Langerhans cell histiocytosis LCH has become an inflammatory myeloid neoplasm [1,2,3]. It is a heterogeneous disease that can affect a single or multisystem with management ranging from observation to intensive therapy; thus tailoring treatment according to risk stratification .This is related to involvement of high risk organ(s) RO+ or low risk organ(s) RO- LCH [5,6,7]. The lung was part of RO+ group until 2012 when it has been excluded as Ronceray et al. showed that it is not an independent cause for mortality . Contrarily to the reactionary adult form related to tobacco smoking, the pediatric pulmonary multisystem PPM LCH is a clonal neoplastic disease diagnosed clinico radiologically [9,10,11]. Clinical diagnosis might be undermined by lacking of respiratory manifestations in a good number of cases [12, 13]. Radiologically, plain chest X-ray (CXR) is used to show honey comb lesions, which might be absent in early cases. However, the pathognomonic nodulocystic condensations is better demonstrated by the usage of low dose high resolution chest CT scan [15,16,17]. Lung involvement at diagnosis is subjected to the physician perception of the disease; either by restricting the diagnosis to severe bilateral nodulocystic lesions  or confirming wrongly LCH lung involvement through isolated nonspecific pneumopathies . This leads to inaccurate stratification of patients with subsequent under or over treatment. Such observations raised a question: Does lung lesion severity affect the outcome? We retrospectively analyzed PPM LCH patients presenting with typical chest high resolution CT nodules and cysts with or without clinical respiratory manifestations.
By standardizing specific clinical and radiological manifestations, the study aimed to examine the prognostic value of lung lesions severity in a single center large cohort.
Patients and methods
During the period from June 2007 to the end December 2020, 425 de novo LCH patients were diagnosed at Children’s Cancer Hospital Egypt 57357. Seventy-five patients out of 425, were excluded from the study because they did not receive systemic treatment as they were unisystem unifocal LCH. This study is a retrospective analysis of 350 patients who received systemic chemotherapy with a median follow-up period of 61 months (0.8–176). Of them, we analyzed sixty seven consecutive PPM LCH patients, not related to tobacco smoking with lung involvement associated with either (RO−) n = 47 or RO+ n = 20.
Data Collection and diagnosis Electronic medical records were reviewed, data were collected and analyzed after the approval of the scientific and medical advisory committee (SMAC) as well as the Institutional Review Board (IRB). All patients were evaluated with comprehensive history and physical examination. Diagnosis was confirmed by a proven biopsy taken mainly from the most accessible and representative site. High resolution chest CT scan and plain chest X-ray were done to all patients. They were stratified according to the Histiocyte Society (HS) into those Low risk (RO−) with Single-system (SS)-unifocal (USUF)/multifocal (USMF)-or Multisystem (MS) LCH involving two or more organs (MSRO−). Otherwise, those High risk (RO+) with “risk organs” including the hematopoietic system, liver and spleen (MSRO+) [4, 20,21,22,23].
Lung involvement is radiologically defined by the presence of pathognomonic honey comb on plain x ray or nodulocystic lesions on high resolution chest CT scan [18, 24]. Clinically, the criteria of respiratory manifestations were extrapolated from the Friedmann classification of respiratory distress ranging from no respiratory complaint, eupnea (stage I) to subjective respiratory complaint, slight tachypnea (stage II) to moderate respiratory distress retractions, moderate tachypnea (stage III) to severe respiratory distress retractions, cyanoses, delirium, decreased consciousness, respiratory arrest (stage IV) . In our study, radiological lung lesions severity was considered if a CT scan radiological triad was fulfilled. This included a triad of lesions that were (1) bilateral, (2) diffuse with pathognomonic nodules or cysts occupying each lobe with more than one segment per lobe and (3) extensive with innumerable nodules/cysts or pneumothorax. On the other hand, non-severe lung involvement was defined if the triad was not fulfilled.
Treatment During the period from mid-2007 till end 2011, the lung was part of RO+ group and patients were treated accordingly as MSRO+ with the LCH III protocol including: Induction I (initial 6 weeks) of oral Prednisone (PRED) 40 mg/m2/d, associated with weekly intravenous vinblastine (VBL) 6 mg/m2/d. Induction II (further 6 weeks) similar to Induction I but with day 1–3 weekly (PRED). Intermediate dose methotrexate (ID MTX) 500 mg/m2 every other week was added to both inductions. This was followed by one year continuation treatment including, 6 mercaptopurine (6MP) 50 mg/m2 daily and oral (MTX) 20 mg/week . After 2011, the lung has been considered a RO− organ and patients shifted to the LCH IV excluding ID MTX from induction. This was followed by continuation treatment of VBL/PRED or Vincristine/Aracytine/PRED /6MP/MTX whether the lung was associated to RO− or RO+ respectively .
Disease response to first line treatment was assessed by the end of induction phase, as no active disease (NAD), active disease better (ADB), active disease intermediate (ADI) and active disease worse (ADW) [20, 26, 27] Radiological response of lung lesions was assessed at end of induction and at last follow up as progressed or stationary or regressed or cleared nodulo-cystic lesions.
Failure of treatment Indicators were either disease progression (DP) or reactivation (REA). Disease progression was recorded, if the patient showed progressed lesions during induction phase or failed to achieve better status (NAD or ADB) by the end of induction. Reactivation was recorded if the patient showed progressive lesions after having achieved better status by the end of the induction phase [20, 26, 27].
Prognostic factors in the lung involvement cohort included the age group, gender, disease risk stratification, and radiological plain CXR changes. The same was used for lung lesions severity whether clinical in the form of respiratory manifestations or radiological through a triad of bilateral, diffuse and extensive lesions and each apart. This radiological lung involvement and its triad of severity were tested for their impact on survival in RO− or RO+ (Hemopoietic or hepatic or splenic).
Collection and statistical analysis
Kaplan–Meier analysis was used to estimate 5-year survival; overall survival (OS) was calculated from date of diagnosis until date of last follow-up or date of death, and event free survival (EFS) from date of diagnosis until date of REA, DP, last follow up or death. The main risk factors studied were binary variables: Age group, liver, spleen, hematopoietic system, and lung involvement. Age was dichotomized at 2 years similar to the pediatric LCH literature. Log rank tested the impact of different risk factors on survival. Lung involvement was collected as three strata: No lung involvement, no severe lung involvement, or severe lung involvement. Since the first two strata were almost identical with regards to their survival experience, they were recoded into the same stratum for the multivariable regression. EFS was modeled by Cox regression using the variables of interest, and adjusted Hazard Ratios and associated 95% confidence intervals were calculated. Model fit, interaction, discrimination, and calibration were evaluated. Proportionality of hazards were inspected graphically via Schoenfeld residuals. All tests are two-sided. Analysis was conducted using R version 4.1.2 and IBM SPSS statistics 22.0. P-values ≤ 0.05 were indicative of statistical significance and, tendency to be statistically significant if between 0.05 and 0.1.