Anaplastic large cell lymphoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]; Grammar Reviewer: Natalie Harpenau, B.S.[3]

Anaplastic large cell lymphoma is an aggressive (fast-growing) type of non-Hodgkin lymphoma that is usually of the T-cell type. ALK negative ALCL T-cells express CD30 but do not express the ALK (Anaplastic Lymphoma Kinase) chimeric protein. Anaplastic lymphoma kinase positive large B-cell lymphoma (ALK+ LBCL) was first described in 1997 by Delsol. In 2008, the World Health Organization (WHO) added anaplastic lymphoma kinase (ALK) negative anaplastic large cell lymphoma and anaplastic lymphoma kinase positive large B-cell lymphoma as provisional entities in the peripheral T-cell lymphoma classification. Anaplastic large cell lymphoma may be classified into several sub-types based on immunophenotype.

Anaplastic lymphoma kinase positive large B-cell lymphoma (ALK+ LBCL) was first described in 1997 by Delsol. In 2008, the World Health Organization (WHO) added anaplastic lymphoma kinase (ALK) negative anaplastic large cell lymphoma and anaplastic lymphoma kinase positive large B-cell lymphoma as provisional entities in the peripheral T-cell lymphoma classification.

Anaplastic large cell lymphoma may be classified into several sub-types based on immunophenotype, clinical presentation, and histology.

The ALK gene is involved in the pathogenesis of ALK positive anaplastic large cell lymphoma. The DUSP22 gene is involved in the pathogenesis of ALK negative anaplastic large cell lymphoma. On microscopic histopathological analysis, medium-sized cells, abundant cytoplasm, kidney shaped nuclei, and paranuclear eosinophilic region are characteristic findings of anaplastic large cell lymphoma.

There are no established causes for anaplastic large cell lymphoma.

Anaplastic large cell lymphoma must be differentiated from other diseases such as metastatic carcinoma, B cell lymphoma, primary cutaneous T-cell lymphoma, rhabdomyosarcoma, peripheral T-cell lymphoma-not otherwise specified, classical Hodgkin’s lymphoma, and diffuse large B cell lymphoma.

Anaplastic large cell lymphoma is a common disease that tends to affect children or young adults. Males are more commonly affected with anaplastic large cell lymphoma than females.^[1]

There are no established risk factors for anaplastic large cell lymphoma.

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for anaplastic large cell lymphoma.

The ALK-positive anaplastic large cell lymphoma is associated with the most favorable prognosis. ALK-positive anaplastic large cell lymphoma is associated with a 5 year survival rate of 70-80%. ALK-positive anaplastic large cell lymphoma is associated with a 5 year survival rate of 30-40%.

According to the Lugano classification, there are four stages of anaplastic large cell lymphoma based on the number of nodes and extranodal involvement.

The most common symptoms of anaplastic cell lymphoma include fever, weight loss, skin rash, night sweats, chest pain, abdominal pain, bone pain, and painless swelling in the neck, axilla, groin, thorax, and abdomen.

Common physical examination findings of mantle cell lymphoma include fever, rash, ulcer, splenomegaly, hepatomegaly, chest tenderness, abdomen tenderness, bone tenderness, peripheral lymphadenopathy, and central lymphadenopathy.^[2]

Laboratory tests for anaplastic large cell lymphoma include complete blood count (CBC), blood chemistry studies, flow cytometry, FISH, immunohistochemistry, and immunophenotyping.^[3][4][5]

Chest X ray may be helpful in the diagnosis of anaplastic large cell lymphoma. Findings on chest X ray, suggestive of anaplastic large cell lymphoma include pulmonary nodules and pleural effusion.

Thorax CT scans may be helpful in the diagnosis of anaplastic large cell lymphoma. Findings on CT scans suggestive of anaplastic large cell lymphoma include mediastinal lymphadenopathy and bilateral pleural effusion.

Thorax MRI scans may be helpful in the diagnosis of anaplastic large cell lymphoma. Findings on MRI scans suggestive of anaplastic large cell lymphoma include large heterogenous, lobulated mass, and lymphadenopathy.

Lymph node or extranodal tissue biopsy is diagnostic of anaplastic large cell lymphoma.

Abdomen and shoulder ultrasound may be helpful in the diagnosis of anaplastic large cell lymphoma.

PET scans may be helpful in the diagnosis of anaplastic large cell lymphoma.

Other diagnostic studies for anaplastic large cell lymphoma include laparoscopy, laparotomy, bone marrow aspiration, and bone marrow biopsy.

The predominant therapy for anaplastic lymphoma is chemotherapy. Adjunctive radiotherapy, stem cell transplantation, and surgery may be required. The optimal therapy for anaplastic large cell lymphoma depends on the type and extent of anaplastic large cell lymphoma.

The feasibility of surgery depends on the type of anaplastic large cell lymphoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2], Kamal Akbar, M.D.[3]; Grammar Reviewer: Natalie Harpenau, B.S.[4]

Anaplastic lymphoma was first described by Stien et al in 1985. In 2008, the World Health Organization (WHO) added anaplastic lymphoma kinase (ALK) negative anaplastic large cell lymphoma and anaplastic lymphoma kinase positive large B-cell lymphoma as transitional bodies in the peripheral T-cell lymphoma classification.^[1][2]

• Anaplastic large cell lymphoma was first described by Stein et al in 1985, whom described it as neoplastic proliferation of lymphoid cells which appears anaplastic. When tumor cells always showed labeling by the monoclonal antibody Ki-1, a marker later shown to recognize the CD30 antigen.^[3]
• In 1988, ALCL was added to the revised Kiel classification.
• In 1994, it was included in the Revised European-American Lymphoma (REAL) classification.^[3]
• Then in 1997, Delsol discovered anaplastic lymphoma kinase-(ALK-) positive large B-cell lymphoma (ALK+ LBCL).
• In 2008, the World Health Organization (WHO) added anaplastic lymphoma kinase (ALK) negative anaplastic large cell lymphoma and anaplastic lymphoma kinase positive large B-cell lymphoma as provisional entities in the peripheral T-cell lymphoma classification.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2], Kamal Akbar, M.D.[3]; Grammar Reviewer: Natalie Harpenau, B.S.[4]

Anaplastic large cell lymphoma may be classified into several subtypes based on immunophenotype, clinical presentation, and histology.

• Anaplastic large cell lymphoma (peripheral T-cell lymphoma Non-Hodgkin Lymphoma) may be classified into 2 sub-types: ^[1]

• Anaplastic large cell lymphoma, ALK positive
• Anaplastic large cell lymphoma, ALK negative

• Based on clinical presentations, anaplastic large cell lymphoma may be classified into 3 sub-types:

• Primary cutaneous anaplastic large cell lymphoma
• Primary systemic anaplastic large cell lymphoma

• Nodal anaplastic large cell lymphoma
• Extra nodal anaplastic large cell lymphoma

• Implant associated anaplastic large cell lymphoma

• Based on histology, anaplastic large cell lymphoma may be classified into 3 sub-types:^[2]

• Classical Variants
• Atypical Variants
• Rare Variants

Classification based on the clinical presentation

Name	Description
Primary cutaneous anaplastic large cell lymphoma	Confined to the skin. Usually a single lump or tumor in the skin. May also spread to lymph nodes in the area. Associated with a rare skin condition called lymphomatoid papulosis. Less aggressive than primary systemic anaplastic large cell lymphoma. Occasionally individuals have a spontaneous remission. Fairly good prognosis
Primary systemic anaplastic large cell lymphoma	Usually involves the lymph nodes. Can also occur in organs or tissues other than the lymph nodes (extranodal sites) including: lungs, liver, bone marrow, bone, gastrointestinal tract, skin, and soft tissue. Most individuals have advanced stage (stage III or IV) disease when they are diagnosed. Usually a fast-growing (aggressive) lymphoma.
Implant associated anaplastic large cell lymphoma	The tumor initially manifests with swelling of the breast due to fluid accumulation around the implant. May progress to invade the tissue surrounding the capsule, and if left untreated may progress to axillary lymph nodes. [3]

Histological Classification ^[4]

Name	Description
Classical Variants
Common pattern	ALK positive anaplastic large cell lymphoma Most common morphological variant (75%) [5] In large cells, nucleoli tend to be more prominent. The cytoplasm may be either basophilic or eosinophilic and the cell may have many nuclei with dispersed or clumped chromatin. Given that the lymphomatous cells grow in the lymph node’s sinuses, this variant may resemble a metastatic tumor.
Atypical Variants
Small cell	ALK positive anaplastic large cell lymphoma. Cells have nuclear irregularity and perivascular/intravascular distribution.[6] Occasionally, lymphomatous cells have a pale cytoplasm with a central nucleus, described as “fried egg cell”.[4]
Lymphohistiocytic	ALK positive anaplastic large cell lymphoma Histiocytes have an acidophilic cytoplasm and a perinuclear clear area, with an eccentric nuclei and condensed chromatin.[7] Lymphomatous cells cluster around the perivascular area as demonstrated by immunostaining with CD30 and ALK antibodies.[4]
Giant cell	ALK positive anaplastic large cell lymphoma
Hodgkin’s like	The morphological characteristics of this pattern are similar to the nodular sclerosis variant of Hodgkin’s lymphoma.[8] This pattern is predominately more common among females. There are two immunophenotypes:[8][2] Positive: CD30, ALK, epithelial membrane antigen (EMA), CD43 (only 66% of the times), and perforin Negative: CD15, CD20, Pax5/BSAP, and EBV
Rare Variants
Sarcomatoid	ALK positive anaplastic large cell lymphoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shivali Marketkar, M.B.B.S. [2], Sowminya Arikapudi, M.B,B.S. [3], Kamal Akbar, M.D.[4]; Grammar Reviewer: Natalie Harpenau, B.S.[5]

The ALK gene is involved in the pathogenesis of ALK positive anaplastic large cell lymphoma. The DUSP22 gene is involved in the pathogenesis of ALK negative anaplastic large cell lymphoma. On microscopic histopathological analysis, medium sized cells, abundant cytoplasm, kidney shaped nuclei, and a paranuclear eosinophilic region are characteristic findings of anaplastic large cell lymphoma.

• ALK-positive lymphoma is associated with a translocation in the ALK gene [T(2;5)(p23;q35)], which expresses the ALK protein.^[1]
• ALK negative anaplastic large cell lymphoma is characterized by a translocation T(6;7)(p25.3;q32.3), which inactivates the DUSP22 gene and leads to a higher proliferation rate.^[2]
• In healthy people, the product of the DUSP22 gene, the DUSP22 protein (also known as the JNK pathway-associated phosphatase or JKAP), inactivates the lymphocyte-specific tyrosine kinase protein during T-cell receptor signaling.^[3]
• DUSP22 mutations are also associated with breast cancer (the UDSMP22 protein can also block estrogen receptors)^[4] and primary cutaneous anaplastic large cell lymphoma.^[5]

• The majority of anaplastic large cell lymphomas, greater than 90%, contain a clonal rearrangement of the T-cell receptor. This may be identified using PCR techniques, such as T-gamma multiplex PCR.
• Oncogenic potential is conferred by up regulation of a tyrosine kinase gene on chromosome 2. Several different translocations involving this gene have been identified in different cases of this lymphoma
• The most common is a chromosomal translocation involving the nucleophosmin gene on chromosome 5.
• The translocation may be identified by analysis of giemsa-banded metaphase spreads of tumor cells and is characterized by t(2;5)(p23;q35).
• The product of this fusion gene may be identified by immunohistochemistry using antiserum to ALK protein. Probes are available to identify the translocation by fluorescent in-situ hybridization (FISH).
• The nucleophosmin component associated with the common translocation results in nuclear positivity as well as cytoplasmic positivity. Positivity with the other translocations may be confined to the cytoplasm.
• Mutagenesis and functional studies have identified a plethora of NPM1–ALK interacting molecules, which ultimately lead to the activation of key pathways including: Erk, PLC-γ, PI3K, and Jak/signal transducers and activators of transcription (STAT) pathways. These molecules then control cell proliferation and survival and cytoskeletal rearrangements.^[6]
• Other gene mutations include:^[7]
  • T(1;2), encoding a tropomyosin 3 (TPM3)/ALK fusion protein (10 to 20%)
  • T(2;3), encoding a TRK fusion gene (TFP)/ALK fusion protein (2 to 5%)
  • Inv(2), encoding a ATIC (Pur H gene)/ALK fusion protein (2 to 5%)
  • T(2;17), encoding a clathrin heavy (CLTC)/ALK fusion protein (2 to 5%)
  • T(2;17), encoding a ALO17/ALK fusion protein (2 to 5 percent of cases)
  • T(2;19), encoding a tropomyosin 4 (TPM4)/ALK fusion protein (<1%)
  • T(2;22), encoding a non-muscle myosin (MYH9)/ALK fusion protein (<1%)

• The hallmark cells portray immunopositivity for CD30^[8] (also known as Ki-1)
• True positivity requires pinpointing of the signal to the cell membrane and/or paranuclear region.
• Another useful marker, which helps to decipher this lesion from Hodgkin lymphoma, is Clusterin.
• The neoplastic cells have a golgi staining pattern (hence paranuclear staining), which is tell tale indicator of this lymphoma.
• The cells are also typically positive for a subset of markers of T-cell lineage.
• However, as with other T-cell lymphomas, they are usually negative for the pan T-cell marker CD3.
• Occasional examples are of neither T nor B cell type. These lymphomas show immunopositivity for ALK protein in 70% of cases.
• They are also typically positive for epithelial membrane antigen (EMA). In contrast to many B-cell anaplastic CD30 positive lymphomas, the neoplastic cells are negative for markers of Epstein-Barr Virus (EBV).

The histological features of anaplastic large cell lymphoma are variable. The hallmark cells are of medium size and feature abundant cytoplasm (which may be clear, amphophilic or eosinophilic), kidney shaped nuclei, and a paranuclear eosinophilic region. Occasional cells may be identified in which the plane of section passes through the nucleus in such a way that it appears to enclose a region of cytoplasm within a ring; such cells are called “doughnut” cells.

Histological Classification ^{[9] [1]}

Name	Description
Classical Variants
Common pattern	ALK positive anaplastic large cell lymphoma Most common morphological variant (75%)[10] In large cells, nucleoli tend to be more prominent. The cytoplasm may be either basophilic or eosinophilic, and the cell might have many nuclei with dispersed or clumped chromatin. Given that the lymphomatous cells grow in the lymph node’s sinuses, this variant may resemble a metastatic tumor.
Atypical Variants
Small cell	ALK positive anaplastic large cell lymphoma Cells have nuclear irregularity and perivascular/intravascular distribution.[11] Occasionally, lymphomatous cells have a pale cytoplasm with a central nucleus, described as “fried egg cell”.[1]
Lymphohistiocytic	ALK positive anaplastic large cell lymphoma Histiocytes have an acidophilic cytoplasm and a perinuclear clear area, with an eccentric nuclei and condensed chromatin.[12] Lymphomatous cells cluster around the perivascular area as demonstrated by immunostaining with CD30 and ALK antibodies.[1]
Giant cell	ALK positive anaplastic large cell lymphoma
Hodgkin’s like	The morphological characteristics of this pattern are similar to the nodular sclerosis variant of Hodgkin’s lymphoma.[13] This pattern is predominately more common among females. There are two immunophenotype:[13] Positive: CD30, ALK, epithelial membrane antigen (EMA), CD43 (only 66% of the times), and perforin Negative: CD15, CD20, Pax5/BSAP, and EBV
Rare Variants
Sarcomatoid	ALK positive anaplastic large cell lymphoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

There are no established causes for anaplastic large cell lymphoma.

There are no established causes for anaplastic large cell lymphoma.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2], Kamal Akbar, M.D.[3]; Grammar Reviewer: Natalie Harpenau, B.S.[4]

Anaplastic large cell lymphoma is a common disease that tends to affect children or young adults. Males are more commonly affected with anaplastic large cell lymphoma than females.^[1]

• The incidence/prevalence of Anaplastic large cell lymphoma is approximately 2-8% of adult cases of non-Hodgkins lymphoma and as much as 30% of childhood non-Hodgkins lymphomas^[2][3]

• Prevalence for this condition is not known

• Patients of all age groups may develop anapastic large cell lymphoma.
• Anaplastic large cell lymphoma is a common disease that tends to affect children or young adults.
• ALK-positive anaplastic large cell lymphoma usually affects younger individuals (between 10 and 29 years).^[4]
• ALK-negative anaplastic large cell lymphoma usually affects older individuals (between 40-60 years).

• Males are more commonly affected with anaplastic large cell lymphoma than females.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2], Kamal Akbar, M.D.[3]

There are no established risk factors for anaplastic large cell lymphoma.

• There are no real established risk factors for anaplastic large cell lymphoma, but the following are some known predisposing factors:^[1][2]
  • Male predominance
  • 2;5 translocation in the sub-types of Anaplastic large cell lymphoma
  • Textured breast implants (also know as breast implant associated anaplastic large cell lymphoma)^[3][4][5][6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2]

There is insufficient evidence to recommend routine screening for Anaplastic large cell lymphoma

• There is insufficient evidence to recommend routine screening for Anaplastic large cell lymphoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sowminya Arikapudi, M.B,B.S. [2], Kamal Akbar, M.D.[3]; Grammar Reviewer: Natalie Harpenau, B.S.[4]

The ALK-positive anaplastic large cell lymphoma is associated with the most favorable prognosis. ALK-positive anaplastic large cell lymphoma is associated with a 5 year survival rate of 70-80%. ALK-positive anaplastic large cell lymphoma is associated with a 5 year survival rate of 30-40%.

• If left untreated, patients with anaplastic large cell lymphoma may progress to develop anemia, intestinal obstruction, and immuno-suppression thus causing infection.

• Common complications of anaplastic large cell lymphoma include:
  • Organ failure due metastasis
  • Immuno-suppression thus causing infection
  • CNS involvement causing:
    • Meningitis
    • Visual disturbance
    • Facial numbness
  • Anemia due to bleeding
  • Stroke due to vascular occlusion from leukemic cells

• Those with ALK positivity have a better prognosis. ^[1]
• ALK-negative anaplastic large cell lymphomas represent other T-cell lymphomas in a final common pathway of disease progression.
• Overall better prognosis than other aggressive lymphomas.
• ALK-positive anaplastic large cell lymphoma is associated with a 5 year survival rate of 70-80%.
• ALK-positive anaplastic large cell lymphoma is associated with a 5 year survival rate of 30-40%.

• The International Prognostic Iindex (IPI) is used to estimate the prognosis of patients.
• The IPI takes into account 5 variables:

• Patient’s age (>60 years)
• Elevated serum lactate dehydrogenase (LDH)
• Eastern Cooperative Oncology Group (ECOG) performance status
• Ann Arbor clinical stage III or IV
• Number of involved extra nodal sites > 1

• If any of this criteria is met, one point is awarded for the IPI. The interpretation of the total score is as follows:

• 0 to 1: Low risk
• 2: Low-intermediate risk
• 3: High-intermediate risk
• 4 to 5: High risk

• According to the International Peripheral T cell Lymphoma Project, the estimated 5-years survival for each of the IPI stages are as follows:^[2]

• Low risk (IPI 0-1): 90%
• Low-intermediate risk (IPI 2): 68%
• High-intermediate risk (IPI 3): 23%
• High risk (IPI 4-5): 33%

• However, more recently, the International peripheral T-cell lymphoma Project score (IPTCLP) has demonstrated to be the most accurate score to predict overall survival in patients.^[3] This score includes:

• Age
• Eastern Cooperative Oncology Group (ECOG) performance status
• Platelet count

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