BRAF-Mutant Pulmonary Langerhans Cell Histiocytosis Mimicking Recurrence of Early-Stage KRAS-Mutant Lung Adenocarcinoma

Surveillance imaging after the resection of early-stage lung cancer is the primary method for identifying recurrence; however, new pulmonary nodules on the imaging may result from multiple alternative causes. We describe a patient with early-stage lung adenocarcinoma, treated with platinum-doublet chemotherapy and programmed cell death protein 1 inhibitor followed by surgical resection, who developed bilateral pulmonary nodules concerning for progression.

Case Report

A 45-year-old woman with chronic obstructive pulmonary disease and currently use tobacco (>30 pack-years) presented with right-sided chest pain, hemoptysis, and night sweats. Initial computed tomography (CT) imaging results revealed a 2.1-cm spiculated right upper lobe lesion (Fig. 1A) and right hilar and right paratracheal adenopathy. The results of a 4R lymph node biopsy revealed lung adenocarcinoma (Fig. 2A), consistent with stage IIIB disease and a programmed death-ligand 1 tumor proportion score of 70% (Fig. 2B). She received an investigational neoadjuvant regimen of platinum, pemetrexed, and a programmed cell death protein-1 inhibitor, followed by right upper and lower lobe wedge resections with lymph node dissection. Right upper lobe histopathology revealed a fibrotic nodule with chronic inflammation in a 1.3-cm tumor bed, with no residual viable tumor in the primary tumor and eight hilar and mediastinal lymph nodes, consistent with complete histopathologic response (Fig. 2C). A separate lesion was found in the right lower lobe (Fig. 2D), present in a background of smoking-related changes, including desquamative interstitial pneumonia-type airspace filling and nodular peribronchiolar scars; results of Langerin and CD1a stains revealed scattered Langerhans cells. This lesion had a programmed death-ligand 1 tumor proportion score of 0% and KRAS G12D mutation, without other oncogenic alterations (Fig. 3A).

Figure 1.

CT scan of the chest. (A) The patient’s right upper lobe lesion (arrow) was noted on initial presentation. (B) Two months after wedge resection of the patient’s primary tumor, the imaging result revealed the development of bilateral pulmonary nodules (arrows), predominantly in the upper lobes of the lungs. (C) A repeat CT scan 3 months after the surgery revealed increased size and density of these irregular nodules (arrows), which are somewhat centrilobular in distribution; some nodules had cavitation (black arrows). (D) Imaging 4 months after the diagnosis of LCH revealed a decrease in size and density of these nodules. CT, computed tomography; LCH, Langerhans cell histiocytosis.

Figure 2.

Histologic findings. (A) The result of the patient’s initial 4R lymph node biopsy (H&E) revealed lung adenocarcinoma, (B) with PD-L1 immunohistochemistry revealing a TPS of 70%. (C) After chemoimmunotherapy and surgery, the right upper lobe tumor bed (H&E) had complete pathologic response, (D) whereas the right lower lobe lesion (H&E) was found to contain adenocarcinoma. (E) A sample of the left upper lobe tissue obtained after the development of bilateral pulmonary nodules (H&E) was found to have nodules of histiocytes and eosinophils in a fibrous background, consistent with pulmonary LCH, confirmed by immunohistochemical staining for (F) Langerin. Scale bars are as follows: (A) 50 μm, (B) 50 μm, (C) 200 μm, (D) 100 μm, (E) 20 μm, and (F) 20 μm. H&E, hematoxylin and eosin; LCH, Langerhans cell histiocytosis; PD-L1, programmed death-ligand 1; TPS, tumor proportion score.

Figure 3.

Genomic sequencing. (A) Tissue from the patient’s right upper lobectomy containing the primary tumor revealed a KRAS c.35G>A (p.G12D) mutation (top panel) and BRAF wild type (bottom panel). (B) Sequencing of tissue from the patient’s wedge resection containing the pulmonary LCH identified a BRAF c.1799T>A (p.V600E) mutation (bottom panel) with no KRAS mutation (top panel). LCH, Langerhans cell histiocytosis.

Imaging 1 month after the surgery was unremarkable. The patient developed pleuritic chest pain 2 months after the surgery, and a chest CT result revealed scattered, small nodules bilaterally, predominantly in the upper lobes of the lungs, with unchanged lymphadenopathy (Fig. 1B). The chest CT result approximately 3 months after the surgery revealed new, increasing nodules, and the patient underwent diagnostic left upper lobe wedge resection. Histopathologic examination revealed Langerhans cell histiocytosis (Fig. 2E), positive for CD1a, Langerin (Fig. 2F), and S100, without evidence of recurrence. Genomic sequencing identified a BRAF V600E mutation and no KRAS mutation (Fig. 3B). The imaging 1 month after the patient’s left upper lobe resection revealed irregular nodules (Fig. 1C), with subsequent scans after tobacco reduction revealing reduced nodule size and density (Fig. 1D).

Discussion

There are many radiographic mimics of lung cancer, including lymphoproliferative disorders, infectious or inflammatory processes, vascular conditions, and second malignancy.1, 2, 3 Given previous treatment with an immune checkpoint inhibitor, an immune-related pneumonitis must be considered.⁴ Although pulmonary Langerhans cell histiocytosis is rarely diagnosed in the setting of lung cancer, reports in association with primary lung cancers exist.⁵ It is challenging to exclude lung cancer recurrence on the basis of imaging and clinical findings alone, and, in our patient, coexisting lymphadenopathy increased the concern for malignant progression.³ Although recurrent malignancy must be considered with new or progressing imaging findings, histopathologic analysis is critical in distinguishing cancer recurrence from alternative diagnoses.