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Anaplastic Large-Cell Lymphoma

Anaplastic large cell lymphoma (ALCL) is a hematological malignancy, characterized by the uncontrollable proliferation of lymphocytes and specifically T-cells. ALCL may be limited to the skin or may disseminate to various other distant locations.

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Presentation

Clinical characteristics vary between the two subtypes of ALCL:

ALK-positive ALCL

Individuals affected by ALK-positive ALCL are typically younger than those with ALK negative ALCL. ALK-positive lymphoma is usually diagnosed during one's early adulthood. The lymph nodes are commonly affected and malignant cells are frequently observed as disseminated structures in other organs, such as the bones and soft tissue [16].

ALK-negative ALCL

Patients are usually male and belong to the age group of 55-60 years old [17] [18]. Often the malignancy is in advanced stages (III or IV) at the time of diagnosis and the classical symptom triad of B symptoms are usually present (weight loss, night sweats, fever). Other typical characteristics are [18] [19] :

  • Elevated IPI score (International Prognostic Index)
  • Elevated LDH levels in the serum
  • Aggressive rate of progression

The malignancy is usually limited to the lymph nodes, in contradistinction to ALK-positive ALCL, with only a minority displaying dissemination to distant locations, mainly the skin and hepatic parenchyma [20] [21]. Only in rare occasions will ALCL manifest a leukemic phase [22]. Both types of ALCL have even possibilities of leading to an organized proliferative T-cell structure in the central nervous system [23].

Lymphadenopathy
  • Abstract Cervical lymphadenopathy in adults has a broad differential diagnosis, including bacterial and viral infections, Kikuchi-Fujimoto disease, systemic lupus erythematosus, and various neoplasms.[ncbi.nlm.nih.gov]
Fever
  • She underwent elective repeat cesarean section with a postoperative course complicated by skin and gingival ulcers and persistent fever. Imaging revealed lung and brain nodules.[ncbi.nlm.nih.gov]
Weight Loss
  • Abstract A woman aged 48 years presented with fevers, chills, weight loss, and night sweats. She had significant lymphadenopathy of the left neck as well as the left axilla.[ncbi.nlm.nih.gov]
  • The most classic manifestations are the B symptoms, which are characteristic for many types of lymphoma: weight loss, fever, night sweats.[symptoma.com]
  • Any weight loss? More tired than usual? Any skin bumps? Do they itch? To see if you have ALCL, doctors may take a biopsy from a swollen lymph node. It's quick and doesn't require a hospital stay.[webmd.com]
  • Other symptoms may include: Loss of appetite Tiredness Night sweats High temperatures and fever Weight loss ALCL is usually diagnosed by taking a biopsy of an enlarged lymph node or another abnormal area.[leukaemiacare.org.uk]
  • Less common symptoms include night sweats, weight loss, and unexplained high core-body temperatures.[knowcancer.com]
Weakness
  • Here, we report a case of an 82-year-old man with a history of cerebrovascular disease presented with weakness and iron deficiency anemia. He denied any abdominal discomforts.[ncbi.nlm.nih.gov]
  • You may feel weak or tired, and you may be sick to your stomach To help you feel better: Eat enough calories and protein each day to keep up weight and stay strong. Try several small meals instead of fewer bigger ones.[webmd.com]
  • It can include unexplained weight loss, weakness, night sweats, and frequent infections, apart from organ-specific clinical features A biopsy of the affected region may help establish a diagnosis of ALK-Negative ALCL.[dovemed.com]
  • In Hodgkin lymphoma, virtually all tumor cells show weak PAX-5 expression which, is not reported in systemic ALCL. Primary cutaneous ALCL is typically negative for ALK staining; however, a few cases ALK positivity in PC-ALCL have been reported.[emedicine.medscape.com]
Fatigue
  • Additionally, patients may experience a loss of appetite and/or fatigue. Less common symptoms include night sweats, weight loss, and unexplained high core-body temperatures.[knowcancer.com]
  • You may also have symptoms like: Fatigue Fever Loss of appetite Night sweats Weight loss With cutaneous ALCL, you may first notice one or more raised, red bumps on the skin that don't go away. These are tumors.[webmd.com]
  • Typical symptoms of a systemic ALCL include fever, chills, weight loss, night sweats, lymph node enlargement without pain and fatigue. Cutaneous ALCL involves solely lesions on the skin.[symptoma.com]
  • The signs and symptoms of ALK-Negative Anaplastic Large Cell Lymphoma may include: Unintentional weight loss; changes in appetite Fatigue and weakness, headache High temperatures and excessive night sweats (may be recurrent) Anemia (low red blood cell[dovemed.com]
  • […] when their implants were removed. 14 The scientific evidence regarding ALCL and implants once again raises questions about the possible impact of breast implants on autoimmune disease or symptoms such as joint pain, body pain, memory loss, and chronic fatigue[breastimplantinfo.org]
Generalized Lymphadenopathy
  • lymphadenopathy, and circulating neoplastic T-cells in peripheral blood (Figure 4).[zdoc.site]
Axillary Lymphadenopathy
  • Case A 31-year-old Caucasian man presented to an outside hospital with a three week history of breathlessness, fever, diarrhoea, and axillary lymphadenopathy. He was diagnosed with infectious mononucleosis 4 years ago.[omicsonline.org]
Loss of Appetite
  • Additionally, patients may experience a loss of appetite and/or fatigue. Less common symptoms include night sweats, weight loss, and unexplained high core-body temperatures.[knowcancer.com]
  • You may also have symptoms like: Fatigue Fever Loss of appetite Night sweats Weight loss With cutaneous ALCL, you may first notice one or more raised, red bumps on the skin that don't go away. These are tumors.[webmd.com]
  • Other symptoms may include: Loss of appetite Tiredness Night sweats High temperatures and fever Weight loss ALCL is usually diagnosed by taking a biopsy of an enlarged lymph node or another abnormal area.[leukaemiacare.org.uk]
  • There were no symptoms of fever, weight loss, and loss of appetite. There was no history of preceding insect bite, trauma, and drugs. His personal and family history was noncontributory.[idoj.in]
Abdominal Pain
  • Before transplant, he was admitted with severe abdominal pain, which turned out to result from ileal perforation.[ncbi.nlm.nih.gov]
  • pain, and a general feeling of illness Bone marrow involvement can be seen in 1 in 4 individuals (25% of the cases) If the brain is involved, then neurological symptoms such as the following may be observed: Confusion Tinnitus (ringing in the ears) Hearing[dovemed.com]
Abdominal Mass
  • The patient presented with right middle abdominal mass for 1 month with sporadic pain. Computed tomography (CT) showed a mass measured 8.5   7.4   4 cm at the junction of jejunum and ileum.[ncbi.nlm.nih.gov]
Gingival Ulceration
  • She underwent elective repeat cesarean section with a postoperative course complicated by skin and gingival ulcers and persistent fever. Imaging revealed lung and brain nodules.[ncbi.nlm.nih.gov]
Back Pain
  • One month later, the patient returned with worsening back pain, and the follow up studies depicted collapse of the T12 vertebral body. A diagnosis of anaplastic large cell lymphoma in T12 was made.[ncbi.nlm.nih.gov]
  • pain Swelling of the legs Abdominal pain and swelling; constipation Frequent urination Some individuals may not have any systemic symptoms (known as ‘A’ symptoms), while some may have them (known as ‘B’ symptoms) Depending upon the site and organ involved[dovemed.com]
Ulcer
  • The present study report the case of a 16-year-old boy presenting PCALCL with single nodules, ulcer, keloid, and scab in his right-side face.[ncbi.nlm.nih.gov]
Skin Lesion
  • The rare morphological variant of anaplastic large cell lymphoma (ALCL) may pose a challenge in diagnosis, especially when presentation primarily involves skin lesions.[ncbi.nlm.nih.gov]
  • After diagnosis, the patient was treated with chemotherapy; however, she presented to the hospital several days later with recurrent skin lesions. Campath was administered.[path.upmc.edu]
  • T3 Skin lesions of widespread areas of skin, such as areas far apart on the body or 3 adjacent areas.[clfoundation.org]
  • The characteristic features of primary cutaneous ALCL include the appearance of solitary or multiple raised, red skin lesions that do not go away, have a tendency to ulcerate, and may itch.[lymphoma.org]
Night Sweats
  • Abstract A woman aged 48 years presented with fevers, chills, weight loss, and night sweats. She had significant lymphadenopathy of the left neck as well as the left axilla.[ncbi.nlm.nih.gov]
  • The most classic manifestations are the B symptoms, which are characteristic for many types of lymphoma: weight loss, fever, night sweats.[symptoma.com]
  • Other symptoms may include: Loss of appetite Tiredness Night sweats High temperatures and fever Weight loss ALCL is usually diagnosed by taking a biopsy of an enlarged lymph node or another abnormal area.[leukaemiacare.org.uk]
  • Less common symptoms include night sweats, weight loss, and unexplained high core-body temperatures.[knowcancer.com]
  • They usually have B symptoms, which are unexplained fever, drenching night sweats and unexplained weight loss. Treatments Many people with primary systemic ALCL can be successfully treated even when the disease is at an advanced stage.[cancer.ca]
Red Skin Lesion
  • The characteristic features of primary cutaneous ALCL include the appearance of solitary or multiple raised, red skin lesions that do not go away, have a tendency to ulcerate, and may itch.[lymphoma.org]
Pruritus
  • Palmoplantar hyperkeratosis, ungual dystrophies, and alopecia, are common findings and patients complain of intense pruritus.[zdoc.site]
Cesarean Section
  • She underwent elective repeat cesarean section with a postoperative course complicated by skin and gingival ulcers and persistent fever. Imaging revealed lung and brain nodules.[ncbi.nlm.nih.gov]

Workup

The diagnosis of anaplastic large cell lymphoma is largely based on histopathological findings. Biopsies need to be harvested, either by excisional or incisional biopsy. Depending on the histological characteristics, four distinct sub-types of ALCL have been established, which can be detected simultaneously in some cases [24] [25]. The identification of anaplastic T cells or CD30+ pleomorphic cells is the most typical characteristic of ALCL; the latter cellular type is found in the majority of the patients affected by primary cutaneous ALCL [26] [27] [28].

In order for a precise and effective treatment plan to be drawn, staging procedures are also mandatory. Further diagnostic modalities that can be used towards this cause include the following:

  • Thorough physical examination
  • Biochemical profile
  • Hematological profile
  • Total-body computerized tomography scan (total-body CT)
  • Bone marrow biopsy
  • Radiograph to eliminate the possibility of bone lesions
  • Endoscopy (possibly) for staging of intestinal lesions
  • Magnetic resonance imaging scans or ultrasonographic scans to detect lesions in the CNS, brain, breasts, liver, soft tissues salivary glands and other locations
  • CSF cytology in those with CNS involvement
Pseudomonas
  • Antigen/metabolism Klebsiella oxytoca/isolation & purification Lymphocytes/cytology Lymphocytes/metabolism Lymphoma, Large-Cell, Anaplastic/pathology* Macrophages/cytology Macrophages/metabolism Middle Aged Neutrophils/cytology Neutrophils/metabolism Pseudomonas[ncbi.nlm.nih.gov]

Treatment

Primary cutaneous anaplastic large cell lymphoma does not require chemotherapy. Surgical resection of the site of lymphocytic proliferation, according to the safe oncological guidelines for excision, or radiation therapy usually suffice. Approximately 95% of the individuals achieve complete remission after this type of treatment; however, half of the patients are expected to relapse. The combination of both surgical resection and radiation therapy may lead to a delayed relapseOn the other hand, systemic ALCL requires chemotherapy in order to subside. Doxorubicin is one of the recommended agents, as well as the CHOP therapeutic regimen. Younger individuals affected by ALK-positive ALCL may benefit considerably from the addition of etoposide to the chemotherapeutic regimen. After the pharmaceutical treatment has been completed, further evaluation may reveal the need for additional radiation therapy.The role of high-dose chemotherapy and autologous stem cell transplantation is currently being debated. Brentuximab vendotin, an antibody-drug conjugate or immunoconjugate directed to the CD30 protein, is usually reserved for refractory cases [29].

Prognosis

Generally, the primary cutaneous form of anaplastic large cell lymphoma is slow growing with a good prognosis and the 5-year survival rate is 90% [15]. It has been shown that the degree of lymphoma cutaneous expansion plays a significant prognostic role in primary cutaneous lymphoma. Patients with considerable involvement of the extremities may be faced with a 50% 5-year survival rate, in contradistinction to those whose extremities are minimally affected, whose survival rate is 90% after 5 years. Some occurrences of ALCL have even subsided without treatment of any kind.

Furthermore, ALK-positive and ALK-negative systemic ALCL, which are more commonly diagnosed in younger patients, display a prognosis with an immense discrepancy; the former's 5-year survival rate is 70-90%, whereas the latter has a respective rate of maximum 60%. Lastly, poor prognostic markers are also the involvement of the internal organs and mediastinal involvement.

Etiology

The cutaneous form of ALCL has not yet been proven to have a genetic background and the etiological factors remain unknown. On the other hand, the widespread, systemic ALCL has been proven to be primarily caused by a genetic mutation, and specifically a translocation t(2;5); this chromosomal abnormality leads to the production of a defective protein known as nucleophosmin-anaplastic lymphoma kinase (NMP-ALK), which greatly contributes to the development of the malignancy.

With regard to the risk factors, a study that researched the possible correlation of ALCL and insect bites found that the 5 subjects in the study exhibited lesions which on immunostatin application demonstrated ALK-positive cells positive for CD 30 and EMA[2]. Draining lymph node also tested positive for ALK, CD30 and EMA. A single patient progressed to systemic lymphoma with lung involvement. The study concluded that the insect bite and consecutive inflammation and cytokine activation induce, in some cases, the uninhibited reproduction of lymphocytes (T-cells) featuring the t(2;5) mutation.

Except for insect bites, various medications have been also incriminated for their contribution to cutaneous ALCL pathogenesis, such as glatiramer acetate [3].

Lymphomas like peripheral T-cell lymphomas, mycosis fungoides, Hodgkin disease or LyP can evolve to secondary ALCL. This type of ALCL is often ALK negative, occurs in older adults and has a poor prognosis.

Epidemiology

Anaplastic large cell lymphoma constitutes a minority of adult Non-Hodgkin lymphomas (3%). It is more common amongst pediatric patients, as it constitutes 10-20% of all lymphomas diagnosed in childhood [4]. With regard to its particular subtype, it has been established that ALK-positive ALCL tends to affect children and individuals in their early adulthood, whereas ALK-negative ALCL is more frequently seen in adults [5] [6] [7].

The malignancy evinces a predilection for men and most patients are diagnosed in the late stages of the disease. Systemic ALCL usually affects the skin, pulmonary parenchyma, bones, liver and central nervous system [8] [9] [10].

Sex distribution
Age distribution

Pathophysiology

The translocation t(2;5) is the primary pathophysiological alteration that underlies anaplastic large cell lymphoma. The translocation causes the amine group end of the protein nucleophosmin (NPM) and the carboxyl end of the ALK protein (anaplastic lymphoma kinase) to fuse together, thus producing a hybrid protein. Wild type NPM is expressed in practically every cell, whereas the wild type ALK remains restricted to the central nervous system [11] [12].

Other translocations have also been identified, but every single one of them involves the ALK protein which is fused with another proteinic part. Lastly, even though its contribution has not yet been clarified, multiple gene overexpressions have been observed in ALCL lymphoma, with different genes being overexpressed in ALK-positive and ALK-negative ALCL types [13] [14].

Prevention

Unfortunately, anaplastic large cell lymphoma cannot be prevented.

Summary

Anaplastic large cell lymphoma (ALCL) is a rare malignancy of the lymphocytes and particularly the T cells. It is included in the wider category of T cell lymphomas and in the even wider category of non-Hodgkin lymphomas.

There are two distinct types of anaplastic large cell lymphomas - the primary cutaneous type and the systemic type. The former is limited to the skin and the symptoms encompass only the cutaneous, cancerous lesions that may spread over a restricted area of one's skin or be extensive. The latter is characterized by a more aggressive progression rate and causes malignant lymphocytic dissemination in various organs of the body. Another classification is based on the presence / absence of the abnormal protein ALK (anaplastic lymphoma kinase): patients whose cellular surface includes ALK are described as having ALK-positive ALCL and are typically younger; and those whose cellular surface does not have ALK are believed to be suffering from ALK-negative lymphoma.

The existence of ALK can greatly influence prognosis, individuals with ALK-positive ALCL usually go into remission after treatment and experience no or fewer relapses [1]. Patients with ALK-negative anaplastic large cell lymphoma may go into remission but relapse often.

Typical symptoms of a systemic ALCL include fever, chills, weight loss, night sweats, lymph node enlargement without pain and fatigue. Cutaneous ALCL involves solely lesions on the skin.

ALCL requires a biopsy so that a definitive diagnosis can be established. It is harvested from the skin in the case of cutaneous lymphomas, or from an organ or lymph node, in the case of systemic ALCL. Radiation therapy or surgical excision can be interchangeably used to treat cutaneous lymphoma, which is extremely responsive and requires no further intervention. On the other hand, systemic lymphoma must be treated with chemotherapy and, if the need arises, with additional radiation therapy. The medication usually opted for is doxorubicin and CHOP.

Patient Information

Anaplastic large cell lymphoma (ALCL) is a type of hematopoietic cancer, namely a type of cancer that affects the cells of the blood. Cancer is practically the abnormally quick and uncontrollable reproduction of cells of a particular type, that either remain localized in the site of their production, or are disseminated to distant locations, thus further spreading cancer. Anaplastic large cell lymphoma is a type of cancer that affects the white blood cells and particularly the T cells: it falls under the wider category of Non-Hodgkin lymphomas and the category of T cell lymphomas.

According to the sites where the over-proliferative T cells are organized, ALCL has two distinct types: the primary cutaneous ALCL, which is limited to the skin, and the systemic ALCL, with involvement of other parts of the body. Another classification based on the presence or absence of a dysfunctional protein known as ALK: there is the type of anaplastic lymphoma which is ALK-positive and another which is ALK-negative type. ALK-positive lymphoma is more frequently diagnosed in younger individuals- children and young adults-, whereas ALK-negative lymphoma is more common amongst people in their 50s.

The causes of lymphoma, as in the case of many malignancies are not yet been fully understood. The systemic type of lymphoma is caused by a genetic mutation, but the cutaneous type is due to unknown factors. However, some study-based suggestions have been made that cutaneous lymphoma may be associated with insect bites or medications.

A lymphoma can have multiple manifestations, depending on its type. In general, cutaneous lymphoma is restricted to the skin and it is treated with surgical excision or radiation therapy, with both being effective. Systemic lymphoma has a poorer prognosis, requires chemotherapy and causes many more symptoms, due to the involvement of more organs. The most classic manifestations are the B symptoms, which are characteristic for many types of lymphoma: weight loss, fever, night sweats. Additionally, depending on the organ where the lymphocytic collection is organized, various symptoms can occur. Lymph node enlargement almost always accompanies the manifestations of an ALCL, since the lymph nodes are the first affected organs. Neurological symptoms such as diplopia, loss of coordination and lethargy can also occur, if the cancerous lymphocytic cells manage to infiltrate the central nervous system, which is a possibility.

References

Article

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  2. Lamant L, Pileri S, Sabattini E, et al. Cutaneous presentation of ALK-positive anaplastic large cell lymphoma following insect bites: evidence for an association in five cases. Haematologica. 2010; Mar; 95(3):449-55
  3. Madray MM, Greene JF Jr, Butler DF. Glatiramer acetate-associated, CD30+, primary, cutaneous, anaplastic large-cell lymphoma. Arch Neurol. 2008; Oct; 65(10):1378-9.
  4. Mora J, Filippa DA, Thaler HT, et al. Large cell non-Hodgkin lymphoma of childhood: Analysis of 78 consecutive patients enrolled in 2 consecutive protocols at the Memorial Sloan-Kettering Cancer Center. Cancer 2000;88(1):186-197.
  5. Savage KJ, Harris NL, Vose JM, et al; International Peripheral T-Cell Lymphoma Project. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 2008;111(12):5496-5504.
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Last updated: 2019-06-28 09:43