Histiocytic Proliferative Disorders

Clinical Findings

The clinical manifestations of LCD have historically been described as four separate disease entities. However, it is now recognized that each of these entities represents a clinical variant within a spectrum of findings found in this one disease process.

Congenital Self-Healing Reticulohistiocytosis (Hashimoto-Pritzker)

This rare form is seen at birth or in neonates. Solitary or multiple papules, vesicles, or nodules, possibly ulcerated, are located on the head, trunk, palms, and soles. There is usually spontaneous resolution over weeks to months, possibly leaving behind areas of hyperpigmentation or hypopigmentation. However, congenital self-healing reticulohistiocytosis (CSHR) may progress toward a Letterer-Siwe clinical picture.

Many clinical presentations do not neatly fit into any of the “classic” variants of LCD, such as limited localized maculopapular cutaneous disease ( Fig. 15-1 ).

Histologic Features

The common histologic feature is the accumulation of cells with abundant amphophilic or eosinophilic cytoplasm and large, vesicular folded, lobulated, or reniform nuclei without prominent nucleoli in the papillary dermis and epidermis ( Fig. 15-2 ) and, in nodular forms, in the reticular dermis. There are often accompanying nonhistiocytic inflammatory cells, including lymphocytes, eosinophils, and neutrophils. Occasionally, a more granulomatous pattern with occasional xanthomatous cells and multinucleated giant cells may be seen.

Ancillary Studies

Langerhans cells are positive for CD1a, S100 protein, and Lanergin (CD207) ( Fig. 15-3 ). They are also positive for CD43 and CD4. They are negative for CD68.

Electron microscopy demonstrates characteristic racquet-shaped or rocket-shaped Birbeck granules ( Fig. 15-4 ). Lesions of CSHR can also show myelinoid laminated inclusions, known as vermiform bodies. Electron microscopy is currently no longer part of the routine diagnostic workup of LCD.

Immunohistochemistry using the monoclonal antibody VE1 can help document the presence or absence of the mutant BRAFV600E protein. This may facilitate selection of patients with symptomatic systemic disease for treatment with vemurafenib. Immunoreactivity may be weak (generally weaker than in metastatic melanoma cells carrying the same mutation). Analysis by other methods (e.g., pyrosequencing or mass spectroscopy) may be necessary for confirmation of mutation status.

Differential Diagnosis

Langerhans cells may be confused with non-Langerhans histiocytes (e.g., foam-cell poor xanthogranuloma) or on occasion with a mast cell, immature or leukemic myeloid infiltrate, or even a melanocytic proliferation. Close attention to nuclear detail (reniform nucleus) is helpful. Immunostains allow for a ready distinction.

Reactive LHC hyperplasia as part of an allergic reaction, such as eczema, which may on occasion be florid, may be mistaken as LCD and lead to overtreatment. Whereas in LCD, there are typically dense clusters of LHCs, in reactive hyperplasia, LHCs tend to be more dispersed as solitary units, although there may be many of them in the dermis and epidermis admixed with lymphocytes and eosinophils. Careful attention to clinical history and presentation is important. One should hesitate, for example, to make a new diagnosis of LCD (histiocytosis) in an adult with a long history of eczema.

Prognosis and Treatment

The disease course is variable and does not correlate with histology. Adverse prognostic features include age younger than 1 year (except in CSHR), organ dysfunction, and male gender. Complete remission occurs in 30%; the majority of patients have a chronic course. Systemic involvement may lead to severe morbidity and even death. Treatment strategies are related to the extent of disease. Patients with localized disease can be treated with topical nitrogen mustard, oral thalidomide, or ultraviolet light therapy. A variety of chemotherapy agents, steroids, and possibly bone marrow transplant are used in cases of systemic disease. Recent evidence suggests that patients with tumors harboring the BRAFV600E mutation respond well to treatment with vemurafenib.

Clinical Findings

This exceedingly rare disorder occurs in both children and adults of each gender. It generally presents as a solitary, soft, erythematous, ulcerated nodule or as crops of firm, red-brown papules that develop over several months or years. Extracutaneous involvement has been documented.

Histologic Features

The dermis contains a well-circumscribed or diffuse infiltrate of histiocytes admixed with lymphocytic aggregates. The histiocytes have eosinophilic or granular cytoplasm.

Ancillary Studies

The histiocytes are immunoreactive for CD68, S100 protein, and factor XIIIa and weakly or focally positive for CD1a. No Birbeck granules are detectable by electron microscopy.

Differential Diagnosis

This disorder should be distinguished from other histiocytoses (CSHR, JXG, GEH, MRH).

Prognosis and Treatment

Solitary lesions can be treated with simple excision. Multiple lesions are usually stable or only slowly progressive, and treatment is usually not necessary.

Clinical Findings

Juvenile xanthogranuloma is the most common non-LHC histiocytosis. It is a normolipemic condition that pre­sents congenitally in 15% to 30% of cases and within the first year of life in approximately 75% of cases. Identical lesions may also be seen in adults (adult xanthogranuloma). Skin lesions are more often solitary but can be multiple, and they consist of well-demarcated, rubbery, reddish brown to yellow asymptomatic papules measuring 2 to 5 mm. They are located mostly on the upper body but have been documented in skin of all sites. Less commonly, there are shiny, translucent, red to yellow nodules, sometimes with telangiectasias, measuring 5 to 20 mm. Giant forms measuring greater than 20 mm in diameter have been reported. There is a male predominance, especially in cases with multiple skin lesions. Mucous membrane and extracutaneous involvement can occur, with or without accompanying skin lesions. The eye is the most common extracutaneous site; ocular lesions occur in 1% to 10%, are usually unilateral, and may precede skin lesions. Systemic involvement may occur, affecting the oropharynx, orbit, nasal and paranasal sinus areas, central nervous system (CNS), liver, spleen, lungs, bone marrow, testis, breast, or kidney. Lesions of JXG may be associated with neurofibromatosis type I or with juvenile chronic myelogenous leukemia or juvenile myelomonocytic leukemia.