PLCH: The Prototypical Adult Pulmonary

Histiocytic Disorder

Introduction

PLCH typically occurs in younger adults, usually during the third or fourth decade of life, but can also affect older individuals [1]. PLCH is best characterized as a progressive lung disease of smokers that causes extensive infammation and cystic and nodular remodeling in the lung. The disease has been reported to be more common in males, but the sex discrepancy has narrowed over time as the prevalence of smoking in males and females has declined in both groups and become more equal. It is important to note key similarities and differences between PLCH and LCH. Both LCH and PLCH are caused by the in ltration of tissues with mutant myeloid cells. LCH usually presents in childhood as localized or systemic disease, but it can also occur in adults. The disease has been reported to be more common in males in some series, but not all. LCH can result in lytic lesions in bones, mass lesions in subcutaneous tissues or lymph nodes, skin lesions, CNS involvement, and visceral in ltration, including the lung. The pulmonary involvement in children with LCH is usually in the form of nodules. The most striking epidemiological characteristic that distinguishes adult LCH from PLCH is the almost invariable association with smoking in the latter, usually with consumption rates of more than 20 cigarettes per day [19]. PLCH most commonly presents as a single-system disease, affecting only the lungs, but can also be associated with extrapulmonary manifestations, including bone lesions, pituitary in ltration resulting in diabetes insipidus, and skin lesions [19]. Occasionally, children with LCH who begin smoking as teenagers develop extensive cystic and nodular changes in the lung. Although we recognize that LCH is a spectrum of disorders with considerable overlap, the classi cation of LCH that we prefer includes LCH, adult LCH, and PLCH.

The nomenclature that has been used to describe PLCH has evolved over time. Abandoned names for PLCH include eosinophilic granuloma of the lung, pulmonary Langerhans cell granulomatosis, and pulmonary histiocytosis X. Even the term PLCH is a bit of a misnomer because the characteristic cells within the PLCH lesion do not have all the elements of a true Langerhans cell. Initial descriptions of ‘Langerhans cells’ in PLCH lesions were based on the presence of Birbeck granules but the neoplastic cells of PLCH do not share the same antigen-presenting functions of epidermal Langerhans cells and have features that suggest developmental arrest in an early state of cell activation [13].

Cellular and Molecular Pathogenesis

The pathophysiology of PLCH is incompletely understood, but likely involves an abnormal immune response to toxic substances present in cigarette smoke or to cells injured by smoke [20]. Dendritic cells normally reside in epithelial linings and submucosa and sample epithelial fuid for foreign antigens through the extension of dendritic-like projections between epithelial cells [1, 6]. When dendritic cells are exposed to antigens, toll-like receptors (TLR) and CD40 receptors are activated leading to maturation, activation, migration to lymphoid tissue, and co-stimulation of B and T cells [1, 6, 11, 20]. Accumulation of dendritic cells is more likely related to recruitment or enhanced survival than local proliferation, based on the low expression of proliferation markers in affected tissues [1, 8, 20]. Finally, when dendritic cells accumulate in a tissue, an infammatory cascade is triggered that results in the recruitment of abundant stromal cells that cause destructive remodeling and varying degrees of organ dysfunction [6].

The identi cation of activating mutations in the MAPK pathway in LCH followed by PLCH has provided valuable insights into disease pathogenesis [11] (Fig. 16.1). The most common mutation identi ed to date has been in BRAF which, as part of the RAS signaling pathway, integrates signals from cell surface receptor tyrosine kinases. Activating mutations (such as the most common BRAF V600E) trigger a signaling cascade that culminates in the translocation of ERK (MAPK) to the nucleus, where it activates gene transcription regulating processes such as cell survival and proinfammatory mediator production. These signaling events play essential roles in mediating cellular differentiation, proliferation, senescence, and survival in response to diverse extracellular cues [8]. Additional studies have now identi ed many additional mutations in RAS/MAPK pathway proteins [4, 21]. Recent data suggests that disease pathogenesis depends in part on the stage of myeloid differentiation at which mutations occur (Fig. 16.2).

Pathology

Gross pathologic evaluation of the PLCH lung demonstrates cysts on the pleural and cut surfaces that can be small, 1–5 mm, or as large as 15 mm, and which can become increasingly profuse and coalescent in late disease evolving into large bullous and cystic lesions [1, 9]. PLCH can affect the bronchiolar, interstitial, alveolar, and vascular compartments of the lung, and is often associated with hyperinfation

Fig. 16.3  Pathology of Langerhans cell histiocytosis (LCH). (a, b) Pulmonary-based LCH is a bronchocentric disease with nodular aggregates of lesional histiocytes destroying the airways and leading to cystic airspaces (a, H&E 2×). The LCH cells are composed of ovoid cells with indented nuclear contours and ample eosinophilic cytoplasm with a few admixed eosinophils (b, H&E 100×). The lesional cells are highlighted by CD1a (c, immunostain 20×, d, immunostain 100×) and Langerin/

CD207, which highlights many but not all of the cells as it corresponds to the cytoplasmic Birbeck granules (e, immunostain 2×, f, immunostain 100×). Pulmonary LCH may harbor mutations in MAPK pathway for which the mutant-speci c BRAF VE1 immunostain with strong expression (2–3+) correlates with the BRAF-V600E mutation (g, immunostain, 40×), whereas negative to weak (0–1+) punctate BRAF VE1 staining should be interpreted as negative (h, immunostain, 100×)

and advanced brosis [1]. Concomitant smoking-related pathologies including respiratory bronchiolitis or desquamative interstitial pneumonia are frequently encountered in histopathological evaluation [20].

In early PLCH, histopathologic evaluation reveals in ltration and proliferation of dendritic cells, macrophages, and eosinophils [10] around respiratory bronchioles and the adjacent interstitium in a symmetric, stellate pattern [1, 20] (Fig. 16.3). Dendritic cells in PLCH are identi ed by their pale cytoplasm and distinctive, convoluted and elongated nuclei with a “coffee bean” appearance [1, 20]. Adjacent pigmented alveolar macrophage accumulation (“pseudo-­desquamative pneumonia”) is often present [1]. The pathognomonic feature of Langerhans cells includes the presence of Birbeck granules [1, 11, 20] and surrogate positive staining for langerin, in addition to S100 and CD1a [1, 11, 20]. As in ltrative lesions evolve, the cellular in ltration characteristic of early disease gradually evolves to more collagenous, burnt-out lesions that form brotic stellate scars [11, 20] surrounding small airways with loss of typical immunohistochemical features [20]. Demonstration of the mutant-speci c BRAF VE1 immunostain can serve as a surrogate for the BRAF-V600E mutation if there is strong and diffuse cytoplasmic staining (Fig. 16.3).

Clinical Presentation

The clinical presentation of PLCH is variable. Patients typically present with cough or dyspnea on exertion. Asymptomatic patients may be incidentally discovered to

have abnormalities on radiographs obtained for another purpose. Chest CT typically reveals a mixed pattern of cysts and nodules in various stages of evolution, but predominantly nodular or predominantly cystic patterns on the initial scan are also common (Fig. 16.4). Enlargement of the main pulmonary artery may be indicative of associated pulmonary hypertension. Patients may present with chest pain or acute dyspnea secondary to a spontaneous pneumothorax which occurs in 10–20% of patients [1].

Treatment and Prognosis

Treatment approaches for LCH are outlined in Fig. 16.5, and those for PLCH are depicted in Fig. 16.6 and are more extensively covered in Chap. 30. The prognosis of PLCH is generally favorable, with some patients achieving spontaneous remission or durable stability. In those less fortunate, respiratory failure or major pulmonary hypertension due to PLCH may require lung transplantation, with outcomes similar to those found in patients with other patterns of diffuse in ltrative lung disease [1], or lead to death. The median duration of survival from the time of diagnosis of PLCH is 12.5 years [23]. Furthermore, PLCH has been reported to recur following radiological regression of nodular lung abnormalities up to 7.5 years after the patient’s initial presentation, even in individuals who have stopped smoking [20]. There has been promising evidence supporting the use of MEK inhibitors to treat PLCH if progression occurs despite smoking cessation [24].

Fig. 16.4  Radiographic manifestations of PLCH. (a, b) 60 years old woman with 30 pack-year smoking history present with shortness of breath. (a) Contrast enhanced CT at the level of the carina reveals scattered centrilobular nodules. Lucency refecting the bronchiolocentric nature of this process is seen on the left (white arrow). (b) Coronal multiplanar reformatting demonstrates the gradient of zonal involvement. The nodules are most severe in the apices with sparing at the bases. (c, d) 33 years old woman with severe tobacco abuse disorder

presents with cough. (c) Noncontrast axial chest CT shows a combination of centrilobular nodules and bizarrely shaped lung cysts. (d) Coronal chest CT is notable for nodules and cysts with sparing of the costophrenic angles. (e, f) 47 years old man with a 90 pk yr smoking history and pulmonary arterial hypertension. (e) Contrast enhanced chest CT reveals confuent lung cysts in the apices. (f) Sagittal multiplanar reformat shows severe confuent cystic lung disease with sparing of the tip of the right middle lobe and anterior right lower lobe (arrow)