ. The growing problem of nonAIDS-defining malignancies in HIV. Curr Opin Oncol 2006; 18:469-78. 3. Aghaji AE, Odoemene CA. Renal cell carcinoma in Enugu, Nigeria. West Afr J Med 2000; 19:254-8. 4. Mbulaiteye SM, Katabira ET, Wabinga H, et al. Spectrum of cancers among HIV-infected persons in Africa: the Uganda AIDS-Cancer Registry Match Study. Int J Cancer 2006; 118:985-90. 5. Baynham SA, Katner HP, Cleveland KB. Increased prevalence of renal cell carcinoma in patients with HIV infection. AIDS Patient Care STDS 1997; 11:161-5. 6. Azón-Masoliver A, Moreno A, Gatell JM, et al. Renal cell adenocarcinoma associated with AIDS-related Kaposi’s sarcoma. AIDS 1990; 4:818-9. 7. Frisch M, Biggar RJ, Engels EA, et al. Association of cancer with AIDSrelated immunosuppression in adults. JAMA 2001; 285:1736-45. 8. Grulich AE, van Leeuwen MT, Falster MO, et al. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007; 370:59-67. 9. Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med 2005; 353:2477-90.
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10. Crothers K, Griffith TA, McGinnis KA, et al. The impact of cigarette smoking on mortality, quality of lifer, and comorbid illness among HIV-infected veterans. J Gen Int Med 2005; 20:1142-5. 11. Adjiman S, Zerbib M, Flam T, et al. Genitourinary tumors and HIV1 infection. Eur Urol 1990; 18:61-3. 12. Lee LK, Dinneen MD, Ahmad S. The urologist and the patient infected with human immunodeficiency virus or with acquired immunodeficiency syndrome. BJU Int 2001; 88:500-10. 13. Seney FD Jr, Burns DK, Silva FG. Acquired immunodeficiency syndrome and the kidney. Am J Kidney Dis 1990; 16:1-13. 14. Saurina A, Ramírez de Arellano M, Chiné M, et al. Acute kidney failure as the clinical presenting form of renal Burkitt’s lymphoma in an HIV-positive patient [in Spanish]. Nefrologia 2001; 21:601-5. 15. Busi Rizzi E, Schinina V, Cristofaro M, et al. Primary renal nonHodgkin’s lymphoma with inferior vena cava involvement: report of one case in HIV-infected patient. Radiol Med (Torino) 2002; 103:27982. 16. Norton KI, Godine LB, Lempert C. Leiomyosarcoma of the kidney in an HIV-infected child. Pediatr Radiol 1997; 27:557-8. 17. National Cancer Institute. SEER Table XI-5. Kidney and renal pelvis cancer (invasive). Survival rates by race, sex, diagnosis year, stage and age. Available at: http://seer.cancer.gov/cgi-bin/csr/1975_2004/search. pl#results. Accessed: September 9, 2008. 18. Puppo P, Perachino M, Ricciotti G, et al. Laparoscopic tumorectomy for renal cell carcinoma in a HIV-positive patient. Eur Urol 1997; 31:497-8. 19. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:125-34. 20. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115-24. 21. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356:227181. 22. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370:2103-11. 23. Mitsuyasu R, Gelman R, Cherng DW, et al. The virologic, immunologic, and clinical effects of interleukin 2 with potent antiretroviral therapy in patients with moderately advanced human immunodeficiency virus infection: a randomized controlled clinical trial--AIDS Clinical Trials Group 328. Arch Intern Med 2007; 167:597-605.
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