I
CASEREPORTS
Sarcoidosis, "Sarcoid-Like Lymphadenopathy," and Testicular Germ Cell Tumors GUYC. TONER,M.B.B.S., GEORGEJ. BOSL,M.D.,
New York, New York
n increased incidence of cancer in patients with
A sarcoidosis reported to the Danish Institute of Clinical Epidemiology was described by Brincker and Wilbek [1] in 1974. They found 48 patients who developed a malignancy among 2,544 patients with sarcoidosis. There was a higher frequency of lung cancer and lymphoma compared with that expected in the general population and the higher incidence only occurred in the first 4 years after the diagnosis of sarcoidosis. No cases of testicular neoplasms were reported. It was suggested that the development of malignancy may be related to immunologic defects in these patients. Indeed, multiple immunologic abnormalities associated with sarcoidosis have been studied [2]. These include impaired systemic cell-mediated immunity which may improve after resolution of the sarcoidosis [2]. The findings of Brincker and Wilbek were challenged after review of the case records of the 48 patients identified [3,4]. Fourteen patients were believed to have not been correctly diagnosed and in particular some of them were thought to have a regional sarcoid-like reaction to a malignancy. After exclusion of the 14 patients, the incidence of malignancy in patients with sarcoidosis was the same as expected in the general population [3,4]. There has, however, been continued speculation in the medical literature regarding a possible association of sarcoidosis and malignancy [5-9]. The development of sarcoidosis after malignancy has also been reviewed and reported most frequently in association with testicular malignancy [9]. One report found four cases of "sarcoid reaction in hilar and paratracheal lymph nodes" which regressed spontaneously in patients previously treated for
From the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center and the Department of Medicine, Cornell University Medical College, New York. This study was supported in part by Grants CA 05826 and CM 57732 from the National Institutes of Health, Bethesda, Maryland and the Brian Piccolo Research Fund. Requests for reprints should be sent to George J. Bosl, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 100212. Manuscript submitted April 20, 1990, and accepted in revised form July 12, 1990.
clinical stage I germ-cell tumors [10]. The four cases were identified among 700 patients treated for testis cancer. This incidence (0.6%) was increased compared with the finding of hilar adenopathy in men during army service (0.13%). However, there was no difference in the frequency when the denominator was taken as the number of chest roentgenograms performed because the 700 patients had more frequent roentgenograms than the men in army service. As sarcoidosis is often asymptomatic and may resolve spontaneously, comparison of the number of cases diagnosed in patients during regular followup with the frequency of the diagnosis in the general population is liable to be inaccurate [11]. Comparison based on the number of chest radiographs performed is also likely to be biased, however, as the chance of a new finding of hilar enlargement in each chest roentgenogram cannot be assumed to be the same, particularly in patients receiving frequent follow-up. We have been impressed with the number of patients diagnosed to have sarcoidosis and germ-cell tumors at this institution. The aim of this study was to identify and characterize patients treated at Memorial Hospital with testicular malignancies and a diagnosis of sarcoidosis. Reported cases of this association in the medical literature were also reviewed. Analysis of patients with both diagnoses may define possible etiologic associations between sarcoidosis and testicular neoplasms and illustrates the importance of careful diagnostic and staging evaluation of patients with these malignancies.
PATIENTS AND METHODS Cases of possible sarcoidosis occurring in patients with testicular cancer were identified from the personal experiences of treating physicians and the recorded diagnoses of patients admitted to Memorial Hospital between 1980 and 1989. Case records were reviewed and patient characteristics and outcome tabulated. Reported cases of sarcoidosis and testicular malignancies in the medical literature between 1966 and March 1990 were identified by computerized searching of the Medline and Cancerlit databases. Estimates of the number of patients seen at Memorial Hospital with testicular malignancies
November 1990 The American Journal of Medicine
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651
SARCOIDOSlS AND TESTICULAR GERM CELL TUMORS / TONER AND BOSL TABLE I Patient Characteristics, Therapy, and Outcome of Nine Patients with Testicular Germ Cell Tumors and a Diagnosis of Sarcoidosis Testicular Malignancy Ageat Metastatic Therapyof Status Patient Diagnosis Histology Sites Metastases (Interval)*
Interval Sarcoidosis Between Involved Diagnoses Symptoms Biopsy Areas Therapy Course
Testis malignancy after sarcoidosis diagnosed 1
38
2
51
3
28
4
33
5
37
Yolk sac, seminoma Emb ca, chorioca Seminoma, emb ca Seminoma Seminoma, emb ca
None
Observed
Lung RP, lung
Chemo, RPLND Chemo
RP
RT (Abdo)
RP
Chemo
NED 17 years (9 months) NED 13 years (16 months) NED 8years (9 years) NED 20 months (8 years) NED 3 months (5 years)
None
Yes
None
Resolved
No
Med, scalene Med, lung
Yes
None
Regressed
Yes
Yes(X2)
Med, lung
Steroid
Regressed
None
Yes
Med, lung
None
Stable
Yes
Yes
Med
Steroid
Regressed
Simultaneous testis malignancy and sarcoidosis diagnosis 6
23
Seminoma
None
RT (Abdo)
7
36
Seminoma
None
RT (Abdo)
NED (5 years) NED (5 years)
None
None
Yes
Med
None
Regressed
None
None
Yes
Med
None
Stable
NED (6 years) NED (4 years)
30 months
None
Yes
Med
None
Regressed
38 months
Yes
Yes
Med
None
Resolved
Sarcoidosis diagnosed after testis malignancy 8
27
Teratoca
RP
RPLND
9
31
Seminoma, yolk sac, emb ca
None
Observed
Ca = carcinoma;Emb ca = embryonalcarcinoma;chorioca = choriocarcinoma;teratoca = teratocarcinoma;RP = retroperitoneallymph nodes;RPLND= retroperitoneallymph node dissection; RT (Abdo) = radiation therapy to the abdomenonly; NED = no evidenceof recurrent or metastatic disease;Med = mediastinallymph nodesincludinghilar and paratrachealnodes. * Intervalfrom diagnosisof testicular malignancy.
were made by analysis of diagnostic coding of patients admitted to the hospital and analysis of patients treated with protocols for the management of testicular malignancies. RESULTS
Clinical features of the nine patients seen at Memorial Hospital with testicular germ-cell tumors over the last 10 years and diagnosed to have sarcoidosis are shown in T a b l e I. All patients were white men aged 23 to 51. Pathologic diagnoses from the orchiectomy specimens included pure seminoma and mixed germ-cell tumors. No seminomatous elements were identified in the primary tumor specimens of two patients. Treatment received included radiation therapy for clinical stage I and II seminoma and surgery and chemotherapy for nonseminomatous tumors. All of these features are typical of the patient population treated for this malignancy at Memorial and do not suggest any particular associations with sarcoidosis. Only one case of sarcoidosis preceding testicular malignancy has been reported previously. This report includes five new patients in whom a germ-cell tumor was diagnosed after sarcoidosis with intervals between diagnoses of 3 months and 20 months, and 8, 13, and 17 years. Features of the 18 cases of possible association of sarcoidosis and testicular germ-cell tumors reported in the medical literature are shown in T a b l e II. 652
November 1990 The American Journal of Medicine
In addition, one case of Leydig cell tumor of the testis and concurrent sarcoidosis has been reported [24]. A mixture of tumor histologies, stages of disease, and treatments were present in these patients and no pattern of features associated with sarcoidosis is evident. A total of 874 patients older than 15 years were admitted to Memorial Hospital between 1980 and 1988 (97 patients per year) with testicular primary malignancies other than Leydig cell, Sertoli cell, mesothelioma, embryonal rhabdomyosarcoma, and lymphoma. This includes admissions to the urology and medical oncology services. The number of admissions per year has remained approximately constant. Complete information for 1989 is not yet available. For the purposes of predicting the total number of patients seen at this institution with testicular germ-cell tumors, we estimated that an additional 60 patients per year were seen in consultation but not admitted. This would include an average of 107 patients per year who have been seen at Memorial Hospital since 1979 and entered into chemotherapy trials for germ-cell tumors. Not all patients entered into chemotherapy protocols were admitted to Memorial Hospital as some were treated elsewhere. Sarcoidosis was evident in eight of the nine patients presented here during treatment and follow-up for their testis malignancy. The prevalence of sarcoidosis in patients treated for testicular
Volume 89
SARCOIDOSIS AND TESTICULAR GERM CELL TUMORS / TONER AND BOSL
TABLEII PreviouslyReported Casesof TesticularGerm Cell Tumorsand PossibleSarcoidosis No. of Patients
Age
Histologyof Testis
Outcome Testis Cancer
Interval BetweenDiagnoses
Died
8 years
Stable
[12, 13]
NED (3) NS (1)
None
Regressed (1) NS (3)
[ 14-17]
NED (12) NS (1)
5 months to 8 years
Resolved (6) Regressed (5) Stable (1)
[10, 17-23]
Outcomeof Sarcoidosis
Reference
Testis malignancy after sarcoidosis diagnosed 1
33
Seminoma
Simultaneous testis malignancy and sarcoidosis diagnosis 4 33-43 Seminoma (2) Nonseminoma (2) Sarcoidosis diagnosed after testis malignancy 13
26-35
Seminoma (1) Nonseminoma (12)
NS(1)
NED = no evidenceof recurrentor metatstaticdisease;NS = not stated.
germ-cell tumors could, therefore, be estimated to be 8/1,570 or 510/100,000. COMMENTS
Nine patients with testicular germ-cell tumors and a diagnosis of sarcoidosis are presented. Eighteen patients have been described previously although in only one of these was sarcoidosis diagnosed prior to the germ-cell tumor. The five new cases of sarcoidosis occurring prior to a diagnosis of testis cancer extend the reported association of the two conditions and suggest that sarcoidosis was not caused or precipitated by the malignancy or therapy for the malignancy. All of the cases in this report and the majority of cases previously reported occurred in white men. In contrast, sarcoidosis is reported to be approximately 10 times more common in black patients in the United States [25]. Whether the predominance of reported cases of sarcoidosis and testis cancer in white patients merely reflects the patient population with testis cancer at the institutions involved or alternatively that the association of the two disorders is more common in white patients remains unclear. The association of sarcoidosis and testicular malignancies raises two major issues. The first is the difficulty of accurate staging and diagnosis that may occur as a result of concurrence of these two conditions in a single patient. The second is a possible etiologic association between the two diseases. The coexistence of sarcoidosis and testicular malignancy is rare but can confuse clinical evaluation. Several case reports have indicated the vital importance of accurate diagnostic and staging evaluation in these patients. Colebunders et al [12,13] reported a case of a young man with seminoma, a normal lymphangiogram and computed tomographic scan of the abdomen, and an abnormal chest roentgenogram with enlarged bilateral hilar nodes and nodu-
larity in the lung fields. The patient was treated for metastatic seminoma with chemotherapy and died on the fourth day of treatment. Autopsy studies showed no evidence of malignancy but extensive changes consistent with sarcoidosis. In contrast, "sarcoidosis" may mask a diagnosis of malignancy. Heffner and Milam [26] reported a case of a young man with embryonal carcinoma of the left testis with a normal abdominal computerized tomographic scan who had bilateral hilar and paratracheal nodal enlargement and lung nodules. Biopsy of mediastinal nodes was consistent with granulomatous inflammation but embryonal carcinoma was subsequently found in enlarging pulmonary nodules. Patients with sarcoidosis may develop testicular enlargement due to granulomatous inflammation [27-30]. A careful diagnostic approach is needed and orchiectomy is recommended in cases of unilateral lesions [28,31]. The need for careful histologic evaluation has been emphasized as granulomatous inflammation can be associated with testicular malignancies, especially seminoma. Pickard et al [32] reported a case of seminoma in which an initial histologic diagnosis of granulomatous orchitis was considered in view of the extensive granulomatous reaction around tiny islands of seminoma. In our experience, the clues to a diagnosis of sarcoidosis in patients with testis cancer have been the pattern of metastatic disease and radiologic findings in the chest. Patients with testicular germ-cell tumors rarely have isolated mediastinal adenopathy due to metastatic disease without simultaneous metastatic involvement of the retroperitoneum or lung parenchyma. Of 510 patients with an advanced germ-cell tumor occurring in the testis, who were treated with front-line chemotherapy protocols at this institution, 55 had metastatic spread to the mediastinum. However, the mediasti-
November 1990 The American Journal of Medicine Volume 89
653
SARCOIDOSISAND TESTICULARGERMCELLTUMORS/ TONERAND BOSL
Figure 1. Chest radiograph of Patient 7 at presentation showing bilateral hilar adenopathy consistent with sarcoidosis.
num was the exclusive site of metastatic disease in only four patients (0.8%). Patients diagnosed as having sarcoidosis in this report commonly had bilateral hilar and paratracheal adenopathy typical of sarcoidosis (Figure 1). If sarcoidosis is considered in the differential diagnosis, exploratory surgery is warranted when the finding of granulomatous inflammation exclusively will alter the management of the patient. Typical examples of this are Patients 6 through 9 of the current report in whom chemotherapy for metastatic disease was avoided after biopsy of mediastinal nodes showed changes consistent with sarcoidosis. The second major issue raised is the possible increased incidence of sarcoidosis in patients with testicular malignancy. The incidence and prevalence of sarcoidosis in the general population are difficult to establish because many asymptomatic cases may remain undetected. Autopsy studies suggest that the true prevalence may be four to 10 times that suggested by the number of proven cases [25]. Among 1,216,425 recruits entering the United States Navy between 1958 and 1969 the rates of diagnosis of sarcoidosis were 7.6/100,000 in whites and 76.2/100,000 in blacks [33]. All recruits had at least one chest roentgenogram performed. In a mass radiologic survey for tuberculosis, performed between 1956 and 1962 in New York City, 449,605 individuals had chest radiographs [34]. Sarcoidosis was diagnosed in 174 cases. The diagnosis was often made on radiographic appearance alone although biopsy or Kveim test was performed in over 50% of the cases. The overall prevalence rate was calculated to be 39/100,000. The prevalence in districts where more than 81% of the population was white was lower at 17/100,000. 654
November 1990
In this study, nine patients with testicular malignancies treated at Memorial Hospital since 1980 were also diagnosed to have sarcoidosis. All nine cases occurred in white patients. Eight of the nine had evidence of sarcoidosis during the same period (1980 to 1989). An exact assessment of the number of patients seen at this institution with testicular malignancy since 1980 is not possible. We estimate that an average of 157 patients per year were seen for management of a testicular germ-cell tumor. The prevalence of sarcoidosis might, therefore, be estimated to be 510/100,000 in this group. This is much higher than the rate expected from the studies quoted earlier and other international epidemiologic data [25]. However, there are a number of possible biases in this calculation that cannot be controlled and, therefore, may make this estimate unreliable. Potential biases that preclude an accurate comparison of prevalence include patient selection by referral to a tertiary institution and the increased frequency of chest radiograph studies and clinical follow-up of patients after therapy for malignancy. Another issue to be considered is the validity of a diagnosis of sarcoidosis in any patient with malignancy. Sarcoidosis is a systemic disorder of unknown etiology that is characterized pathologically by noncaseating granulomata [2,35,36]. No laboratory test unequivocally establishes the diagnosis. Granuloma formation occurs in association with more than 50 separate clinical entities. Exclusion of other possible causes of the clinical picture is, therefore, recommended before a diagnosis of sarcoidosis can be made. Sarcoid-like granulomata are found in primary malignant tumors, in the regional lymph nodes of neoplasms, and rarely in uninvolved or-
The American Journal of Medicine Volume 89
gans such as the spleen of patients with malignancy [37]. These pathologic findings have been termed "sarcoid reactions." In patients with malignancy and features typical of sarcoidosis, the possibility that the pathologic findings in lymph nodes may be a sarcoid reaction caused by the malignancy cannot be excluded. It has, therefore, been suggested that the term sarcoidosis should not be used in patients with malignancy and a more general term such as "sarcoid-like lymphadenopathy" has been proposed [10]. Despite these reservations, the clinical features and course of patients presented in this report were typical of sarcoidosis. Among the nine patients presented, only three received systemic chemotherapy and in two of these the sarcoidosis preceded the diagnosis of malignancy by at least 8 years. The remaining patients received only surgery or radiotherapy directed at the primary tumor or retroperitoneal nodes. No patients have had a relapse of the malignancy despite prolonged follow-up in the majority. This tends to preclude the possibility that the changes in mediastinal nodes were a result of unrecognized pulmonary or disseminated malignancy. Three patients in this series had sarcoidosis diagnosed at least 8 years prior to the finding of the testis tumor. In these patients, it is very unlikely that the sarcoidosis was related to the malignancy. The clinical course in all our patients was also typical of sarcoidosis. Four patients who received no treatment for sarcoidosis and two patients who had brief courses of prednisone therapy had regression or resolution of the abnormal radiologic findings. Two patients, who have remained asymptomatic and received no therapy, have had little change in their chest roentgenogram findings. Whether a diagnosis of sarcoidosis or 8arcoid-like lymphadenopathy is used, it is clear that, after the diagnosis of a germ-cell tumor, the findings of hilar and mediastinal adenopathy with noncaseating granulomata are not necessarily a harbinger of recurrent malignancy. These patients can be safely observed after careful evaluation, including biopsy, to exclude recurrent or metastatic tumor. Patients with sarcoidosis may have an increased incidence of testis cancer but further epidemiologic data are required. If testicular enlargement develops in a patient with sarcoidosis, a detailed evaluation to exclude testicular malignancy is needed including orchiectomy for unilateral lesions. Lastly, when patients with newly diagnosed testicular germ-cell tumors also have an abnormal chest radiograph, sarcoidosis should be considered in the differential diagnosis. This is especially true if there is no abdominal or pulmonary metastases and the pattern of mediastinal adenopathy is typical of sarcoidosis.
Surgical exploration is warranted if the finding of granulomatous inflammation alone in the chest will change the patient's management. Increased awareness of the association of testicular germ-cell tumors and sarcoidosis or sarcoid-like adenopathy will help to avoid errors in the diagnosis, staging, and management of patients with this malignancy. Further epidemiologic studies are indicated and may reveal an etiologic link between the two conditions.
REFERENCES 1. Brincker H, Wilbek E. The incidence of malignant tumours in patients with respiratory sarcoidosis. Br J Cancer 1974; 29: 247-51. 2. Daniele RF, Dauber JH, Rossman MD. Immunologic abnormalities in sarcoidosis. Ann Intern Med 1980; 92: 406-16. 3. Romer FK. Case 7-1982: sarcoidosis and cancer (letter). N Engl J Med 1982; 306: 1490. 4. Romer FK. Sarcoidosis and cancer--a critical view. In: Jones Williams W, Davies BH, eds, Eighth international conference on sarcoidosis and other granuIomatous diseases. Cardiff: Alpha Omega Publishing, 1980: 201-5. 5. Sakula A. Bronchial carcinoma and sarcoidosis. Br J Cancer 1963; 17: 20612. 6. Brincker H. The sarcoidosis-lymphoma syndrome. Br J Cancer 1986; 54: 467-73. 7. Israel HI. Sarcoidosis, malignancy and immunosuppressive therapy. Arch Intern Med 1978; 138: 907-8. 8. Brincker H. Sarcoid reactions and sarcoidosis in Hodgkin's diseaseand other malignant lymphomata. Br J Cancer 1972; 26: 120-8. 9. Brincker H. Solid tumors preceding or following sarcoidosis. Med Pediatr Oncol 1987; 15: 82-8. 10. FossaSD, Abeler V, Marton PF, Lien HH, Hie J. Sarcoid reaction of hilar and paratracheal lymph nodes in patients treated for testicular cancer. Cancer 1985; 56: 2212-6. 11. HennessyTW, Ballard DJ, DeRemeeRA, Chu CP, Melton LJ. The influence of diagnostic access bias on the epidemiology of sarcoidosis: a population-based study in Rochester, Minnesota, 1935-1984. J Clin Epidemio11988; 41: 565-70. 12. Colebunders R, Bultinck J, Servais J, Denis L. A patient with testis seminoma, sarcoidosis, and neutropenic enterocolitis. Human Patho11984; 15: 3946. 13. Colebunders R. Sarcoidosis after testicular carcinoma treatment [Letter]. AJR 1983; 140: 831. 14. Blacher EJ, Maynard JF. Seminoma and sarcoidosis: an unusual association. Urology 1985; 26: 288-9. 15. Geller RA, Kuremsky DA, Copeland JS, Stept R. Sarcoidosis and testicular neoplasm: an unusual association. J Urol 1977; 118: 487-8. 16. O'Connell M, Powell S, Horwich A. Sarcoid-like lymphadenopathy in malignant teratoma. Postgrad Med J 1983; 59: 108-10. 17. Parr MJ, Williams MV. Sarcoidosis mimicking metastatic testicular tumour. Br J Radiol 1988; 61: 516-18. 18. Trump DL, Ettinger DS, Feldman MJ, Dragon LH. Sarcoidosis and sarcoidlike lesions: their occurrence after cytotoxic and radiation therapy of testis cancer. Arch Intern Med 1981; 141: 37-8. 19. Sieber PR, Duggan FE. Sarcoidosis and testicular tumors. Urology 1988; 31: 140-1. 20. Gefter WB, Glick JH, Epstein DM, Miller WT. Sarcoidosis: a cause of intrathoracic lymphadenopathy after treatment of testicular carcinoma. AJR 1982; 139: 820-1. 21. Allison RE, Urbanski SJ. More about association of seminoma and sarcoidosis. Urology 1986; 27: 86-7. 22. Wettlaufer JN, Modarelli RO. Thoraeotomy in re-staging germinal testis tumors. J Urol 1979; 122: 845-8. 23. Urbanski SJ, Alison RE, Jewett MA, GospodarowiczMK, Sturgeon JF. Association of germ cell tumours of the testis and intrathoracic sarcoid-like lesions. Can Med Assoc J 1987; 137: 416-7. 24. Biglino A, Cariti G, Musset M, Gioannini P. Pulmonary sarcoidosis associated with Leydig cell testicular neoplasm. Chest 1988; 94: 428-9.
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25. TeJrstein AS, Lesser M. Worldwide distribution and epidemiology of sarcoidosis. In: Fanburg BL, ed., Sarcoidosis and other granulomatous diseases of the lung. New York: Marcel Dekker, Inc, 1983, 10i-34. 26. Heffner JE, Milam MG. Sarcoid-like hilar and mediastinal lymphadenopathy in a patient with metastatic testicular cancer. Cancer 1987; 60: 1545-7. 27. Chowdhury 8D, Higgms PM. 8arcoid of the testis. Br J Uro11973; 45: 21820. 28. Haas GP, Badalament R, Wonnell DM, Miles BJ. Testicular sarcoidosis: case report and review of the literature. J Urol 1986; 135: 1254-6. 29. McWilliarns WA, Abramowitz L, Tiamson EM. Epididymal sarcoidosis: case report and review. J Urol 1983; 130: 1201-3. 30, Opal SM, Pittman DL, Hofeldt FE. Testicular sarcoidosis. Am J Med 1979; 67: 147-50. 31. Seaworth JF, Davis SJ, Donovan WN. Aggressive diagnostic approach indi-
656
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cated in testicular sarcoidosis. Urology 1983; 21: 396-8. 32. Pickard WR, Clark AH, Abel BJ. Florid granulomatous reaction in a seminoma. Postgrad Med J 1983; 59: 334-5. 33. Sartwell PE, Edwards LB. Epidemiology of sarcoidosis in the U.S. navy. Am J Epidemiol 1974; 99: 250-7. 34. Robins AB, Abeles H, Chaves AD. Prevalence and Demographic Characteristics of Sarcoidosis. New York: Bureau of Tuberculosis, the City of New York, Department of Health, 1962, 149-51. 35. Mitchell DN, Scadding JG, Heard BE, Hinson KFW. Sarcoidosis: histopathological definition and clinical diagnosis. J Clin Pathol 1977; 30: 395-408. 36. Daniele RP, Rossman MD, Kern JA, Elias JA. Pathogenesis of sarcoidosis. State of the art. Chest 1986; 89: 174S-7S. 37. Brincker H. Sarcoid reactions in malignant tumours. Cancer Treat Rev 1986; 13: 147-156.
Volume 89
CASEREPORTS
Sarcoidosis, "Sarcoid-Like Lymphadenopathy," and Testicular Germ Cell Tumors GUYC. TONER,M.B.B.S., GEORGEJ. BOSL,M.D.,
New York, New York
n increased incidence of cancer in patients with
A sarcoidosis reported to the Danish Institute of Clinical Epidemiology was described by Brincker and Wilbek [1] in 1974. They found 48 patients who developed a malignancy among 2,544 patients with sarcoidosis. There was a higher frequency of lung cancer and lymphoma compared with that expected in the general population and the higher incidence only occurred in the first 4 years after the diagnosis of sarcoidosis. No cases of testicular neoplasms were reported. It was suggested that the development of malignancy may be related to immunologic defects in these patients. Indeed, multiple immunologic abnormalities associated with sarcoidosis have been studied [2]. These include impaired systemic cell-mediated immunity which may improve after resolution of the sarcoidosis [2]. The findings of Brincker and Wilbek were challenged after review of the case records of the 48 patients identified [3,4]. Fourteen patients were believed to have not been correctly diagnosed and in particular some of them were thought to have a regional sarcoid-like reaction to a malignancy. After exclusion of the 14 patients, the incidence of malignancy in patients with sarcoidosis was the same as expected in the general population [3,4]. There has, however, been continued speculation in the medical literature regarding a possible association of sarcoidosis and malignancy [5-9]. The development of sarcoidosis after malignancy has also been reviewed and reported most frequently in association with testicular malignancy [9]. One report found four cases of "sarcoid reaction in hilar and paratracheal lymph nodes" which regressed spontaneously in patients previously treated for
From the Genitourinary Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center and the Department of Medicine, Cornell University Medical College, New York. This study was supported in part by Grants CA 05826 and CM 57732 from the National Institutes of Health, Bethesda, Maryland and the Brian Piccolo Research Fund. Requests for reprints should be sent to George J. Bosl, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 100212. Manuscript submitted April 20, 1990, and accepted in revised form July 12, 1990.
clinical stage I germ-cell tumors [10]. The four cases were identified among 700 patients treated for testis cancer. This incidence (0.6%) was increased compared with the finding of hilar adenopathy in men during army service (0.13%). However, there was no difference in the frequency when the denominator was taken as the number of chest roentgenograms performed because the 700 patients had more frequent roentgenograms than the men in army service. As sarcoidosis is often asymptomatic and may resolve spontaneously, comparison of the number of cases diagnosed in patients during regular followup with the frequency of the diagnosis in the general population is liable to be inaccurate [11]. Comparison based on the number of chest radiographs performed is also likely to be biased, however, as the chance of a new finding of hilar enlargement in each chest roentgenogram cannot be assumed to be the same, particularly in patients receiving frequent follow-up. We have been impressed with the number of patients diagnosed to have sarcoidosis and germ-cell tumors at this institution. The aim of this study was to identify and characterize patients treated at Memorial Hospital with testicular malignancies and a diagnosis of sarcoidosis. Reported cases of this association in the medical literature were also reviewed. Analysis of patients with both diagnoses may define possible etiologic associations between sarcoidosis and testicular neoplasms and illustrates the importance of careful diagnostic and staging evaluation of patients with these malignancies.
PATIENTS AND METHODS Cases of possible sarcoidosis occurring in patients with testicular cancer were identified from the personal experiences of treating physicians and the recorded diagnoses of patients admitted to Memorial Hospital between 1980 and 1989. Case records were reviewed and patient characteristics and outcome tabulated. Reported cases of sarcoidosis and testicular malignancies in the medical literature between 1966 and March 1990 were identified by computerized searching of the Medline and Cancerlit databases. Estimates of the number of patients seen at Memorial Hospital with testicular malignancies
November 1990 The American Journal of Medicine
Volume 89
651
SARCOIDOSlS AND TESTICULAR GERM CELL TUMORS / TONER AND BOSL TABLE I Patient Characteristics, Therapy, and Outcome of Nine Patients with Testicular Germ Cell Tumors and a Diagnosis of Sarcoidosis Testicular Malignancy Ageat Metastatic Therapyof Status Patient Diagnosis Histology Sites Metastases (Interval)*
Interval Sarcoidosis Between Involved Diagnoses Symptoms Biopsy Areas Therapy Course
Testis malignancy after sarcoidosis diagnosed 1
38
2
51
3
28
4
33
5
37
Yolk sac, seminoma Emb ca, chorioca Seminoma, emb ca Seminoma Seminoma, emb ca
None
Observed
Lung RP, lung
Chemo, RPLND Chemo
RP
RT (Abdo)
RP
Chemo
NED 17 years (9 months) NED 13 years (16 months) NED 8years (9 years) NED 20 months (8 years) NED 3 months (5 years)
None
Yes
None
Resolved
No
Med, scalene Med, lung
Yes
None
Regressed
Yes
Yes(X2)
Med, lung
Steroid
Regressed
None
Yes
Med, lung
None
Stable
Yes
Yes
Med
Steroid
Regressed
Simultaneous testis malignancy and sarcoidosis diagnosis 6
23
Seminoma
None
RT (Abdo)
7
36
Seminoma
None
RT (Abdo)
NED (5 years) NED (5 years)
None
None
Yes
Med
None
Regressed
None
None
Yes
Med
None
Stable
NED (6 years) NED (4 years)
30 months
None
Yes
Med
None
Regressed
38 months
Yes
Yes
Med
None
Resolved
Sarcoidosis diagnosed after testis malignancy 8
27
Teratoca
RP
RPLND
9
31
Seminoma, yolk sac, emb ca
None
Observed
Ca = carcinoma;Emb ca = embryonalcarcinoma;chorioca = choriocarcinoma;teratoca = teratocarcinoma;RP = retroperitoneallymph nodes;RPLND= retroperitoneallymph node dissection; RT (Abdo) = radiation therapy to the abdomenonly; NED = no evidenceof recurrent or metastatic disease;Med = mediastinallymph nodesincludinghilar and paratrachealnodes. * Intervalfrom diagnosisof testicular malignancy.
were made by analysis of diagnostic coding of patients admitted to the hospital and analysis of patients treated with protocols for the management of testicular malignancies. RESULTS
Clinical features of the nine patients seen at Memorial Hospital with testicular germ-cell tumors over the last 10 years and diagnosed to have sarcoidosis are shown in T a b l e I. All patients were white men aged 23 to 51. Pathologic diagnoses from the orchiectomy specimens included pure seminoma and mixed germ-cell tumors. No seminomatous elements were identified in the primary tumor specimens of two patients. Treatment received included radiation therapy for clinical stage I and II seminoma and surgery and chemotherapy for nonseminomatous tumors. All of these features are typical of the patient population treated for this malignancy at Memorial and do not suggest any particular associations with sarcoidosis. Only one case of sarcoidosis preceding testicular malignancy has been reported previously. This report includes five new patients in whom a germ-cell tumor was diagnosed after sarcoidosis with intervals between diagnoses of 3 months and 20 months, and 8, 13, and 17 years. Features of the 18 cases of possible association of sarcoidosis and testicular germ-cell tumors reported in the medical literature are shown in T a b l e II. 652
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In addition, one case of Leydig cell tumor of the testis and concurrent sarcoidosis has been reported [24]. A mixture of tumor histologies, stages of disease, and treatments were present in these patients and no pattern of features associated with sarcoidosis is evident. A total of 874 patients older than 15 years were admitted to Memorial Hospital between 1980 and 1988 (97 patients per year) with testicular primary malignancies other than Leydig cell, Sertoli cell, mesothelioma, embryonal rhabdomyosarcoma, and lymphoma. This includes admissions to the urology and medical oncology services. The number of admissions per year has remained approximately constant. Complete information for 1989 is not yet available. For the purposes of predicting the total number of patients seen at this institution with testicular germ-cell tumors, we estimated that an additional 60 patients per year were seen in consultation but not admitted. This would include an average of 107 patients per year who have been seen at Memorial Hospital since 1979 and entered into chemotherapy trials for germ-cell tumors. Not all patients entered into chemotherapy protocols were admitted to Memorial Hospital as some were treated elsewhere. Sarcoidosis was evident in eight of the nine patients presented here during treatment and follow-up for their testis malignancy. The prevalence of sarcoidosis in patients treated for testicular
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SARCOIDOSIS AND TESTICULAR GERM CELL TUMORS / TONER AND BOSL
TABLEII PreviouslyReported Casesof TesticularGerm Cell Tumorsand PossibleSarcoidosis No. of Patients
Age
Histologyof Testis
Outcome Testis Cancer
Interval BetweenDiagnoses
Died
8 years
Stable
[12, 13]
NED (3) NS (1)
None
Regressed (1) NS (3)
[ 14-17]
NED (12) NS (1)
5 months to 8 years
Resolved (6) Regressed (5) Stable (1)
[10, 17-23]
Outcomeof Sarcoidosis
Reference
Testis malignancy after sarcoidosis diagnosed 1
33
Seminoma
Simultaneous testis malignancy and sarcoidosis diagnosis 4 33-43 Seminoma (2) Nonseminoma (2) Sarcoidosis diagnosed after testis malignancy 13
26-35
Seminoma (1) Nonseminoma (12)
NS(1)
NED = no evidenceof recurrentor metatstaticdisease;NS = not stated.
germ-cell tumors could, therefore, be estimated to be 8/1,570 or 510/100,000. COMMENTS
Nine patients with testicular germ-cell tumors and a diagnosis of sarcoidosis are presented. Eighteen patients have been described previously although in only one of these was sarcoidosis diagnosed prior to the germ-cell tumor. The five new cases of sarcoidosis occurring prior to a diagnosis of testis cancer extend the reported association of the two conditions and suggest that sarcoidosis was not caused or precipitated by the malignancy or therapy for the malignancy. All of the cases in this report and the majority of cases previously reported occurred in white men. In contrast, sarcoidosis is reported to be approximately 10 times more common in black patients in the United States [25]. Whether the predominance of reported cases of sarcoidosis and testis cancer in white patients merely reflects the patient population with testis cancer at the institutions involved or alternatively that the association of the two disorders is more common in white patients remains unclear. The association of sarcoidosis and testicular malignancies raises two major issues. The first is the difficulty of accurate staging and diagnosis that may occur as a result of concurrence of these two conditions in a single patient. The second is a possible etiologic association between the two diseases. The coexistence of sarcoidosis and testicular malignancy is rare but can confuse clinical evaluation. Several case reports have indicated the vital importance of accurate diagnostic and staging evaluation in these patients. Colebunders et al [12,13] reported a case of a young man with seminoma, a normal lymphangiogram and computed tomographic scan of the abdomen, and an abnormal chest roentgenogram with enlarged bilateral hilar nodes and nodu-
larity in the lung fields. The patient was treated for metastatic seminoma with chemotherapy and died on the fourth day of treatment. Autopsy studies showed no evidence of malignancy but extensive changes consistent with sarcoidosis. In contrast, "sarcoidosis" may mask a diagnosis of malignancy. Heffner and Milam [26] reported a case of a young man with embryonal carcinoma of the left testis with a normal abdominal computerized tomographic scan who had bilateral hilar and paratracheal nodal enlargement and lung nodules. Biopsy of mediastinal nodes was consistent with granulomatous inflammation but embryonal carcinoma was subsequently found in enlarging pulmonary nodules. Patients with sarcoidosis may develop testicular enlargement due to granulomatous inflammation [27-30]. A careful diagnostic approach is needed and orchiectomy is recommended in cases of unilateral lesions [28,31]. The need for careful histologic evaluation has been emphasized as granulomatous inflammation can be associated with testicular malignancies, especially seminoma. Pickard et al [32] reported a case of seminoma in which an initial histologic diagnosis of granulomatous orchitis was considered in view of the extensive granulomatous reaction around tiny islands of seminoma. In our experience, the clues to a diagnosis of sarcoidosis in patients with testis cancer have been the pattern of metastatic disease and radiologic findings in the chest. Patients with testicular germ-cell tumors rarely have isolated mediastinal adenopathy due to metastatic disease without simultaneous metastatic involvement of the retroperitoneum or lung parenchyma. Of 510 patients with an advanced germ-cell tumor occurring in the testis, who were treated with front-line chemotherapy protocols at this institution, 55 had metastatic spread to the mediastinum. However, the mediasti-
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Figure 1. Chest radiograph of Patient 7 at presentation showing bilateral hilar adenopathy consistent with sarcoidosis.
num was the exclusive site of metastatic disease in only four patients (0.8%). Patients diagnosed as having sarcoidosis in this report commonly had bilateral hilar and paratracheal adenopathy typical of sarcoidosis (Figure 1). If sarcoidosis is considered in the differential diagnosis, exploratory surgery is warranted when the finding of granulomatous inflammation exclusively will alter the management of the patient. Typical examples of this are Patients 6 through 9 of the current report in whom chemotherapy for metastatic disease was avoided after biopsy of mediastinal nodes showed changes consistent with sarcoidosis. The second major issue raised is the possible increased incidence of sarcoidosis in patients with testicular malignancy. The incidence and prevalence of sarcoidosis in the general population are difficult to establish because many asymptomatic cases may remain undetected. Autopsy studies suggest that the true prevalence may be four to 10 times that suggested by the number of proven cases [25]. Among 1,216,425 recruits entering the United States Navy between 1958 and 1969 the rates of diagnosis of sarcoidosis were 7.6/100,000 in whites and 76.2/100,000 in blacks [33]. All recruits had at least one chest roentgenogram performed. In a mass radiologic survey for tuberculosis, performed between 1956 and 1962 in New York City, 449,605 individuals had chest radiographs [34]. Sarcoidosis was diagnosed in 174 cases. The diagnosis was often made on radiographic appearance alone although biopsy or Kveim test was performed in over 50% of the cases. The overall prevalence rate was calculated to be 39/100,000. The prevalence in districts where more than 81% of the population was white was lower at 17/100,000. 654
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In this study, nine patients with testicular malignancies treated at Memorial Hospital since 1980 were also diagnosed to have sarcoidosis. All nine cases occurred in white patients. Eight of the nine had evidence of sarcoidosis during the same period (1980 to 1989). An exact assessment of the number of patients seen at this institution with testicular malignancy since 1980 is not possible. We estimate that an average of 157 patients per year were seen for management of a testicular germ-cell tumor. The prevalence of sarcoidosis might, therefore, be estimated to be 510/100,000 in this group. This is much higher than the rate expected from the studies quoted earlier and other international epidemiologic data [25]. However, there are a number of possible biases in this calculation that cannot be controlled and, therefore, may make this estimate unreliable. Potential biases that preclude an accurate comparison of prevalence include patient selection by referral to a tertiary institution and the increased frequency of chest radiograph studies and clinical follow-up of patients after therapy for malignancy. Another issue to be considered is the validity of a diagnosis of sarcoidosis in any patient with malignancy. Sarcoidosis is a systemic disorder of unknown etiology that is characterized pathologically by noncaseating granulomata [2,35,36]. No laboratory test unequivocally establishes the diagnosis. Granuloma formation occurs in association with more than 50 separate clinical entities. Exclusion of other possible causes of the clinical picture is, therefore, recommended before a diagnosis of sarcoidosis can be made. Sarcoid-like granulomata are found in primary malignant tumors, in the regional lymph nodes of neoplasms, and rarely in uninvolved or-
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gans such as the spleen of patients with malignancy [37]. These pathologic findings have been termed "sarcoid reactions." In patients with malignancy and features typical of sarcoidosis, the possibility that the pathologic findings in lymph nodes may be a sarcoid reaction caused by the malignancy cannot be excluded. It has, therefore, been suggested that the term sarcoidosis should not be used in patients with malignancy and a more general term such as "sarcoid-like lymphadenopathy" has been proposed [10]. Despite these reservations, the clinical features and course of patients presented in this report were typical of sarcoidosis. Among the nine patients presented, only three received systemic chemotherapy and in two of these the sarcoidosis preceded the diagnosis of malignancy by at least 8 years. The remaining patients received only surgery or radiotherapy directed at the primary tumor or retroperitoneal nodes. No patients have had a relapse of the malignancy despite prolonged follow-up in the majority. This tends to preclude the possibility that the changes in mediastinal nodes were a result of unrecognized pulmonary or disseminated malignancy. Three patients in this series had sarcoidosis diagnosed at least 8 years prior to the finding of the testis tumor. In these patients, it is very unlikely that the sarcoidosis was related to the malignancy. The clinical course in all our patients was also typical of sarcoidosis. Four patients who received no treatment for sarcoidosis and two patients who had brief courses of prednisone therapy had regression or resolution of the abnormal radiologic findings. Two patients, who have remained asymptomatic and received no therapy, have had little change in their chest roentgenogram findings. Whether a diagnosis of sarcoidosis or 8arcoid-like lymphadenopathy is used, it is clear that, after the diagnosis of a germ-cell tumor, the findings of hilar and mediastinal adenopathy with noncaseating granulomata are not necessarily a harbinger of recurrent malignancy. These patients can be safely observed after careful evaluation, including biopsy, to exclude recurrent or metastatic tumor. Patients with sarcoidosis may have an increased incidence of testis cancer but further epidemiologic data are required. If testicular enlargement develops in a patient with sarcoidosis, a detailed evaluation to exclude testicular malignancy is needed including orchiectomy for unilateral lesions. Lastly, when patients with newly diagnosed testicular germ-cell tumors also have an abnormal chest radiograph, sarcoidosis should be considered in the differential diagnosis. This is especially true if there is no abdominal or pulmonary metastases and the pattern of mediastinal adenopathy is typical of sarcoidosis.
Surgical exploration is warranted if the finding of granulomatous inflammation alone in the chest will change the patient's management. Increased awareness of the association of testicular germ-cell tumors and sarcoidosis or sarcoid-like adenopathy will help to avoid errors in the diagnosis, staging, and management of patients with this malignancy. Further epidemiologic studies are indicated and may reveal an etiologic link between the two conditions.
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25. TeJrstein AS, Lesser M. Worldwide distribution and epidemiology of sarcoidosis. In: Fanburg BL, ed., Sarcoidosis and other granulomatous diseases of the lung. New York: Marcel Dekker, Inc, 1983, 10i-34. 26. Heffner JE, Milam MG. Sarcoid-like hilar and mediastinal lymphadenopathy in a patient with metastatic testicular cancer. Cancer 1987; 60: 1545-7. 27. Chowdhury 8D, Higgms PM. 8arcoid of the testis. Br J Uro11973; 45: 21820. 28. Haas GP, Badalament R, Wonnell DM, Miles BJ. Testicular sarcoidosis: case report and review of the literature. J Urol 1986; 135: 1254-6. 29. McWilliarns WA, Abramowitz L, Tiamson EM. Epididymal sarcoidosis: case report and review. J Urol 1983; 130: 1201-3. 30, Opal SM, Pittman DL, Hofeldt FE. Testicular sarcoidosis. Am J Med 1979; 67: 147-50. 31. Seaworth JF, Davis SJ, Donovan WN. Aggressive diagnostic approach indi-
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cated in testicular sarcoidosis. Urology 1983; 21: 396-8. 32. Pickard WR, Clark AH, Abel BJ. Florid granulomatous reaction in a seminoma. Postgrad Med J 1983; 59: 334-5. 33. Sartwell PE, Edwards LB. Epidemiology of sarcoidosis in the U.S. navy. Am J Epidemiol 1974; 99: 250-7. 34. Robins AB, Abeles H, Chaves AD. Prevalence and Demographic Characteristics of Sarcoidosis. New York: Bureau of Tuberculosis, the City of New York, Department of Health, 1962, 149-51. 35. Mitchell DN, Scadding JG, Heard BE, Hinson KFW. Sarcoidosis: histopathological definition and clinical diagnosis. J Clin Pathol 1977; 30: 395-408. 36. Daniele RP, Rossman MD, Kern JA, Elias JA. Pathogenesis of sarcoidosis. State of the art. Chest 1986; 89: 174S-7S. 37. Brincker H. Sarcoid reactions in malignant tumours. Cancer Treat Rev 1986; 13: 147-156.
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