Uncommon variants of Non-Langerhans Cell Histiocytosis

Background: Histiocytosis are rare disorders of the mononuclear phagocyte system,
characterized by a derangement in differentiation, proliferation or function of monocytes and
dendritic cells. They have been recently reclassified in five different groups based on a
combination of clinical, histopathological and radiographic findings. Specifically, NonLangerhans Cell Histiocytosis are among the rarest and most challenging histiocytoses to
be diagnosed and managed as several entities display large clinical-pathological overlap.
Moreover, this remarkable issue is still poorly investigated.
Observations: We describe four extraordinary cases of Cutaneous Non-Langerhans Cell
Histiocytosis whose clinical-pathological findings did not fulfill the diagnostic criteria for any
specific disorder. The first patient was a 32-year-old male, who initially presented with a
face-limited papular eruption, akin to pediatric Benign Cephalic Histiocytosis and later
manifesting a generalized skin involvement, as in Generalized Eruptive Histiocytosis.
Moreover, histopathology could not discriminate between Xanthogranuloma and
Reticulohistiocytosis. The second case was a 41-year-old woman with multiple
comorbidities, who displayed a papular eruption limited to head and limbs associated with
arthralgia of distal joints. Although the clinical picture was suggestive for Multicentric
Reticulohistiocytosis, skin biopsy showed features intermediate between Rosai-Dorfman
Disease and Adult Xanthogranuloma. The third subject was a 14-year-old woman who
developed a sudden xanthogranulomatous papulo-nodular skin eruption 10 days after HPVvaccination. Molecular analysis of skin biopsy tested positive for HPV-6 type. The fourth
patient was a 47-year-old woman who presented disfiguring nodular facial lesions.
Complessive clinical findings could not discriminate between Progressive Nodular
Histiocytosis and Xanthoma Disseminatum.
Key message: The high heterogeneity of Non-Langerhans Cell Histiocytosis shows how
their differential diagnosis, prognostic stratification and therapeutic approach may be
incredibly troublesome. Therefore, overlapping cases may benefit of a revision of
nomenclature and classification, perhaps considering looser criteria (as already proposed
for Langerhans-Cell Histiocytosis) to avoid misdiagnosis and allowing the development of
standardized management.