What Is Histiocytosis

Overview

Histiocytosis is a group of rare genetic diseases that cause the proliferation and accumulation of a cell type called histiocytes in different tissues of the body.¹ They have been classified previously into two large groups: Langerhans-cells histiocytosis (X-type histiocytosis) and non-Langerhans-cells histiocytosis (non-X-type histiocytosis).² Nowadays, the classification has been updated into five groups to better encompass the nuances of the different conditions.

Most of the time, they are not cancerous and differ from cancer types such as Langerhans cell sarcoma because the cells that proliferate are benign.³ Malignant forms of histiocytosis, however, do exist and have a group of their own in the most recent classification.⁴ 

As a heterogeneous group, it can sometimes be confusing to understand the particularities of these diseases. Let's break down some of the most important points of histiocytosis.

Causes

As mentioned, histiocytosis is a genetic disorder.¹ Mutations in the mitogen-activated protein kinase (MAPK) pathway have been studied and identified as a cause of histiocytosis: this pathway is responsible for mitosis (cell proliferation); alterations caused by genetic mutations stimulate excessive cell proliferation of histiocytes.¹ 

In Langerhans-cell histiocytosis, mutations of the genes of the MAPK pathway, like MAP2K1, are very prevalent, and so are mutations of the BRAF gene.¹ Erdheim-Chester disease (ECD) has been linked to BRAF mutations and other rearrangements of the MAPK pathway involving genes MAP2K1, NRAS KRAS, and ARAF.¹ Other forms of histiocytosis, like Rosai-Dorfman-Destombes disease (RDD) have a less clear cause; although all of the previously mentioned mutations have been found in cells of patients who have RDD, none of them are definite causes, and other previously unknown mutations have been found, marking the heterogeneity of RDD.¹

What are histiocytes?

Histiocytes are a group of cells that are derived from monocytes (a type of white blood cell).⁴ A monocyte can differentiate itself primarily into two cell groups: they can be transformed into macrophages (which are responsible for “digesting” and destroying bacteria, viruses, fungi and even cancer cells), or they can transform into dendritic cells, which are responsible for presenting antigens (molecules that can cause disease, like toxins and pieces of bacteria and viruses) to other immune cells.⁴ Macrophages that reside in a tissue can be called histiocytes, and histiocytes that reside in the skin tissue (and undergo further specialisation) are called Langerhans cells.⁴ Langerhans cells can be easily recognised under microscopic evaluation due to the presence of Birbeck granules, small structures that resemble a tennis racket; this characteristic is used to differentiate Langerhans-cells histiocytosis and non-Langerhans-cells histiocytosis.⁵

In conclusion, mutations of the MAPK pathway stimulate cell proliferation of histiocytes or Langerhans cells, and which cells start to overgrow classify at large what type of histiocytosis a patient has, Langerhans or non-Langerhans. With this information in mind, let’s dive deeper into the different types of histiocytosis.

Types of histiocytosis

Recent classification has divided histiocytosis into five categories.⁴

• “L” group (Langerhans): this group contains Langerhans-cell histiocytosis (LCH) and Erdheim-Chester disease (ECD)⁴
  • Langerhans-cells histiocytosis (LCH): LCH can affect both adults and children, though it most commonly affects children; it usually affects the bones, skin and the pituitary gland; when it affects adults, it usually involves the lungs, and it is linked to smoking⁴
  • Erdheim-Chester disease (ECD): ECD usually affects those over the age of 55, very rarely affecting children; it affects the bones in 95% of cases while also affecting the heart and central nervous system, causing common complications like diabetes insipidus⁴

• The “C” group (cutaneous): as the name suggests, it affects mainly the skin.⁴ The disorders can further be divided into the xanthogranuloma family and non-xanthogranuloma family⁴
  • Xanthogranuloma family: disorders like the juvenile xanthogranuloma (JXG) and adult xanthogranuloma (AXG) can cause skin lesions like red or yellow nodules to appear, either single or multiple lesions; however, the onset starts during the first year of life for JXG, and later on for AXG (with the tendency to appear as a single persistent lesion for AXG)⁴
  • Non-xanthogranuloma family: necrobiotic xanthogranuloma (NXG) and multicentric reticulohistiocytosis (MRH) can be put into this group; NXG is often characterised by affecting the thorax and periorbital area with large yellow plaques and is often related to multiple myeloma, while MRH often affects women of older age and causes lesions in the extremities characterised by their classical “coral bead” appearance⁴

• The “M” group (malignant histiocytoses): the malignant variants of the disease are further divided into primary malignancies and secondary malignancies⁴
  • Primary malignant histiocytosis: these are tumours that originate from histiocytes and suffered malignant transformation; diagnosis can be challenging, as they tend to be anaplastic (undifferentiated) tumours and might require use of special immunohistochemistry (IHC) stains to identify the cells; usually affect the skin, lymph nodes, central nervous system or digestive system⁴
  • Secondary malignant histiocytosis: occurs along with or after another type of neoplasm; they are commonly related to follicular lymphoma, lymphocytic leukaemia, and hairy cell leukaemia⁴

• The “R” group (Rosai-Dorfman disease and other miscellaneous noncutaneous, non-Langerhans cell histiocytoses): this group consists mainly of RDD.⁴ Classical RDD involves the lymph nodes, with painless bilateral masses of the head and neck lymph nodes associated with fever and fatigue, affecting mostly children and often men of African descent.⁴ RDD can be familial (inherited), classical, extranodal (affecting the bones, skin, central nervous system or multiple organs at once), associated with neoplasia or with autoimmune diseases.⁴ When a case of histiocytosis cannot be classified into any other group, it is named “histiocytosis not otherwise specified” and belongs to this group.⁴
• The “H” group (hemophagocytic lymphohistiocytosis and macrophage activation syndrome): this group pertains to hemophagocytic lymphohistiocytosis (HLH), which is a disease that causes intense activation of the immune system.⁴ This activation leads to fever, cytopenia (low blood cell count), hepatosplenomegaly (augmentation of the liver and spleen) and hyperferritinemia (high iron content in blood.)⁴ This dysregulation causes accumulation and activation of macrophages in tissues, resulting in local damage, and can often be fatal⁴
  • Primary hemophagocytic lymphohistiocytosis (PHLH): is an inherited disease of genetic causes.⁴
  • Secondary hemophagocytic lymphohistiocytosis (SHLH): is an acquired disease in response to a viral infection (such as an infection by the Epstein-Barr virus, or cytomegalovirus), to a haematological malignancy (like T-cell and B-cell leukaemias), to an autoimmune disease or to an organ transplant.⁴

To summarise the classification:⁴

Signs and symptoms

Signs and symptoms can vary depending on which type of histiocytosis is present. A few organs that can be affected include:

• Skin: skin lesions are common for the cutaneous types but can appear with other types as well; red or yellow nodules, either single or multiple, are characteristic of the xanthogranulomatous family, while large yellow plaques are typical of NGX, and “coral bead”-like lesions are characteristic of MRH⁴
• Lymph nodes: hard, painless masses affecting the lymph nodes of the head and neck area are typical of the classical form of RDD⁴
• Bones: bilateral symmetrical osteosclerosis is a classic symptom of ECD, being found in about 95% of cases.⁴
• Liver: liver function can be impaired by lesions, and hepatosplenomegaly can be present in HLH⁴
• Central nervous system (CNS): diabetes insipidus is a common complication of ECD, but other types can affect the CNS or cause other varying symptoms.⁴

Diagnosis

Diagnosis can be challenging and might require extensive image and laboratory exams.⁵ If histiocytosis is suspected, imaging like a PET-CT scan can be performed to search for bone lesions, and an MRI might be requested to evaluate brain lesions.⁵ A full blood count should be requested to evaluate whether or not there is cytopenia (which is something that indicates bone marrow involvement) and to discard the possibility of a haematological malignancy that can mimic histiocytosis or be present along with it.⁵ Liver function studies can be performed to evaluate liver function, and an ultrasound can detect enlargement of the liver and spleen.⁵

Above all, a biopsy should be performed to confirm histiocytosis. If Birbeck granules are present, this points to Langerhans histiocytosis.⁵ However, a pathologist might require more than the standard hematoxylin and eosin (H&E) stain in order to properly diagnose a tissue sample, especially when there aren’t Birbeck granules present. Immunohistochemistry (IHC) stains can be useful as they stain specific molecules only; common IHC molecules used are langerin, S100, CD68, CD45, and BRAF VE1.⁵ This proves exceptionally useful for malignant histiocytosis because tissue samples are anaplastic (undifferentiated), and cells don’t resemble their normal, healthy counterparts.

Management and treatment

Management and treatment depend on which type of histiocytosis it is and the sites involved. A few options are:

• Corticosteroids: These are anti-inflammatory drugs used to regulate immune response like prednisolone and dexamethasone. They are usually a good option for young patients, those who have a lesser involvement (single skin lesions or solitary lymph node involvement), or those who have secondary HLH⁶
• Chemotherapy: although not all forms of histiocytosis are cancerous, chemotherapy can be a good option to treat patients with benign lesions; cladribine, vinblastine and etoposide are just some examples of drugs used to treat histiocytosis.⁶ Those with systemic forms of the disease or refractory manifestations (resistant to treatment with corticosteroids) can benefit from chemotherapy⁶
• Antibiotics and antifungals: in cases of fungal or bacterial secondary HLH, treating the primary infection can regulate histiocytosis. Tuberculosis and leishmaniasis have been described as potential causes for secondary HLH, and treatment with Amphotericin B and Rifampicin has been used to eradicate the primary infection and regulate manifestations of histiocytosis in these patients.⁶
• Surgery: single skin lesions can be removed surgically, though it isn’t always necessary.⁷ A full recovery can be achievable if there are no more lesions after a period of 1-2 years after treatment of a single lesion of histiocytosis.⁷

Patients with histiocytosis should have a life-long medical follow-up due to possible complications. About 50% of patients with Langerhans-cell histiocytosis end up developing one or multiple complications like diabetes insipidus, hearing loss, pulmonary impairment, there is a higher risk of secondary malignancy (like leukaemia), and liver cirrhosis.⁷ Although localised forms of the disease have a good prognosis and a full recovery can be expected in these cases, systemic forms of histiocytosis can be life-threatening, and more than half of children under the age of 2 affected by Langerhans-cell histiocytosis will die of it.⁷ Likewise, adults with pulmonary involvement have a poor prognosis.⁷

Summary

Histiocytosis is a group of rare genetic diseases that cause the proliferation and accumulation of histiocytes in different locations: skin, bones, central nervous system, lungs, and liver. Different tissues affected will produce a different array of symptoms. There are currently five groups of histiocytosis: groups “L”, “C”, “M”, “R” and “H”; under these groups, numerous diseases have been divided by their causes, microscopic aspects and signs and symptoms. Image exams like PET scans and MRI scans, as well as a full blood count, are useful for narrowing down a diagnosis, but a complete diagnosis can only be achieved through biopsy and histopathological examination. Management and treatment of histiocytosis depends on the sites affected by the disease and usually involve corticosteroids or chemotherapy agents. A full recovery can be expected in cases with single lesions, but systemic forms of the disease might be more challenging to treat and bring along complications like diabetes insipidus, liver cirrhosis and hearing loss.