To the Editor: A woman in her 60s was admitted to the hospital for exploration of erythema nodosum, lower limb edema, and asthenia. Clinical examination revealed no other abnormalities, and autoimmune and infection results were normal. 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) was performed and showed upper mediastinal, peritracheal, hilar, and left paracardiac adenopathies with strong hypermetabolism (maximum standard uptake value of 18). Surgical biopsy specimens of a mediastinal lymphadenopathy were obtained by cervicotomy and revealed abundant histiocytes. Immunostaining was positive for CD45, CD123, CD14, CD4, and CD33 and negative for CD56, ALK, CD34, CD117, S100, CD1a, and CD68. Almost 90% of tumor cells displayed positive staining for programmed cell death ligand 1 (PD-L1), and phospho-ERK expression was strong. Next-generation sequencing targeting was performed for 75 genes principally involved in the MAP kinase cell signaling pathway; a CALR mutation was identified but no BRAF mutation. The diagnosis was consistent with malignant histiocytosis according to the revised classification of the Histiocyte Society.1Emile J.F. Abla O. Fraitag S. et al.Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages.Monochemotherapy with 60 mg/m2 of doxorubicin was initiated. After 7 cycles, the clinical disorders had resolved, and FDG PET/CT revealed a general improvement of all lesions. However, 4 months later, disease progression was observed. In light of the phospho-ERK overexpression, targeted anti-MEK therapy was initiated. After 7 months of treatment with trametinib, FDG PET/CT showed disease progression. Compassionate treatment with 3 mg/kg of nivolumab was therefore initiated. After 3 courses of treatment, FDG PET/CT revealed a substantial response, with a clear decrease in the number and intensity of hypermetabolic lymphadenopathies (Figure).

Figure18F-Fluorodeoxyglucose positron emission tomography/computed tomography before (A) and after (B) 3 courses of nivolumab, showing a marked regression of the number and intensity of thoracic hypermetabolic adenopathies. Only hypermetabolic nodes persist: left supraclavicular, maximum standard uptake value (SUVmax) of 9 vs 21; anterior para-aortic mediastinal, SUVmax of 10 vs 27; left internal mammary, SUVmax of 14 vs 13; left anterior paracardiac, SUVmax of 3 vs 33. A regression of the size and intensity of paramediastinal infiltration (SUVmax, 5.6 vs 34) was also observed.

Malignant histiocytosis (or histiocytic sarcoma) is a rare disease characterized by a malignant proliferation of cells resembling mature tissue histiocytes.1Emile J.F. Abla O. Fraitag S. et al.Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Median age at diagnosis is 63 years; the prognosis is usually poor, with a median overall survival of 6 months, because no standard treatment has yet been established and responses to conventional chemotherapy at advanced stages are generally poor.2Kommalapati A. Tella S.H. Durkin M. Go R.S. Goyal G. Histiocytic sarcoma: a population-based analysis of incidence, demographic disparities, and long-term outcomes. Mutations affecting the RAS-MAPK signaling pathway are detected in most cases,3Shanmugam V. Griffin G.K. Jacobsen E.D. Fletcher C.D. Sholl L.M. Hornick J.L. Identification of diverse activating mutations of the RAS-MAPK pathway in histiocytic sarcoma. and the off-label use of targeted therapies has been reported to yield clinical responses in several cases.4Jacobsen E. Shanmugam V. Jagannathan J. Rosai-Dorfman disease with activating KRAS mutation—response to cobimetinib. It has been suggested that PD-L1 expression is detectable in most cases, but the utility of PD-L1/PD-1 blockade in histiocytic neoplasms remains unclear.5Xu J. Sun H.H. Fletcher C.D.M. et al.Expression of programmed cell death 1 ligands (PD-L1 and PD-L2) in histiocytic and dendritic cell disorders. We report here the first case of a response to nivolumab in an adult with malignant histiocytosis. Next-generation sequencing appears to be essential for the diagnosis of this rare histiocytic condition, given the therapeutic options available. However, immune checkpoint inhibition may also be a valuable therapeutic option for patients with malignant histiocytosis expressing PD-L1.Potential Competing Interests

L.C. and J-P.S.: consultant or advisory role (fees): Bristol Myers Squibb. J.H., J-F.E., A.V. and D.K. have no conflicts of interest to disclose.

ReferencesEmile J.F. Abla O. Fraitag S. et al.

Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages.

Blood. 127: 2672-2681Kommalapati A. Tella S.H. Durkin M. Go R.S. Goyal G.

Histiocytic sarcoma: a population-based analysis of incidence, demographic disparities, and long-term outcomes.

Blood. 131: 265-268Shanmugam V. Griffin G.K. Jacobsen E.D. Fletcher C.D. Sholl L.M. Hornick J.L.

Identification of diverse activating mutations of the RAS-MAPK pathway in histiocytic sarcoma.

Mod Pathol. 32: 830-843Jacobsen E. Shanmugam V. Jagannathan J.

Rosai-Dorfman disease with activating KRAS mutation—response to cobimetinib.

N Engl J Med. 377: 2398-2399Xu J. Sun H.H. Fletcher C.D.M. et al.

Expression of programmed cell death 1 ligands (PD-L1 and PD-L2) in histiocytic and dendritic cell disorders.

Am J Surg Pathol. 40: 443-453Article InfoIdentification

DOI: https://doi.org/10.1016/j.mayocp.2022.05.012

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