Coexistence of Sarcoidosis and Malignancy

LTC (ret) William E. Caras, MD, FCCP, COL (ret) Thomas Dillard, MD, FCCP, LTC Thomas Baker, MD, COL (ret) Jerry Pluss, MD, FCCP

Disclosures

South Med J. 2003;96(9) 

In This Article

Discussion

The proposed link between sarcoidosis and malignancy has remained controversial ever since Brincker and Wilbek's[1] original investigation nearly three decades ago. Evidence favoring an association between sarcoidosis and malignancy is based on case reporting and statistical analysis from cross-registry studies.

After Brincker and Wilbek's[1] study in 1973, many investigators began to report a wide variety of lymphoreticular neoplasms among sarcoid patients. Finke et al[3] reported a case of malignant lymphoplasmacytoid lymphoma associated with a monoclonal band on electrophoresis in a patient with prior histologically confirmed sarcoidosis. Karakantza et al[4] reported five cases of lymphoreticular neoplasms in patients with a biopsy-proved sarcoid. On the basis of cumulative experience, the term sarcoid-lymphoma syndrome emerged. The typical features of this syndrome are the development of lymphoreticular neoplasms, especially Hodgkin's lymphoma, in a patient with a preexisting diagnosis of sarcoidosis. Typically, the patient is older than average for the sarcoid population (median, 45 years of age) and has had chronically active pulmonary sarcoidosis for a period of several years. Patient 1 in this article represents an example of the sarcoid-lymphoma syndrome.

In Brincker and Wilbek's[1] original investigation, an excess of lung malignancies was also noted. Since then, other investigators have noted the development of solid tumors in patients with biopsy-proved sarcoidosis. Most of these reports have involved cases of breast or lung cancer, but other solid tumors including testicular, ovarian, uterine, and gastric cancer have been noted as well.[5] In 1990, Suen et al[6] reported six cases of patients with biopsy-proved malignancy that preceded the diagnosis of sarcoidosis and used the term malignancy-sarcoidosis syndrome to describe their clinical experience. Four of their six cases involved lymphoproliferative diseases (HD, NHL, and T-cell lymphoma), and all had biopsy-proved sarcoidosis that was diagnosed an average of 9 months after the development of malignancy.

To avoid the observer bias inherent with case reporting, epidemiologic surveys have been used to examine the relationship between sarcoid and malignancy. Yamaguchi et al[7] examined the incidence of malignancy in a nationwide prevalence survey of sarcoid patients in Japan. Excess deaths were analyzed by calculating standardized mortality ratios. Excess lung cancer and uterine cancer deaths were noted (standardized mortality ratios of 3.26 and 8.7, respectively). Askling et al[8] studied two cohorts of sarcoid patients, one consisting of 474 consecutively diagnosed sarcoid patients from Uppsala County in Sweden and a second, larger group of 8,541 patients identified from a national inpatient sarcoid registry. Over a 30-year period, both groups were cross-referenced to nationwide cancer and death registries. Standardized incidence ratios were determined for a variety of malignancies and were increased in both cohorts for lung cancer, skin cancer, and melanoma. The risk of lymphomas was increased in the inpatient cohort as well.

As with case reporting, there are problems inherent with epidemiologic studies, which can confound any link between sarcoid and malignancy. Misclassification is perhaps the most significant. Misclassification occurs when either sarcoid or malignancy is misdiagnosed. For example, a mass-like lesion on CXR in a patient with sarcoidosis may be attributed to malignancy when, in fact, it is due to sarcoid. Likewise, mediastinal adenopathy in a patient with known malignancy is often assumed to be cancer when, in fact, it could represent thoracic sarcoid. To make matters more confusing, the histologic hallmark of sarcoid, noncaseating granulomas, can be seen in lymph nodes and other tissues as a nonspecific reaction to malignancy and has been termed the sarcoid reaction.[9] The importance of misclassification was stressed by Seersholm et al,[10] who noted misclassification of 3 of 36 malignancies in an epidemiologic survey of 254 sarcoid patients. After taking these into account, they found no link between sarcoid and lymphoma, although a link between sarcoid and other malignancies could not be disproved. In an effort to circumvent some of these problems, Reich et al[11] used "clinical linkage criteria" to assess the true relationship between malignancy and sarcoidosis. Their linkage criteria included close temporal relationship between sarcoid and malignancy and the presence of local sarcoid reactions that generalize over time. Reich et al proposed that sarcoidosis might represent an immunologic reaction to dispersal of tumor antigen. The complex linkage criteria proposed by Reich et al have thus far not been uniformly accepted in establishing linkage between sarcoid and malignancy.

To date, the link between sarcoid and malignancy is unproved, and some authors continue to doubt whether any association truly exists. However, clinicians should be aware of the potential risk of malignancy in sarcoid patients. Until more definitive data are available, sarcoid patients who develop new lesions or adenopathy should be considered for histologic biopsy to rule out coexistent neoplasm. Furthermore, in patients with established malignancy and newly discovered radiographic findings, the possibility of sarcoidosis should be considered.

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