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EW: A 51-year-old Caucasian male smoker (>30 pack-year) was referred due to generalised lymphadenopathy and disseminated, apical accentuated pulmonary nodules (up to 12 mm) on CT scans that demonstrated an elevated 18F-FDG uptake. There was a history of childhood pulmonary tuberculosis with ongoing positivity in the interferon-gamma release assay. The patient had night sweats and frequent coughs.
Lymph node and bone marrow biopsies demonstrated infiltration by a small cell lymphocytic lymphoma-Non Hodgkin Lymphoma (SCL-NHL) with chronic lymphocytic leukemia (CLL-like) immunophenotype (Matutes score 4/5) staged as Ann Arbor IV B disease (figure 1A,B).
WW: SCL-NHL is an indolent B-cell-Non-Hodgkin Lympoma (B-NHL), biologically quite related to CLL with a more nodal and less leukaemic pattern of involvement. Treatment indication is based on severity of symptoms or the development of complications. Extranodal pulmonary involvement would be a highly unusual presentation of SCL-NHL.
EW: Lung function tests were suggestive of a restrictive pattern (forced vital capacity 3.19 L, 60.9%; forced expiratory volume in one second 2.43 L, 56.8%; R 76.24%) and diffusing capacity of the lung for carbon monoxide was mildly reduced (72.9%). Due to the CT findings suspicious of infectious disease, lymphoma infiltration or metastasis a CT-guided lung biopsy was performed.
The initial pulmonary histological examination revealed eosinophilic pneumonia.
JLR: The nodular radiographic pattern was not compatible with the diagnosis of eosinophilic pneumonia, and therefore, an external reference pathologist was involved. The ‘eosinophils’ revealed to be CD1a positive Langerhans cells with eosinophilic cytoplasm organised into loosely formed granulomas. In addition, molecular analysis confirmed the presence of the BRAF V600E mutation (figure 1C,D,F). Meanwhile, a follow-up CT scan showed beginning cavitation of the pulmonary nodules.
These findings and the disease course now established the diagnosis of pulmonary Langerhans cell histiocytosis (PLCH). No extra pulmonary involvement of PLCH was observed, neither histologically nor in the imaging studies.
PLCH is a rare diagnosis, difficult to recognise due to variable presenting manifestations.1 The diagnosis should be considered in young to middle-aged smokers with upper lobe predominant small nodules associated with thin-walled and/or thick-walled cysts on high-resolution CT scans. These characteristic radiological features are sufficient to establish a presumptive diagnosis. Whenever feasible a lung biopsy with histological confirmation of typical lesions should be performed. At initial presentation, the patient did not show typical PLCH high-resolution CT aspects, presenting with large randomly distributed pulmonary nodules (up to 12 mm). However, the initial histological diagnosis of eosinophilic pneumonia was not compatible with the radiological pattern. An interdisciplinary discussion and re-evaluation resulted in the diagnosis of PLCH. The FDG uptake was compatible with this diagnosis, but unspecific. Predominant nodular patterns of PLCH have been described in rare instances and may determine the early phase of the disease, whereas cystic patterns prevail in later phases. To the best of our knowledge, it has yet still to be determined how cystic lesions are formed, and the dynamics of lung parenchymal abnormalities evolve.
PLCH is a differential diagnosis in smokers with isolated nodular lesions of upper lung fields. Expert histological confirmation is of paramount importance.
JLR: Analyses of PLCH tissues recently revealed activating mutations of specific mitogen-activated protein kinases (BRAF V600E and others). The current consensus is that PLCH represents a myeloid-derived neoplasm with inflammatory properties: the myeloid tumour cells exhibit surface CD1a expression and up to 50% of patients harbour activating BRAF or other MAPK mutations (Youssem et al. Chest . 2013 Jun;143(6):1679-1684).
EW: Because of the unusual double malignancy diagnosed in this patient, an extensive molecular analysis of both tumours as well as the patient’s germ line and somatic (lymphocytic) genetic background (in buccal swabs and Fluorescent activated cell sorting (FACS) sorted normal peripheral lymphocytes) by next generation sequencing (NGS) was entertained.
The NGS analysis demonstrated a ‘tumour-prone’ genetic background in the patient harbouring germ line mutations in KIT, KDR and SMAD4 (heterozygous) and an inactivating homozygous p53 mutation. The SCL-NHL harboured additionally the same BRAF V600E mutation, in both lymph node and bone marrow biopsies, (figure 1) as the PLCH, while the PLCH had acquired an additional activating NOTCH1 mutation. Furthermore, both tumours, as well as the normal peripheral lymphocytes had acquired the same distinct second non-frameshift KDR deletion.
WW: Up to now no cases of BRAF mutations in SCL-NHL have been described, while rare cases (<5%) of mutated CLL have been identified analysing large series of patients.2
What makes this case intriguing is the possibility to draw a hypothetical clonal architecture from the germ line to the lymphocyte compartment via the lymphoma to the PLCH. Thus, we can hypothesise either a linear evolution from a lymphoid to a putatively myeloid neoplasm or (more probable) a branching evolution from an early non-line committed haematological precursor cell. This is corroborated by the findings of Berres et al 3 demonstrating the existence of BRAF mutated circulating lymphocytes and haematological precursor cells in patients with PLCH. Additionally, one should bear in mind that the typical CD1a expression in PLCH is also highly conserved in thymic T-ALL. Furthermore, other groups have reported the transdifferentiation of PLCH from follicular lymphomas4 and the coexistence of PLCH with Hodgkin’s lymphoma.5 Adding to these data the case of this patient challenges the current theories on the tumourigenesis of PLCH, at least in some cases.
The evolution of PLCH might not be a purely myeloid derivation in all cases.
EW: After failure of tobacco abstinence alone, treatment with daily orally methylprednisolon (4 weeks 30 mg, 3 weeks 20 mg, 10 mg maintenance) was initiated with impressive regression of pulmonary nodules and residual infiltration after 1 month of therapy, as well as a massive diminishment of the lesions 18F-FDG uptake on Positron-Emission-Tomography (PET-CT). Measures of lung function returned to normal.
Substitutet Overlappingly by Concurrently, the lymphoma was treated first with rituximab monotherapy 375 mg/m² d1 q 28 intravenously without achieving an objective response. Thus, we escalated to chemoimmunotherapy therapy adding bendamustine 70 mg/m² d1, 2 q28 intravenously (BR). After 6x cycles of BR, the patient achieved an ongoing complete remission. Long-term follow-up over 6 years shows haematological and pulmonal remission of both BRAF-mutated diseases. Unfortunately, the patient started again to smoke.
Responses to smoking cessation and/or steroid monotherapy in PLCH can be complete and durable, even in case of complex underlying genetic alterations. Because of frequent spontaneous regression of lesions, smoking cessation alone should come first.
WW: The treatment of the SCL-NHL was straightforward, and standard of care chemoimmunotherapy was applied with achieving a long-lasting, ongoing complete remission.
JLR: The disease course of PLCH is unpredictable in the individual patient and lesions may frequently resolve spontaneously, as has been reported in the context of Hodgkin’s disease-associated PLCH.5 Therefore, the general recommendation is smoking cessation with close follow-up. A smoking cessation programme was initiated but was not of permanent success. Oral corticosteroids (OCS) have no controlled proof of efficacy but are described in progressive disease. Cladribine is currently evaluated in a phase II trial in patients with PLCH.1 The presented patient responded to OCS within 1 month of therapy. The long-term impact of this strategy in BRAF V600E positive PLCH patients and the possible usefulness of targeted therapies with BRAF inhibitors (eg, vemurafenib, dabrafenib, etc) in progressive refractory PLCH remains to be validated clinically. However, early therapeutic intervention, before conversion into cystic stages of PLCH, in a ‘nodule-rich’ stage may have the largest benefit.
Contributors Conception and design: EW, WW and JL-R. Development of methodology: EW, WW and JL-R. Acquisition of data: EW, WW and JL-R. Analysis and interpretation of data: EW, WW and JL-R. Writing, review and/or revision of the manuscript: EW, WW andJL-R. Study supervision: EW, WW and JL-R.
Funding This work was supported by the Krebsforschungsverein Tirol, a registered charity.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Obtained.