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Keywords:

  • interleukin-2;
  • renal cell carcinoma;
  • testicular metastasis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. Acknowledgments
  7. References

Abstract:  We present a case of metastatic spreading to the testicle in a 46-year-old patient with renal cell carcinoma, ‘clear-cell’ type, during interleukin-2 combined subcutaneous plus aerosol treatment. Testicular metastasis occurred while the patient showed a response to the treatment with disappearance of lung lesions and reduction of lymph-nodes lesions. After orchiectomy with spermatic cord resection and disease re-evaluation confirming the previous response, the patient re-started immunotherapy. The contrast between systemic disease response to treatment and disease testicular progression might be explained by a relative insensitivity of the testicle to interleukin-2 immunotherapy as a result of a possible establishment of an immunosuppressive microenvironment. We believe that the rarity of this metastatic site and the intriguing possible mechanisms at its base, makes an interesting case for clinicians.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. Acknowledgments
  7. References

Renal cell carcinoma (RCC) is known to have in some cases a capricious clinical behavior ranging from an aggressive presentation with rapid disease progression until death to a mild course with metastatic long-term survivor. Metastatic dissemination can affect a large number of organs usually spared from cancer colonization. Furthermore, the interval between primary diagnosis and the occurrence of distant metastasis can be very long.1 We describe the case of a 46-year-old man affected from metastatic RCC with ipsilateral right testicular metastatic dissemination during response to interleukin-2 (IL-2) combined subcutaneous plus aerosol treatment.

Case report

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. Acknowledgments
  7. References

On February 2005, the patient (46-year-old Caucasian male, smoker) underwent total right nephrectomy for RCC ‘clear-cell’ type. Pathologic examination showed a maximum lesion diameter of 7.5 cm with histological grading 2 according to Fuhrman scale, no-invasion of right renal vein (confirmed at re-evaluation after testicle metastasis onset), renal capsule, adrenal gland and no lymph-node involvement (pT2pN0). Thoracic and abdominal computed tomography (CT) scan and bone-scan showed no-evidence of metastatic disease with a final tumor node metastasis-International Union Against Cancer classification as stage II.2 After surgery no adjuvant therapy was given. Two months later because of the onset of pain in the right leg, a magnetic resonance imaging (MRI) scan was carried out and a lesion area of 4 cm × 3 cm in the distal metaphysis of the right femur was detected. The patient underwent bone metastasis resection with prosthetic reconstruction and histology confirmed renal origin. One month later, a planned thorax CT-scan detected a small (maximum diameter 9 mm) lesion area in the posterior part of the apex of the right lung. The patient newly underwent metastasectomy but during surgical inspection, multiple lesion areas were detected on the visceral pleura. Renal origin was confirmed by a pathologist and no therapy was given.

The patient was referred to our center on June 2005 and a complete disease assessment (total body CT-scan and bone-scan) showed bone metastasis in the right femur, multiple bilateral lung lesions and one pathologic lymph-node in the left posterior part of the neck. The patient started combined immunotherapy with aerosol and subcutaneous IL-2 plus zoledronic acid. Treatment schedule was planned with an induction phase of 4 weeks (aerosol: 18 × 106 UI twice-a-day day 1 to 5 for 3 weeks; subcutaneous: 9 × 106 UI day 1–5 a week continuously) to be repeated for three courses followed by a maintenance phase (aerosol: 18 × 106 UI twice-a-day day 1 to 5 alternate weeks; subcutaneous: 9 × 106 UI day 1–5 a week continuously) until disease progression. Standard premedication with acetaminophen 500 mg three times-a-day was given. Because of the occurrence of fever (≥38.5°C) insensitive to acetaminophen treatment and hypotension dose was reduced at 50% after the first course of induction therapy. Disease evaluation after the first cycle of the induction phase showed a complete pulmonary response, a partial lymph-nodal response and stability of bone lesions. Disease response was kept also at the end of induction phase (after 3 months of therapy).

At a planned control examination after 1 month during maintenance phase, the onset of a painless intrascrotal mass was confirmed. Medical examination showed a non-transilluminable, solid, grossly round shape mass in the right testicle. Echography confirmed the presence of a solid mass of 2.2 cm maximum diameter. The patient underwent right orchiectomy with spermatic cord resection and histology confirmed renal origin (Fig. 1). To date, after 1 month from surgery and a new complete disease assessment that confirmed the previous response to the treatment, the patient started a new cycle of immunotherapy.

image

Figure 1. Testicle metastasis from renal cell carcinoma (RCC). Arrow indicates ‘clear-cell’ type RCC substitution of normal testicle. Original magnifications: (a) ×200, (b) ×400 (insert).

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. Acknowledgments
  7. References

An unpredictable clinical behavior is often characteristic of RCC. The occurrence of metastatic localizations in unusual sites is widely described. Testicular involvement in the general cancer population is rare and accounts for only 0.06% of cases in a wide autoptic series.3 The kidney is a common primary site of testicular metastasis and testicular metastasis from RCC have been previously reported.4,5 The feature of the presented case is twofold: first we report a case of ipsilateral right metastasis (testicle metastasis are usually ipsilateral left or contralateral) and testicle metastasis showed an opposite clinical behavior than other metastasis sites respective to IL-2 treatment. In fact, the disease response of lung and lymph-node lesions to the treatment apparently contrast with testicle unexpected disease progression.

A possible explanation is that the testicle might be considered as an ‘hard workplace’ for chemotherapeutic agents and IL-2 (the testicle is regarded as a ‘tumor-sanctuary’ such as the central nervous system). The combination of systemic plus aerosol IL-2 therapy is a therapeutic option for a RCC patient with pulmonary metastasis showing a good tolerability profile and interesting response rates.5 The main mechanism of anti-tumor effect of IL-2 (irrespectively of the route of administration) is activation of T-cell mediated acquired immunity response against cancer cells.6 The presence of the blood–testis barrier formed by Sertoli cells, having a physiologic aim for the protection of spermatozoa, might also play an indirect role in the development of the testicular metastasis of the presented case. In fact, activated testicle T-lymphocytes can undergo apoptosis under the effect of the products of Sertoli cells during spermatogenesis, so we can speculate that a similar mechanism acts inhibiting the therapeutic effect of IL-2. Furthermore, testicular extracts in animal models suppress lymphocyte activation.7 Sertoli cell products inhibit the capacity of B and T lymphocyte to proliferate in response to mitogenic stimuli inducing a G1 phase block.8,9,10 To test this hypothesis, we carried out immunohistochemistry to detect the presence and check the functional status of metastasis infiltrating T-lymphocytes. Interestingly, we observe only a weak lymphocyte infiltrate mainly composed by CD3/CD8-positive cells without evidence of apoptosis. This apparent paradox can be explained with the consideration that the observed small number of lymphocytes might be the final consequence of the prolonged pro-apoptotic action of Sertoli cells on lymphocytes possibly enhanced by tumor local production of apoptotic agents. Taken together, these observations can explain the apparent insensitivity to IL-2 treatment of testicle and explain the very different clinical behavior observed. Although the patient experienced treatment benefits in the lung, bone and lymph-nodes that are not immunologic privileged organs, he experienced disease progression in testicle probably as a consequence of the above described IL-2 immunologic resistance mechanism. In our case the therapeutic approach to testicular metastasis was surgery in consideration of the good response to the treatment and to the good performance status of the patient.

The usual explanation of testicle involvement in RCC is the retrograde descent of cancer cells via the spermatic vein. This possibility is particularly considered for both primary tumor and metastasis at the left side because of anatomic outlet of spermatic vein into renal vein at this side. In the presented case we could exclude this route (given the different outlet of right spermatic vein into inferior cava) and explain the metastatic colonization of the testicle as the consequence of arterial spreading of cancer cells. Pathologic examination showed focal tumor vascular invasion of spermatic.

In view of the great number of patients with advanced RCC treated with IL-2 and the usually (and fortunately) prolonged period of responsiveness to IL-2 treatment of patients, we suggest to carry out careful medical examinations with particular attention to possible unusual sites of metastatic dissemination. Particular attention to the testicle, which can be considerd ‘immunologically resistant’ to IL-2 treatment should be regarded.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. Acknowledgments
  7. References

AC prepared the manuscript and bibliographic research; GT, SD and PP collected data; LM was responsible for pathologic findings; DA assessed the manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Case report
  5. Discussion
  6. Acknowledgments
  7. References
  • 1
    Gogus C, Kilic O, Tulunay O, Tulunay O, Beduk Y. Solitary metastasis of renal cell carcinoma to the parotid gland 10 years after radical nephrectomy. Int. J. Urol. 2004; 11: 8946.
  • 2
    Sobin LH, Witteking C. International Union Against Cancer (UICC). TNM Classification of Malignant Tumours, 6th edn. Wiley-Liss,New York, 2002.
  • 3
    Pienkos EJ, Jablokow VR. Secondary testicular tumors. Cancer 1972; 30: 4815.
  • 4
    Steiner G, Heimbach D, Pakos E, Muller S. Simultaneous contralateral testicular metastasis from a renal clear cell carcinoma. Scand. J. Urol. Nephrol. 1999; 33: 1367.
  • 5
    Lauro S, Lanzetta G, Bria E, Trasatti L, Costarelli L, Vecchione A. Contralateral solitari testis metastasis antedating renal cell carcinoma: a case-report and review. Anticancer Res. 1998; 18: 46834.
  • 6
    Merimsky O, Gez E, Weitzen R et al. Targeting pulmonary metastases of renal cell carcinoma by inhalation of interleukin-2. Ann. Oncol. 2004; 15: 61012.
  • 7
    Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG. Goodman and Gilman’s the Pharmacological Basis of Therapeutics, 9th edn. Mc Graw-Hill, New York, 1996.
  • 8
    Emoto M, Nishikawa F, Oku D, Hamuro A, Kita E, Kashiba S. Suppressive effect of a mouse testicular extract on lymphocyte activation. Int. J. Androl. 1991; 14: 291302.
  • 9
    De Cesaris P, Filippini A, Cervelli C et al. Immunosuppressive molecules produced by Sertoli cells cultured in vitro: biological effects on lymphocytes. Biochem. Biophys. Res. Commun. 1992; 186: 163946.
  • 10
    Selawry HP, Kotb M, Herrod HG, Lu ZN. Production of a factor, or factors, suppressing IL-2 production and T cell proliferation by Sertoli cell-enriched preparations. A potential role for islet transplantation in an immunologically privileged site. Transplantation 1991; 52: 84650.