The clinical presentation varies according to the type of ALCL. Two of the ALCL subtypes are systemic lymphomas, in that they usually present with enlarged lymph nodes in multiple regions of the body, or with tumors outside the lymph nodes (extranodal) such as bone, intestine, muscle, liver, or spleen. These 2 subtypes usually associate with weight loss, fevers and night sweats, and can be lethal if left untreated without chemotherapy. The third type of ALCL is so-called cutaneous ALCL, and is a tumor that presents in the skin as ulcers that may persist, or occasionally may involute spontaneously, and commonly recur. This type of ALCL usually manifests in different regions of the body and may extend to regional lymph nodes, i.e., an axillary lymph node if the ALCL presents in the arm.

A rare subtype of ALCL has been identified in a few women who have silicone breast implants (protheses) as a result of breast reconstruction after a diagnosis of breast cancer. The tumor initially manifests with swelling of the breast due to fluid accumulation around the implant. The disease may progress to invade the tissue surrounding the capsule, and if left untreated may progress to the axillary lymph nodes.

It typically presents at a late stage and is often associated with systemic symptoms ("B symptoms").

The median age of diagnosis is approximately fourth and fifth decades. The disease often arises in the oral cavity, particularly in HIV disease, but other sites include nasal cavity, gastrointestinal tract, skin, bone soft tissue, and lung. There is usually immunodeficiency, such as HIV, organ transplants, autoimmune diseases

Like Burkitt's lymphoma, the morphology has a "starry sky". However, the immunophenotype resembles plasma cells: CD45-, CD20-, CD79a+/-, PAX5-, CD38+, CD38+ and MUM1+. Ki67 is over 90%. EBV is positive in 75%; HHV-8 is negative.

Plasmablastic lymphoma is a type of large B-cell lymphoma, recognized in the WHO 2008 classification. It is CD20 negative, and has an immunophenotype that resembles plasma cells. In formal use, lymphomas with plasmablastic immunophenotype such as primary effusion lymphoma, ALK+ large B-cell lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman's disease and extracavitary HHV–8-positive lymphoma are not part of this category, although sometimes the literature has confused this point.

Large B-cell lymphoma arising in HHV8-associated multicentric Castleman's disease is a type of large B-cell lymphoma, recognized in the WHO 2008 classification. It is sometimes called the plasmablastic form of multicentric Castleman disease. It has sometimes been confused with plasmablastic lymphoma in the literature, although that is a dissimilar specific entity. It has variable CD20 expression and unmutated immunoglobulin variable region genes.

Anaplastic large-cell lymphoma (ALCL) is a type of non-Hodgkin lymphoma involving aberrant T cells or null lymphocytes. It is described in detail in the "Classification of Tumours of the Haematopoietic and Lymphoid Tissues" edited by experts of the World Health Organisation (WHO). The term anaplastic large cell lymphoma (ALCL) encompasses at least 4 different clinical entities, all sharing the same name, and histologically have also in common the presence of large pleomorphic cells that express CD30 and T-cell markers. Two types of ALCL present as systemic disease and are considered as aggressive lymphomas, while two types present as localized disease and may progress locally.

Its name derives from anaplasia and large-cell lymphoma.

Langerhans cell sarcoma is a form of malignant histiocytosis. It should not be confused with Langerhans cell histiocytosis, which is cytologically benign. Langerhans cell sarcoma is known to transform into leukemia. It can present in the lung, but such cases are rare.

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.

The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are "blood cancers" in the lymph nodes. They develop more frequently in older adults and in immunocompromised individuals.

B-cell lymphomas include both Hodgkin's lymphomas and most non-Hodgkin lymphomas. They are typically divided into low and high grade, typically corresponding to indolent (slow-growing) lymphomas and aggressive lymphomas, respectively. As a generalisation, indolent lymphomas respond to treatment and are kept under control (in remission) with long-term survival of many years, but are not cured. Aggressive lymphomas usually require intensive treatments, with some having a good prospect for a permanent cure.

Prognosis and treatment depends on the specific type of lymphoma as well as the stage and grade. Treatment includes radiation and chemotherapy. Early-stage indolent B-cell lymphomas can often be treated with radiation alone, with long-term non-recurrence. Early-stage aggressive disease is treated with chemotherapy and often radiation, with a 70-90% cure rate. Late-stage indolent lymphomas are sometimes left untreated and monitored until they progress. Late-stage aggressive disease is treated with chemotherapy, with cure rates of over 70%.

There are numerous kinds of lymphomas involving B cells. The most commonly used classification system is the WHO classification, a convergence of more than one, older classification systems.

Castleman disease (CD) is a lymphoproliferative disorder of unknown cause. CD is associated with an increased risk of B-cell lymphoma.

Human herpesvirus 8 (HHV-8), also known as Kaposi sarcoma-associated herpesvirus (KSHV) has been found in some cases of multicentric Castleman disease (MCD). The HHV8 can give rise to an increased number of plasmablast cells within the mantle zone of B-cell follicles. These plasmablasts express IgM-immunoglobulin light chains, most often of lambda subtype. These plasmablasts can give rise to a spectrum of abnormalities including progression to microlymphoma (microscopic clusters of plasmablast cells) or clinical lymphoma.

This type of lymphoma is predominantly seen in acquired immunodeficiencies, including acquired immunodeficiency syndrome (AIDS) but it can also occur in immunosuppression such as with organ transplantation or the elderly. The plasmablasts do not show rearranged immunoglobulin genes, and typically lack EBV infection.

The disease predominantly affects lymph nodes and the spleen, a pattern dissimilar to plasmablastic lymphoma of the oral cavity of AIDS which is not associated with HHV-8 infection. Despite traditional chemotherapy with CHOP (cyclophosphamide, doxorubicin, prednisone, vincristine), and the possible addition of antiviral therapy and inhibition of specific cellular targets including the use of rituximab, the prognosis in this lymphoma has been poor.

This lymphoma subtype has sometimes been confused with plasmablastic lymphoma in the literature, although that is a dissimilar specific entity. Similarly, this subtype is considered distinct from other lymphomas which have a plasmablastic immunophenotype such as primary effusion lymphoma, ALK+ large B-cell lymphoma, and extracavitary HHV–8-positive lymphoma.

HHV8 is also associated with Kaposi's sarcoma and with another subtype of lymphoma, primary effusion lymphoma, previously called body cavity-based lymphoma.

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.

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.

LCH provokes a non-specific inflammatory response, which includes fever, lethargy, and weight loss. Organ involvement can also cause more specific symptoms.

- Bone: The most-frequently seen symptom in both unifocal and multifocal disease is painful bone swelling. The skull is most frequently affected, followed by the long bones of the upper extremities and flat bones. Infiltration in hands and feet is unusual. Osteolytic lesions can lead to pathological fractures.

- Skin: Commonly seen are a rash which varies from scaly erythematous lesions to red papules pronounced in intertriginous areas. Up to 80% of LCH patients have extensive eruptions on the scalp.

- Bone marrow: Pancytopenia with superadded infection usually implies a poor prognosis. Anemia can be due to a number of factors and does not necessarily imply bone marrow infiltration.

- Lymph node: Enlargement of the liver in 20%, spleen in 30% and lymph nodes in 50% of Histiocytosis cases.

- Endocrine glands: Hypothalamic pituitary axis commonly involved. Diabetes insipidus is most common. Anterior pituitary hormone deficiency is usually permanent.

- Lungs: some patients are asymptomatic, diagnosed incidentally because of lung nodules on radiographs; others suffer from chronic cough and shortness of breath.

- Less frequently gastrointestinal tract, central nervous system, and oral cavity.

Langerhans cell histiocytosis (LCH) is a rare disease involving clonal proliferation of Langerhans cells, abnormal cells deriving from bone marrow and capable of migrating from skin to lymph nodes. Clinically, its manifestations range from isolated bone lesions to multisystem disease. LCH is part of a group of clinical syndromes called histiocytoses, which are characterized by an abnormal proliferation of histiocytes (an archaic term for activated dendritic cells and macrophages). These diseases are related to other forms of abnormal proliferation of white blood cells, such as leukemias and lymphomas.

The disease has gone by several names, including Hand–Schüller–Christian disease, Abt-Letterer-Siwe disease, Hashimoto-Pritzker disease(a very rare self-limiting variant seen at birth) and histiocytosis X, until it was renamed in 1985 by the Histiocyte Society.

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.

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.

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:

The disease is often rapidly fatal, with a five year survival rate of 50%. The development of thrombocytopenia is a poor prognostic sign.

.Letterer-Siwe is characterized by skin lesions, ear drainage, lymphadenopathy, osteolytic lesions, and hepatosplenomegaly. The skin lesions are scaly and may involve the scalp, ear canals, and abdomen.

Lymphadenopathy can occur in one or more groups of lymph nodes. Among 358 cases of Rosai–Dorfman disease that Rosai collected in a disease registry for which the location of lymphadenopathy was specified, 87.3% had cervical lymphadenopathy. Axillary, inguinal, and mediastinal lymphadenopathy are also found in Rosai–Dorfman disease.

Long bone involvement is almost universal in ECD patients and is bilateral and symmetrical in nature. More than 50% of cases have some sort of extraskeletal involvement. This can include kidney, skin, brain and lung involvement, and less frequently retroorbital tissue, pituitary gland and heart involvement is observed.

Bone pain is the most frequent of all symptoms associated with ECD and mainly affects the lower limbs, knees and ankles. The pain is often described as mild but permanent, and in nature. Exophthalmos occurs in some patients and is usually bilateral, symmetric and painless, and in most cases it occurs several years before the final diagnosis. Recurrent pericardial effusion can be a manifestation, as can morphological changes in adrenal size and infiltration.

A review of 59 case studies by Veyssier-Belot, C et al. in 1996 reported the following symptoms in order of frequency of occurrence:

- Bone pain

- Retroperitoneal fibrosis

- Diabetes insipidus

- Exophthalmos

- Xanthomas

- Neurological signs ("including Ataxia")

- Dyspnea caused by interlobular septal and pleural thickening.

- Kidney failure

- Hypopituitarism

- Liver failure

The histiocytosis of Rosai–Dorfman disease can occur in lymph nodes, causing lymphadenopathy, or can occur outside lymph nodes in extranodal disease.

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-.

The onset of HLH occurs under the age of 1 year in ~70% of cases. Familial HLH should be suspected if siblings are diagnosed with HLH or if symptoms recur when therapy has been stopped. Each full sibling of a child with familial HLH has a 25% chance of developing the disease, a 50% chance of carrying the defective gene (which is very rarely associated with any risk of disease) and a 25% chance of not being affected and not carrying the gene defect.

Patients with HLH, especially when untreated, may need intensive therapy. Therefore, HLH should be included in the differential diagnosis of ICU (Intensive Care Unit) patients with cytopenia and hyperferritinemia.

HLH clinically manifests with fever, enlargement of the liver and spleen, enlarged lymph nodes, yellow discoloration of the skin and eyes, and a rash.

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)