Diagnosis is confirmed histologically by tissue biopsy. Hematoxylin-eosin stain of biopsy slide will show features of Langerhans Cell e.g. distinct cell margin, pink granular cytoplasm. Presence of Birbeck granules on electron microscopy and immuno-cytochemical features e. g. CD1 positivity are more specific. Initially routine blood tests e.g. full blood count, liver function test, U&Es, bone profile are done to determine disease extent and rule out other causes. Radiology will show osteolytic bone lesions and damage to the lung. The latter may be evident in chest X-rays with micronodular and interstitial infiltrate in the mid and lower zone of lung, with sparing of the Costophrenic angle or honeycomb appearance in older lesions. MRI and CT may show infiltration in sella turcica. Assessment of endocrine function and bonemarrow biopsy are also performed when indicated.

- S-100 protein is expressed in a cytoplasmic pattern

- peanut agglutinin (PNA) is expressed on the cell surface and perinuclearly

- major histocompatibility (MHC) class II is expressed (because histiocytes are macrophages)

- CD1a

- langerin (CD207), a Langerhans Cell–restricted protein that induces the formation of Birbeck granules and is constitutively associated with them, is a highly specific marker.

Langhans cells are often found in transbronchial lung biopsies or lymph node biopsies in patients suffering from sarcoidosis.

Recently, a research paper has shown that when activated CD4+ T cells and monocytes are in close contact, interaction of CD40-CD40L between these two cells and subsequent IFNγ secretion by the T cells causes upregulation and secretion of fusion-related molecule DC-STAMP (dendritic cell-specific transmembrane protein) by the monocytes, which results in LGC formation.

The pathogenesis of Langerhans cell histiocytosis (LCH) is a matter of debate. There are ongoing investigations to determine whether LCH is a reactive (non-cancerous) or neoplastic (cancerous) process. Arguments supporting the reactive nature of LCH include the occurrence of spontaneous remissions, the extensive secretion of multiple cytokines by dendritic cells and bystander-cells (a phenomenon known as cytokine storm) in the lesional tissue, favorable prognosis and relatively good survival rate in patients without organ dysfunction or risk organ involvement.

On the other hand, the infiltration of organs by monoclonal population of pathologic cells, and the successful treatment of subset of disseminated disease using chemotherapeutic regimens are all consistent with a neoplastic process. In addition, a demonstration, using X chromosome–linked DNA probes, of LCH as a monoclonal proliferation provided additional support for the neoplastic origin of this disease. While clonality is an important attribute of cancer, its presence does not prove that a proliferative process is neoplastic. Recurrent cytogenetic or genomic abnormalities would also be required to demonstrate convincingly that LCH is a malignancy.

Activating mutation of a protooncogen in the Raf family, the BRAF gene, was detected in 35 of 61 (57%) LCH biopsy samples with mutations being more common in patients younger than 10 years (76%) than in patients aged 10 years and older (44%). This study documented the first recurrent mutation in LCH samples. Two independent studies have confirmed this finding. Presence of this activating mutation could support the notion to characterize LCH as myeloproliferative disorder.

Most patients with "ETV6-ACSL6"-related disease present with findings similar to eosinophilia, hypereosinophila, or chronic eosinophilic leukemia; at least 4 cases presented with eosinophilia plus findings of the red blood cell neoplasm, polycythemia vera; three cases resembled acute myelogenous leukemia; and one case presented with findings of a combined Myelodysplastic syndrome/myeloproliferative neoplasm. Best treatments for "ETV6-ACSL6"-related disease are unclear. Patients with the polycythemia vera form of the disease have been treated by reducing the circulating red blood cell load by phlebotomy or suppressing red blood cell formation using hydroxyurea. Individual case studies report that "ETV6-ACSL6"-associated disease is insensitive to tyrosine kinase inhibitors. Best treatment currently available, therefore, may involve chemotherapy and bone marrow transplantion.

Flow cytometry is a diagnostic tool in order to count/visualize the amount of lymphatic cells in the body. T cells, B cells and NK cells are nearly impossible to distinguish under a microscope, therefore one must use a flow cytometer to distinguish them.

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.

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.

While the bone marrow is commonly involved, the detection of the neoplastic infiltrate may be difficult due to diffuse, interstitial pattern. Immunohistochemistry can aid in the detection of this lymphoma.

Histologically, ECD differs from Langerhans cell histiocytosis (LCH) in a number of ways. Unlike LCH, ECD does not stain positive for S-100 proteins or Group 1 CD1a glycoproteins, and electron microscopy of cell cytoplasm does not disclose Birbeck granules. Tissue samples show xanthomatous or xanthogranulomatous infiltration by lipid-laden or foamy histiocytes, and are usually surrounded by fibrosis. Bone biopsy is said to offer the greatest likelihood of reaching a diagnosis. In some, there is histiocyte proliferation, and on staining, the section is CD68+ and CD1a-.

Most commonly histiocytomas are found in young dogs and appear as a small, solitary, hairless lump, although Shar Peis may be predisposed to multiple histiocytomas. They are most commonly found on the head, neck, ears, and limbs, and are usually less than 2.5 cm in diameter. Ulceration of the mass is common. Diagnosis is made through cytology of the mass. Cytology reveals cells with clear to lightly basophilic cytoplasm and round or indented nuclei with fine chromatin and indistinct nucleoli.

The current (2008) diagnostic criteria for HLH are

1. A molecular diagnosis consistent with HLH. These include the identification of pathologic mutations of PRF1, UNC13D, or STX11.

OR

2. Fulfillment of five out of the eight criteria below:

- Fever (defined as a temperature >100.4 °F, >38 °C)

- Enlargement of the spleen

- Decreased blood cell counts affecting at least two of three lineages in the peripheral blood:

- Haemoglobin <9 g/100 ml (in infants <4 weeks: haemoglobin <10 g/100 ml) (anemia)

- Platelets <100×10/L (thrombocytopenia)

- Neutrophils <1×10/L (neutropenia

- High blood levels of triglycerides (fasting, greater than or equal to 265 mg/100 ml) and/or decreased amounts of fibrinogen in the blood (≤ 150 mg/100 ml)

- Ferritin ≥ 500 ng/ml

- Haemophagocytosis in the bone marrow, spleen or lymph nodes

- Low or absent natural killer cell activity

- Soluble CD25 (soluble IL-2 receptor) >2400 U/ml (or per local reference laboratory)

In addition, in the case of familial HLH, no evidence of malignancy should be apparent.

It should be noted that not all five out of eight criteria are required for diagnosis of HLH in adults, and a high index of suspicion is required for diagnosis as delays results in increased mortality. The diagnostic criteria were developed in pediatric populations and have not been validated for adult HLH patients. Attempts to improve diagnosis of HLH have included use of the HScore, which can be used to estimate an individual's risk of HLH.

Lymphocyte-variant hypereosinophilia is a rare disease in which eosinophilia is caused by aberrant T cell lymphocytes which secrete cytokines (e.g. interleukin-5) that stimulate the proliferation of eosinophil precursor cells. The disease, which occasionally proceeds to a malignant lymphocytic phase, clearly reflects a clonal disturbance in lymphocytes, not eosinophils, and therefore is not a clonal hypereosinophilia. Similar non-clonal eosinophilia due to eosinophil precursor cell stimulation by clonal malignant cells is sometimes seen in cases of Hodgkin disease, B-cell lymphoma, T-cell lymphomas, T cell leukemias, and Langerhans cell histiocytosis. Other hematological diseases are associated with eosinophilia but regarded as clonal eosinophilia associated with a more important clonal malignancy in another cell type. For example, eosinophilia occurs in 20% to 30% of patients with systemic mastocytosis. Also referred to as SM-eo (systemic mastocytosis with eosinophilia) or SM-SEL (systemic mastocytosis with chronic eosinophilic leukemia), this disease's clonal eosinophils bear the same driving mutation, D816V in the"KIT" gene, as the clonal mast cells.

The differential diagnosis of Rosai–Dorfman disease includes both malignant and nonmalignant diseases, such as granulomatosis with polyangiitis, Langerhans cell histiocytosis, Langerhans cell sarcoma, lymphoma, sarcoidosis, and tuberculosis. The disease is diagnosed by biopsy of affected tissues. Microscopic examination of stained specimens will show histiocytes with lymphocytes and possibly other types of cells trapped within them, a phenomenon known as emperipolesis. Upon immunohistochemical staining, the histiocytes will be positive for S100, CD68, and CD163 but negative for CD1a.

Langerhans cells are dendritic cells (antigen-presenting immune cells) of the skin and mucosa, and contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in the stratum spinosum. They also occur in the papillary dermis, particularly around blood vessels, as well as in the mucosa of the mouth, foreskin, and vagina. They can be found in other tissues, such as lymph nodes, particularly in association with the condition Langerhans cell histiocytosis (LCH).

The blood count typically shows decreased numbers of blood cells—including a decreased amount of circulating red blood cells, white blood cells, and platelets.

The bone marrow may show hemophagocytosis.

The liver function tests are usually elevated. A low level of the protein albumin in the blood is common.

The serum C reactive protein, erythrocyte sedimentation rate, and ferritin level are markedly elevated. In children, a ferritin above 10000 is very sensitive and specific for the diagnosis of HLH, however, the diagnostic utility for ferritin is less for adult HLH patients.

The serum fibrinogen level is usually low and the D-dimer level is elevated.

The sphingomyelinase is elevated.

Bone marrow biopsy shows histiocytosis.

The immunophenotype for hepatosplenic T-cell lymphoma is a post-thymic, immature T-cell.

ANKL is treated similarly to most B-cell lymphomas. Anthracycline-containing chemotherapy regimens are commonly offered as the initial therapy. Some patients may receive a stem cell transplant.

Most patients will die 2 years after diagnosis.

Dermatopathic lymphadenopathy is diagnosed by a lymph node biopsy. It has a characteristic pattern of histomorphology and immunohistochemical staining:

- Paracortical histiocytosis

- Melanin-laden macrophages

- Eosinophils

- Plasma cells (medulla of lymph node)

The disease in the lungs is characterized by enlargement of the tracheobronchial lymph nodes and infiltration of the lungs, sometimes leading to lung lobe consolidation and pleural effusion. Signs and symptoms include cough, loss of appetite, weight loss, anemia, and difficulty breathing. Seizures and rear limb weakness can be seen. Invasion of the bone marrow can cause pancytopenia. Diagnosis requires a biopsy.

Radiologic osteosclerosis and histology are the main diagnostic features. Diagnosis can often be difficult because of the rareness of ECD as well as the need to differentiate it from LCH. A diagnosis from neurological imaging may not be definitive. The presence of symmetrical cerebellar and pontine signal changes on T2-weighted images seem to be typical of ECD, however, multiple sclerosis and metabolic diseases must also be considered in the differential diagnosis. ECD is not a common cause of exophthalmos but can be diagnosed by biopsy. However, like all biopsies, this may be inconclusive. Video-assisted thoracoscopic surgery may be used for diagnostic confirmation and also for therapeutic relief of recurrent pericardial fluid drainage.

Cutaneous T-cell lymphoma may be divided into the several subtypes. Mycosis fungoides is the most common form of CTCL and is responsible for half of all cases.A WHO-EORTC classification has been developed.

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.

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:

A histiocyte is an animal cell that is part of the mononuclear phagocyte system (also known as the reticuloendothelial system or lymphoreticular system). The mononuclear phagocytic system is part of the organism's immune system. The histiocyte is a tissue macrophage or a dendritic cell (histio, diminutive of histo, meaning "tissue", and cyte, meaning "cell").