1. Sarcoidosis & Cancer Giulio Rossi Anatomia Patologica Azienda Policlinico di Modena giurossi68@gmail.com

2. Sarcoidosis Sarcoidosis is a systemic inflammatory disorder of unknown etiology, characterized pathologically by noncaseating epithelioid cell granulomas, primarily involving the lungs and the lymphatics Chronic disease with variable manifestations and clinical course Diagnosis is established when compatible clinico-radiological features are supported by histological evidence of noncaseating epithelioid granulomas

3. Triggered by persistent presentation of as-yet unidentified, poorly degradable antigen(s) in genetically susceptible hosts Th1-type cellular immune response leading to noncaseating epithelioid granulomas Helpful diagnostic tools CD4/CD8 ratio > 3.5 in BAL Angiotensin-converting enzyme (ACE) levels twice higher than the upper normal limit typical abnormal calcium metabolism negative bacterial or fungal cultures may be helpful in establishing the diagnosis Spagnolo P, et al. Am J Med 2012; 125: 118-125 Sarcoidosis

4. Histology of sarcoidosis Granuloma is the histologic hallmark of sarcoidosis Morphology: well formed, compact, generally non- necrotizing, typically surrounded by a rim of lamellar hyaline collagen Growth pattern Granulomas typically coalesce along the lymphatic routes in the pleura, interlobular septa, and bronchovascular bundles Cavazza A, et al. Int J Surg Pathol 2009; 17: 219-230

5. Courtesy: Dr. Cavazza (Reggio Emilia)

6. Sarcoidosis vs sarcoid-like reaction Premise At histology, it may be very challenging, if not impossible, to differentiate sarcoidosis from sarcoid-like reaction These latter may commonly occur either adjacent to the primary malignant site or to local drainage nodes, possibly representing an immunological hypersensitivity reaction to tumor cells

7. Sarcoidosis & Cancer merely a coincidence common pathophysiologic mechanism

8. Incidence of lymphoproliferative disorders is higher among sarcoidosis patients as compared with the general population Precise mechanism of this association is unclear: the chronic active type of sarcoidosis appears to be responsible for an increased risk of malignant transformation of lymphoid cells Persistent active sarcoidosis, anergy, and lymphopenia are usually associated with the syndrome

9. There exists a syndrome of sarcoidosis following malignancy with/without chemotherapy (9 months median interval)

10. Lymphoma-sarcoidosis syndrome Patients with different hematologic malignancies (Hodgkin and non-Hodgkin lymphoma but also T-cell lymphoma, mycosis fungoides, chronic lymphocytic leukemia, nonlymphocytic leukemia) may subsequently develop sarcoidosis Sarcoidosis triggered by the immunosuppressive treatment (?)

11. Chronic inflammation is associated with an increased risk for malignant lymphomas or cancer in the affected tissue

12. Incidence of cancer among 2,013 White and 3,755 Black male patients admitted to Veterans hospitals in the United States during 1969–1996 with a diagnosis of sarcoidosis, with that of 2,792,503 White and 662,204 Black non-sarcoidosis patients admitted to the same hospitals Sarcoidosis patients experience an increased risk of some neoplasms, in particular colo-rectal and renal cancer

13. This study does not support the theory of an association between sarcoidosis and malignancy Selection bias and misclassification

14. Sarcoid reactions in mediastinal lymph nodes occurred in up to 3% of lung cancer cases Relationship between a malignant tumor and sarcoid reaction is a host-versus-tumor response, or a reaction to metabolic disintegration substances released from tumor cells

15. Sarcoid-like reaction was suspected in 1.1% of cancer patients at FDG PET/CT examination SUVmax of confirmed hilar and mediastinal sarcoid- like reaction was 7.3 (range 3.1e13.6) Important to avoid a false-positive interpretation of metastatic disease

16. Sarcoidosis or sarcoid-like reaction ? Several solid tumors (e.g., breast, kidney, testis, lung, melanoma, colon, liver) may show sarcoid-like reactions associated with malignancy, adjacent to the primary malignant site or in local drainage nodes, or at distant sites The majority of the works describing sarcoidosis with cancer report on the presence of non- caseating granulomas in patients who do not fulfill the diagnostic criteria for systemic sarcoidosis The latter situation is the most challenging to diagnose

17. Sarcoidosis or sarcoid-like reaction ?

18. Common variable immunodeficiency Crohn disease Sjogren Drug toxicity (methotrexate) Sclerosing cholangitis Sarcoid-like granulomas in different diseases Courtesy: Dr. Cavazza (Reggio Emilia)

19. Sarcoidosis & colon cancer metastasis

20. “sarcoidosic nodule with numerous epithelioid granulomas and giant cells in the medium lobe” Intrapulmonary reactive lymph node with sarcoid-like reaction

21. Imaging studies alone (CT or 18FDG-PET) failed to discriminate sarcoid-like reaction from metastasis Pathologic confirmation is mandatory FNA cytology is a less invasive and highly effective method in differentiating cancer from sarcoidosis/sarcoid-like reaction A diagnosis of sarcoidosis is based on clinical and radiological presentation, evidence of non-caseating granulomas, and evidence of no alternative diseases Sarcoidosis or sarcoid-like reaction ? Valeyre D, et al. Sarcoidosis. Lancet 2014; 383: 1155–67

22. Final remarks -Sarcoidosis and cancer may co-exist - The mechanisms underlying the association of these 2 diseases is poorly-elucidated - A patient with sarcoidosis may develop a cancer, but even a sarcoid-like reaction may commonly occur in a patient with cancer and may lead to an erroneous diagnosis of cancer progression - In cases of mediastinal nodes, fine needle aspiration cytology can effectively differentiate cancer from sarcoid- like granulomas/sarcoidosis - Sarcoid-like reaction at histology does not mean sarcoidosis (misdiagnosis !) - Whether patients with sarcoidosis have an increased risk for developing malignancies is still debatable - Unbiased studies on large populations are needed