Cutaneous neonatal Langerhans cell histiocytosis: a systematic review of case reports

The authors clearly state their rationale for the review: to identify particular cutaneous presentations that are more frequently associated with progression to multisystem disease. In fact, the authors undermine their study’s potential implications in only mentioning reduced invasive screening. Perhaps equally, if not more important, it can help guide management, decreasing the use of systemic therapy in cases that will likely regress while prompting the use of systemic therapy in patients with high-risk lesions. Nevertheless, while the objective stated by the authors was to identify risk factors which may contribute to mortality risk and risk of progression to systemic disease, this aspect was not adequately addressed in the paper (we do not think that collating published cases is the appropriate methodology for such a scientific question) and is not part of the conclusions.

More details of the methods and analysis are needed to allow for replication by others. A standardized data collection form (not received by reviewers) should accompany the article for readers to understand some of the statements that are not based on findings described in the section “Results”. Furthermore, comparing single versus multiple lesions implies clear definitions for a skin lesion (at least for size and type), and the authors do not provide such definitions. For instance, multiple lesions may describe widespread rashes involving most of the body, two or three distinct nodules, or a rash covering a significant portion of the diaper area. Are these all truly equivalent?

Certain components of the authors’ interpretation need to be addressed. For instance, it is unclear why the authors preferred to study the influence of multiple lesions on length of survival, rather than on progression to systemic disease or mortality, especially considering the limitation of short follow-up period. Also, the authors conclude that the descriptive characteristics in this review significantly differ from descriptions of overall pediatric LCH. However, they do not provide a statistical comparison or clarification of the age range that they consider pediatric. It is also questionable whether meaningful analysis of the impact of lesions type can be performed considering that 31/128 (24%) of lesions were listed as “others” and another 9 were missing. 

In the last paragraph of the results, the authors state that no statistically significant associations or OR were seen between histological markers and clinical outcomes. How could such a conclusion be drawn without central pathology review? In the view of the reviewers, such a correlation cannot be made based on a description of the pathology findings, regardless of how well and detailed they are described, but needs a review of the biopsy specimens by experienced pathologists in a structured way. Additionally, the authors report that they were unable to perform a multivariate analysis due to data heterogeneity. If by heterogeneous the authors were implying that the data was inconclusive and/or insufficient, then this poses questions to the findings of the univariate analysis either.

The following components should also be addressed:
In the 1^st paragraph of the background, the authors write: “Cutaneous Langerhans cell histiocytosis (LCH) is a rare disorder manifest in the proliferation of cells with phenotypical characteristics of Langerhans cells which involves the cutaneous structures¹.” However, it should be noted that Langerhans cells are dendritic cells of the skin and mucosa, and that despite their phenotypic resemblance to Langerhans cells (and shared immunohistochemical markers), the pathologic cells of LCH derive from immature myeloid precursor cells¹. Additionally, reference one used by the authors is a set of guidelines. Accordingly, the original studies should be cited when statistics are noted (i.e. the incidence of cutaneous LCH and rate of progression). The authors write: “Currently, consensus guidelines¹ state that most cases of cutaneous LCH spontaneously regress but some cases do progress to multisystem disease¹”. Do they mean "skin-limited" rather than "cutaneous" according to the distinction made by the authors that “skin-limited” implies the lack of systemic involvement? Though spontaneous remission is the norm for "skin-limited" LCH, skin-limited disease is rare (2% of cases)². The authors write: “It is unclear whether cutaneous LCH is merely clinically more easily identified and hence often precedes diagnosis of internal disease". Actually, cutaneous disease is often misdiagnosed due to its resemblance to other more common conditions (i.e diaper dermatitis and cradle-cap)³. In addition to noting in the background section that screening for multisystem disease at the time of initial presentation is mandatory, the authors should also mention here the need for long-term follow-up due to the potential for disease reactivation following resolution or future progression to multisystem disease. The authors note this in the conclusion, but it should also be stated here. The authors only note one source in the conclusion giving this recommendation, which undermines its importance^4,5,6.

In the 3^rd paragraph of the background, the authors write “Detection of the BRAF-V600E mutation (often seen in systemic LCH but rarely in skin-limited LCH), has also been associated with increased risk of disease recurrence⁴”. Of note, BRAF-V600E mutations are not only associated with recurrence, but also with treatment-refractory disease and permanent sequelae. These associations are observed in both isolated and disseminated LCH (and in disseminated disease are also associated with risk organ involvement)^7,8,9. Furthermore, Héritier’s study in a cohort of 315 patients with determined BRAF status conflict with the statement that BRAF-V600E is rare in skin-limited disease. They report the presence of BRAF-V600E mutations in 87.5% of patients with multifocal single system cutaneous disease and in 80.2% of patients with multifocal cutaneous multisystem disease. What might also be of interest to the authors is that the mutation was absent in the 6 infants with solitary cutaneous lesions and single system disease¹⁰.

In the 4^th paragraph of the background, the authors write: “Overall, given the reports (albeit uncommon) of progression of cutaneous LCH to multisystem disease, the identification of clinical or histological predictive variables may reduce rates of unnecessary invasive screening in neonates with skin-limited LCH". However, as we note above, multisystem disease in patients presenting with cutaneous involvement is the norm.

In the 1^st paragraph of the discussion, the authors write: “This is in line with the literature with earlier onset disease significantly associated with spontaneous resolution^92,93”. In contrast, because high-risk multisystem disease has been negatively correlated with age, younger age is associated with a worse prognosis¹¹. Subsequent to Minkov’s findings, Gadner et al. reported no difference in treatment response between different age groups when correcting for the involvement of risk organ systems. Thus, the difference in prognosis between age groups is likely due to the higher prevalence of multisystem disease in younger patients¹². Similarly, in the 2^nd paragraph, the authors write: “Systemic disease was identified in 48.4% of cases (n=62) lower than the rates for the overall pediatric group at 59%³, and those reported by Stein et al. (63.1%)⁵”. However, in a retrospective analysis of 61 neonates with LCH, Minkov et al. note a higher prevalence of multisystem disease in neonates (ironically, 59%)¹¹.

The authors write in the 4^th paragraph of the discussion: “The presence of multiple lesions was associated with increased length of survival, although the presence of lead-time bias was likely given the non-significant differences in mortality between the two groups”. Despite the evolution in the classification system with increased recognition that the previously distinct categories have some overlapping features, it might still be worth mentioning. Specifically, Hashimoto-Pritzker disease (a.k.a congenital self-healing reticulohistiocytosis) was described as a widespread eruption of red-brown nodules presenting within the first few weeks from birth that resolve spontaneously with isolated cutaneous involvement¹³.

The authors acknowledge a number of limitations, but this does not compensate for them. As they note, limited follow-up prevented them from identifying statistically significant variables that contribute to LCH mortality. Though their stated objective of identifying particular cutaneous presentations that are more frequently associated with progression to multisystem disease and overall mortality is a good one, they were not able to identify any new prognostic factors that would contribute to the literature.