Treatment with chemotherapy has been used with some success, particularly using lomustine, prednisone, doxorubicin, and cyclophosphamide. Because of the rapid progression of this aggressive disease, the prognosis is very poor.

Excellent for single-focus disease. With multi-focal disease 60% have a chronic course, 30% achieve remission and mortality is up to 10%.

Guidelines for management of patients up to 18 years with Langerhans cell histiocytosis has been suggested. Treatment is guided by extent of disease. Solitary bone lesion may be amenable through excision or limited radiation, dosage of 5-10 Gys for children, 24-30 Gys for adults. However systemic diseases often require chemotherapy. Use of systemic steroid is common, singly or adjunct to chemotherapy. Local steroid cream is applied to skin lesions. Endocrine deficiency often require lifelong supplement e.g. desmopressin for diabetes insipidus which can be applied as nasal drop. Chemotherapeutic agents such as alkylating agents, antimetabolites, vinca alkaloids either singly or in combination can lead to complete remission in diffuse disease.

There are competing systems for classifying histiocytoses. According to the 1999 classification proposed by the World Health Organization, they can be divided into three categories. However, the classifications in ICD10 and MeSH are slightly different, as shown below:

Types of LCH have also been known as "Eosinophilic Granuloma", "Hand-Schuller-Christian Disease", "Letterer-Siwe Disease", and "Histiocytosis X". (See Langerhans cell histiocytosis for details).

Alternatively, histiocytoses may be divided into the following groups:

Malignant histiocytosis (also known as "Histiocytic medullary reticulosis") is a rare hereditary disease found in the Bernese Mountain Dog and humans, characterized by histiocytic infiltration of the lungs and lymph nodes. The liver, spleen, and central nervous system can also be affected. Histiocytes are a component of the immune system that proliferate abnormally in this disease. In addition to its importance in veterinary medicine, the condition is also important in human pathology.

In medicine, histiocytosis refers to an excessive number of histiocytes, ("tissue macrophages"), and is typically used to refer to a group of rare diseases which share this as a characteristic. Occasionally and confusingly, the term "histiocytosis" is sometimes used to refer to individual diseases.

According to the Histiocytosis Association of America, 1 in 200,000 children in the United States are born with histiocytosis each year. HAA also states that most of the people diagnosed with histiocytosis are children under the age of 10, although the disease can afflict adults. The University of California, San Francisco, states that the disease usually occurs from birth to age 15.

Histiocytosis (and malignant histiocytosis) are both important in veterinary as well as human pathology.

Most histiocytomas will regress within two or three months. Surgical removal may be necessary if the tumor does not regress or if it is growing rapidly to a large size. Histiocytomas should never be treated with an intralesional injection of a corticosteroid, as remission relies on recognition of the tumour by the body's immune system which is suppressed by steroids.

The prognosis is guarded with an overall mortality of 50%. Poor prognostic factors included HLH associated with malignancy, with half the patients dying by 1.4 months compared to 22.8 months for non-tumour associated HLH patients.

Secondary HLH in some individuals may be self-limited because patients are able to fully recover after having received only supportive medical treatment (i.e., IV immunoglobulin only). However, long-term remission without the use of cytotoxic and immune-suppressive therapies is unlikely in the majority of adults with HLH and in those with involvement of the central nervous system (brain and/or spinal cord).

Some patients have no symptoms, spontaneous remission, or a relapsing/remitting course, making it difficult to decide whether therapy is needed. In 2002, authors from Sapienza University of Rome stated on the basis of a comprehensive literature review that "clinical observation without treatment is advisable when possible."

Therapeutic options include surgery, radiation therapy, and chemotherapy. Surgery is used to remove single lymph nodes, central nervous system lesions, or localized cutaneous disease. In 2014, Dalia and colleagues wrote that for patients with extensive or systemic Rosai–Dorfman disease, "a standard of care has not been established" concerning radiotherapy and chemotherapy.

The basis of management is to find and correct the underlying cause. Many times cats with EGC will respond to treatment with corticosteroids or to ciclosporin.

Current treatment options include:

- Surgical debulking

- High-dose Corticosteroid therapy

- Cyclosporin

- Interferon-α

- Chemotherapy

- Vemurafenib. It would appear that approximately half these patients harbor point mutations of the BRAF gene at codon 600 substituting the amino acid glutamine for valine. Vemurafenib, an oral FDA approved targeted agent to the BRAF protein for melanoma, shows dramatic activity in patients Erdheim–Chester disease whose tumor contains the same mutation. In 2017 the US FDA approved vemurafenib for this indication.

- Radiation therapy

All current treatments have had varying degrees of success.

The vinca alkaloids and anthracyclines have been used most commonly in ECD treatment.

In secondary cases, treatment of the cause, where possible, is indicated. Additionally, treatment for HLH itself is usually required.

While optimal treatment of HLH is still being debated, current treatment regimes usually involve high dose corticosteroids, etoposide and cyclosporin. Intravenous immunoglobulin is also used. Methotrexate and vincristine have also been used. Other medications include cytokine targeted therapy.

An experimental treatment, an anti IFN-gamma monoclonal antibody tentatively named NI-0501, is in clinical trials for treating primary HLH. The FDA awarded breakthrough drug status to NI-0501 in 2016.

X-type histiocytoses are a clinically well-defined group of cutaneous syndromes characterized by infiltrates of Langerhans cells, as opposed to Non-X histiocytosis in which the infiltrates contain monocytes/macrophages. Conditions included in this group are:

Erdheim–Chester disease is associated with high mortality rates. In 2005, the survival rate was below 50% at three years from diagnosis. More recent reports of patients treated with Interferon therapy describe an overall 5-year survival of 68%. Long term survival is currently even more promising, although this impression is not reflected in the recent literature.

Letterer–Siwe disease is one of the four recognized clinical syndromes of Langerhans cell histiocytosis (LCH). It causes approximately 10% of LCH disease and is the most severe form. Prevalence is estimated at 1:500,000 and the disease almost exclusively occurs in children less than three years old. The name is derived from the names of Erich Letterer and Sture Siwe.

Hand–Schüller–Christian disease is associated with multifocal Langerhans cell histiocytosis.

It is associated with a triad of exophthalmos, lytic bone lesions (often in the skull), and diabetes insipidus (from pituitary stalk infiltration).

It is named for the US-American pediatrician Alfred Hand Jr, the Austrian neurologist and radiologist Arthur Schüller, and the US-American internist Henry Asbury Christian, who described it in 1893, 1915/16 and 1919

Interdigitating dendritic cell sarcoma is a form of malignant histiocytosis affecting dendritic cells.

It can present in the spleen. It can also present in the duodenum.

A histiocytoma in the dog is a benign tumor. It is an abnormal growth in the skin of histiocytes (histiocytosis), a cell that is part of the immune system. A similar disease in humans, Hashimoto-Pritzker disease, is also a Langerhans cell histiocytosis. Dog breeds that may be more at risk for this tumor include Bulldogs, American Pit Bull Terriers, American Staffordshire Terriers, Scottish Terriers, Greyhounds, Boxers, and Boston Terriers. They also rarely occur in goats and cattle.

In pathology, dermatopathic lymphadenopathy, also dermatopathic lymphadenitis, is lymph node pathology due to skin disease.

Lymphocytosis is a feature of infection, particularly in children. In the elderly, lymphoproliferative disorders, including chronic lymphocytic leukaemia and lymphomas, often present with lymphadenopathy and a lymphocytosis.

Causes of absolute lymphocytosis include:

- acute viral infections, such as infectious mononucleosis (glandular fever), hepatitis and Cytomegalovirus infection

- other acute infections such as pertussis

- some protozoal infections, such as toxoplasmosis and American trypanosomiasis (Chagas disease)

- chronic intracellular bacterial infections such as tuberculosis or brucellosis

- chronic lymphocytic leukemia

- acute lymphoblastic leukemia

- lymphoma

- post-splenectomy state

- smoking

Causes of relative lymphocytosis include: age less than 2 years; acute viral infections; connective tissue diseases, thyrotoxicosis, Addison's disease, and splenomegaly with splenic sequestration of granulocytes.

Hematopoietic stem cell transplantation from a matched donor is curative although not without significant risk.

Congenital self-healing reticulohistiocytosis (also known as "Hashimoto–Pritzker disease," and "Hashimoto–Pritzker syndrome") is a condition that is a self-limited form of Langerhans cell histiocytosis.

Once a diagnosis is made, each individual's treatment is based on an individual’s clinical condition. Hematopoietic stem cell transplant is a possible treatment of this condition but its effectiveness is unproven.

Additionally, magnesium supplementation is a promising potential treatment for XMEN. One of the consequences of loss of "MAGT1" function is a decreased level of unbound intracellular Mg2+. This decrease leads to loss of expression of an immune cell receptor called "NKG2D", which is involved in EBV-immunity. Remarkably, Mg2+ supplementation can restore "NKG2D" expression and other functions that are abnormal in patients with XMEN. Early evidence suggests continuous oral magnesium threonate supplementation is safe and well tolerated. Nonetheless, further research is needed to evaluate the use of Mg2+ as a treatment for XMEN. It remains unclear if such supplementation will protect against the development of lymphoma in patients with XMEN. Investigators at the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health currently have clinical protocols to study new approaches to the diagnosis and treatment of this disorder.

Rosai–Dorfman disease, originally known as sinus histiocytosis with massive lymphadenopathy, is a rare disorder of unknown cause that is characterized by abundant histiocytes in the lymph nodes or other locations throughout the body.

Eosinophilic granuloma is a form of Langerhans cell histiocytosis. It is a condition of both human and veterinary pathology. Colloquially, the reaction pattern is sometimes referred to as a rodent ulcer.

Feline eosinophilic granuloma complex is synonymous with "feline eosinophilic skin diseases". This is considered to be a cutaneous reaction pattern that can be the manifestation of a number of underlying infections, allergies or ectoparasite infestations. It can also be idiopathic, that is have no known underlying trigger. The eosinophilic reaction is common in feline inflammatory disease and the eosinophilic granuloma can be a hereditary reaction pattern in some lines of domestic cats.