Lymphoma

Lymphoma
Follicular lymphoma replacing a lymph node
SpecialtyHematology and oncology
SymptomsEnlarged lymph nodes, fever, sweats, unintended weight loss, itching, feeling tired[1][2]
Risk factorsEpstein–Barr virus, autoimmune diseases, HIV/AIDS, tobacco smoking[2][3]
Diagnostic methodLymph node biopsy[1][2]
TreatmentChemotherapy, radiation therapy, targeted therapy, surgery[1][2]
PrognosisAverage five year survival 85% (USA)[4]
Frequency4.9 million (2015)[5]
Deaths204,700 (2015)[6]

Lymphoma is a group of blood cancers that develop from lymphocytes (a type of white blood cell).[7] The name often refers to just the cancerous versions rather than all such tumours.[7] Signs and symptoms may include enlarged lymph nodes, fever, drenching sweats, unintended weight loss, itching, and constantly feeling tired.[1][2] The enlarged lymph nodes are usually painless.[1] The sweats are most common at night.[1][2]

There are many subtypes of lymphomas.[8] The two main categories of lymphomas are the non-Hodgkin lymphomas (NHL) (90% of cases) and Hodgkin lymphomas (HL) (10%).[9] The World Health Organization (WHO) includes two other categories as types of lymphoma: multiple myeloma and immunoproliferative diseases.[10] About 90% of lymphomas are non-Hodgkin lymphomas.[9][11] Lymphomas and leukemias are a part of the broader group of tumors of the hematopoietic and lymphoid tissues.[12]

Risk factors for Hodgkin lymphoma include infection with Epstein–Barr virus and a history of the disease in the family.[1] Risk factors for common types of non-Hodgkin lymphomas include autoimmune diseases, HIV/AIDS, infection with human T-lymphotropic virus, immunosuppressant medications, and some pesticides.[2][13] Eating large amounts of red meat and tobacco smoking may also increase the risk.[3][14][15] Diagnosis, if enlarged lymph nodes are present, is usually by lymph node biopsy.[1][2] Blood, urine, and bone marrow testing may also be useful in the diagnosis.[2] Medical imaging may then be done to determine if and where the cancer has spread.[1][2] Lymphoma most often spreads to the lungs, liver, and brain.[1][2]

Treatment may involve one or more of the following: chemotherapy, radiation therapy, targeted therapy, and surgery.[1][2] In some non-Hodgkin lymphomas, an increased amount of protein produced by the lymphoma cells causes the blood to become so thick that plasmapheresis is performed to remove the protein.[2] Watchful waiting may be appropriate for certain types.[2] The outcome depends on the subtype with some being curable and treatment prolonging survival in most.[9] The five-year survival rate in the United States for all Hodgkin lymphoma subtypes is 85%,[4] while that for non-Hodgkin lymphomas is 69%.[16] Worldwide, lymphomas developed in 566,000 people in 2012 and caused 305,000 deaths.[10] They make up 3–4% of all cancers, making them as a group the seventh-most common form.[10][17] In children, they are the third-most common cancer.[18] They occur more often in the developed world than the developing world.[10]

Signs and symptoms

The lymph nodes where lymphoma most commonly develops
Lymphoma and lymphatic system

Lymphoma may present with certain nonspecific symptoms; if the symptoms are persistent, an evaluation to determine their cause, including possible lymphoma, should be undertaken.

Mouth

Asymptomatic soft swelling which may or may not be ulcerated that is primarily seen on the tonsils, buccal mucosa, palate, gums, salivary glands, tongue, floor of the mouth, and retromolar region.

Diagnosis

Lymphoma is definitively diagnosed by a lymph node biopsy, meaning a partial or total excision of a lymph node examined under the microscope.[22] This examination reveals histopathological features that may indicate lymphoma. After lymphoma is diagnosed, a variety of tests may be carried out to look for specific features characteristic of different types of lymphoma. These include:

  • A widened mediastinum due to lymphoma
  • CT chest of a person with lymphoma showing large lymph nodes in the chest
  • Lymphoma may appear as peritoneal lymphomatosis, as can be seen on CT scan. Image depicts non-Hodgkin lymphoma in a 17 year old who is HIV positive. A. Irregular homogenously enhancing wall thickening involving the ileocaecal region with aneurysmal dilatation of involved segments (curved arrow). B. Hepatosplenomegaly with liver metastasis (white arrows).[23]

Classification

Lymph node with mantle cell lymphoma (low-power view, H&E)

According to the World Health Organization (WHO), lymphoma classification should reflect which lymphocyte population the neoplasm arises.[24] Thus, neoplasms which arise from precursor lymphoid cells are distinguished from those which arise from mature lymphoid cells.[24] Most mature lymphoid neoplasms comprise the non-Hodgkin lymphomas.[24] Historically, mature histiocytic and dendritic cell (HDC) neoplasms have been considered mature lymphoid neoplasms since these often involve lymphoid tissue.[24]

Lymphoma can also spread to the central nervous system, often around the brain in the meninges, known as lymphomatous meningitis (LM).[25]

Hodgkin lymphoma

Main article: Hodgkin lymphoma

Hodgkin lymphoma accounts for about 15% of lymphomas.[26] It differs from other forms of lymphoma in its prognosis and several pathological characteristics. A division into Hodgkin and non-Hodgkin lymphomas is used in several of the older classification systems. A Hodgkin lymphoma is marked by the presence of a type of cell called the Reed–Sternberg cell.[27][28]

Non-Hodgkin lymphomas

Non-Hodgkin lymphomas, which are defined as being all lymphomas except Hodgkin lymphoma, are more common than Hodgkin lymphoma. A wide variety of lymphomas are in this class, and the causes, the types of cells involved, and the prognosis vary by type. The number of cases per year of non-Hodgkin lymphoma increases with age. It is further divided into several subtypes.

Epstein-Barr virus-associated lymphoproliferative diseases

Epstein-Barr virus-associated lymphoproliferative diseases are a group of benign, pre-malignant, and malignant diseases of lymphoid cells, i.e. B cells, T cells, NK cells, and histiocytic-dendritic cells in which one or more of these cell types is infected with the Epstein-Barr virus (EBV). The virus may be responsible for the development and/or progression of these diseases. In addition to EBV-positive Hodgkin lymphomas, the World Health Organization (2016) includes the following lymphomas, when associated with EBV infection, in this group of diseases: Burkitt lymphoma; large B cell lymphoma, not otherwise specified; diffuse large B cell lymphoma associated with chronic inflammation; fibrin-associated diffuse large B cell lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK/T cell lymphoma, nasal type; peripheral T cell lymphoma, not otherwise specified; angioimmunoblastic T cell lymphoma; follicular T cell lymphoma; and systemic T cell lymphoma of childhood.[29]

WHO classification

The WHO classification, published in 2001 and updated in 2008,[30][31] is based upon the foundations laid within the "revised European-American lymphoma classification" (REAL). This system groups lymphomas by cell type (i.e. the normal cell type that most resembles the tumor) and defining phenotypic, molecular, or cytogenetic characteristics. The five groups are shown in the table. Hodgkin lymphoma is considered separately within the WHO and preceding classifications, although it is recognized as being a tumor of, albeit markedly abnormal, lymphocytes of mature B cell lineage.

Of the many forms of lymphoma, some are categorized as indolent (e.g. small lymphocytic lymphoma), compatible with a long life even without treatment, whereas other forms are aggressive (e.g. Burkitt's lymphoma), causing rapid deterioration and death. However, most of the aggressive lymphomas respond well to treatment and are curable. The prognosis, therefore, depends on the correct diagnosis and classification of the disease, which is established after examination of a biopsy by a pathologist (usually a hematopathologist).[32]

Lymphoma subtypes (WHO 2008)
Mature B cell neoplasms
DNA-microarray analysis of Burkitt's lymphoma and diffuse large B-cell lymphoma (DLBCL) showing differences in gene expression patterns. Colors indicate levels of expression; green indicates genes that are underexpressed in lymphoma cells (as compared to normal cells), whereas red indicates genes that are overexpressed in lymphoma cells.
3 to 4% of lymphomas in adults
Small resting lymphocytes mixed with variable numbers of large activated cells, lymph nodes diffusely effaced
CD5, surface immunoglobulin
5-year survival rate 50%.[33]
Occurs in older adults, usually involves lymph nodes, bone marrow and spleen, most patients have peripheral blood involvement, indolent
About 5% of lymphomas in adults
Variable cell size and differentiation, 40% show plasma cell differentiation, homing of B cells to epithelium creates lymphoepithelial lesions.
CD5, CD10, surface Ig
Frequently occurs outside lymph nodes, very indolent, may be cured by local excision
About 40% of lymphomas in adults
Small "cleaved" cells (centrocytes) mixed with large activated cells (centroblasts), usually nodular ("follicular") growth pattern
CD10, surface Ig
72–77%[34]
Occurs in older adults, usually involves lymph nodes, bone marrow and spleen, associated with t(14;18) translocation overexpressing Bcl-2, indolent
3 to 4% of lymphomas in adults
Lymphocytes of small to intermediate size growing in diffuse pattern
CD5
50%[35] to 70%[35]
Occurs mainly in adult males, usually involves lymph nodes, bone marrow, spleen and GI tract, associated with t(11;14) translocation overexpressing cyclin D1, moderately aggressive
About 40 to 50% of lymphomas in adults
Variable, most resemble B cells of large germinal centers, diffuse growth pattern
Variable expression of CD10 and surface Ig
5-year survival 60%[36]
Occurs in all ages, but most commonly in older adults, may occur outside lymph nodes, aggressive
< 1% of lymphomas in the United States
Round lymphoid cells of intermediate size with several nucleoli, starry-sky appearance by diffuse spread with interspersed apoptosis
CD10, surface Ig
5-year
survival 50%[37]
Endemic in Africa, sporadic elsewhere, more common in immunocompromised and children, often visceral involvement, highly aggressive
Mature T cell and natural killer (NK) cell neoplasms
Most common cutaneous lymphoid malignancy
Usually small lymphoid cells with convoluted nuclei that often infiltrate the epidermis, creating Pautrier microabscesseses
CD4
5-year
survival 75%[38]
Localized or more generalized skin symptoms, generally indolent, in a more aggressive variant, Sézary's disease, skin erythema and peripheral blood involvement
Most common T cell lymphoma
Variable, usually a mix small to large lymphoid cells with irregular nuclear contours
CD3
Probably consists of several rare tumor types, often disseminated and generally aggressive
Precursor lymphoid neoplasms
15% of childhood acute lymphoblastic leukemia and 90% of lymphoblastic lymphoma.[30]: 635 
Lymphoblasts with irregular nuclear contours, condensed chromatin, small nucleoli and scant cytoplasm without granules
TdT, CD2, CD7
It often presents as a mediastinal mass because of involvement of the thymus. It is highly associated with NOTCH1 mutations, and is most common in adolescent males.
Hodgkin lymphoma
Most common type of Hodgkin lymphoma
Reed-Sternberg cell variants and inflammation, usually broad sclerotic bands that consist of collagen
CD15, CD30
Most common in young adults, often arises in the mediastinum or cervical lymph nodes
    • Mixed cellularity Hodgkin lymphoma
Second-most common form of Hodgkin lymphoma
Many classic Reed-Sternberg cells and inflammation
CD15, CD30
Most common in men, more likely to be diagnosed at advanced stages than the nodular sclerosis form Epstein-Barr virus involved in 70% of cases
Immunodeficiency-associated lymphoproliferative disorders

Previous classifications

Several previous classifications have been used, including Rappaport 1956, Lennert/Kiel 1974, BNLI, Working formulation (1982), and REAL (1994).

The Working Formulation of 1982 was a classification of non-Hodgkin lymphoma. It excluded the Hodgkin lymphomas and divided the remaining lymphomas into four grades (low, intermediate, high, and miscellaneous) related to prognosis, with some further subdivisions based on the size and shape of affected cells. This purely histological classification included no information about cell surface markers, or genetics, and it made no distinction between T-cell lymphomas and B-cell lymphomas. It was widely accepted at the time of its publication, but is now obsolete.[39]

In 1994, the Revised European-American Lymphoma (REAL) classification applied immunophenotypic and genetic features in identifying distinct clinicopathologic entities among all the lymphomas except Hodgkin lymphoma.[40] For coding purposes, the ICD-O (codes 9590–9999)[41] and ICD-10 (codes C81-C96)[42] are available.

Staging

Diagram showing common sites where lymphoma spreads

After a diagnosis and before treatment, a cancer is staged. This refers to determining if the cancer has spread, and if so, whether locally or to distant sites. Staging is reported as a grade between I (confined) and IV (spread). The stage of a lymphoma helps predict a patient's prognosis and is used to help select the appropriate therapy.[43]

The Ann Arbor staging system is routinely used for staging of both HL and NHL. In this staging system, I represents localized disease contained within a lymph node group, II represents the presence of lymphoma in two or more lymph nodes groups, III represents spread of the lymphoma to lymph nodes groups on both sides of the diaphragm, and IV indicates spread to tissue outside the lymphatic system. Different suffixes imply involvement of different organs, for example S for the spleen and H for the liver. Extra-lymphatic involvement is expressed with the letter E. In addition, the presence of B symptoms (one or more of the following: unintentional loss of 10% body weight in the last 6 months, night sweats, or persistent fever of 38 °C or more) or their absence is expressed with B or A, respectively.[44]

CT scan or PET scan imaging modalities are used to stage a cancer. PET scanning is advised for fluorodeoxyglucose-avid lymphomas, such as Hodgkin lymphoma, as a staging tool that can even replace bone marrow biopsy. For other lymphomas, CT scanning is recommended for staging.[43]

Age and poor performance status are other established poor prognostic factors.[45]

  • Mantle cell lymphoma: Notice the irregular nuclear contours of the medium-sized lymphoma cells and the presence of a pink histiocyte. By immunohistochemistry, the lymphoma cells expressed CD20, CD5, and Cyclin D1 (high-power view, H&E)
  • Hodgkin lymphoma, nodular lymphocyte predominant (low-power view): Notice the nodular architecture and the areas of "mottling".(H&E)
  • Hodgkin lymphoma, nodular lymphocyte predominant (high-power view): Notice the presence of L&H cells, also known as "popcorn cells". (H&E)

Differential diagnosis

Certain lymphomas (extranodal NK/T-cell lymphoma, nasal type and type II enteropathy-associated T-cell lymphoma) can be mimicked by two benign diseases which involve the excessive proliferation of non-malignant NK cells in the GI tract, natural killer cell enteropathy, a disease wherein NK cell infiltrative lesions occur in the intestine, colon, stomach, or esophagus, and lymphomatoid gastropathy, a disease wherein these cells' infiltrative lesions are limited to the stomach. These diseases do not progress to cancer, may regress spontaneously and do not respond to, and do not require, chemotherapy or other lymphoma treatments.[46]

Treatment

Prognoses and treatments are different for HL and between all the different forms of NHL,[47] and also depend on the grade of tumour, referring to how quickly a cancer replicates. Paradoxically, high-grade lymphomas are more readily treated and have better prognoses: Burkitt lymphoma, for example, is a high-grade tumour known to double within days, and is highly responsive to treatment. Lymphomas may be curable if detected in early stages with modern treatment.

Low-grade

Many low-grade lymphomas remain indolent for many years. Treatment of the nonsymptomatic person is often avoided. In these forms of lymphoma, such as follicular lymphoma, watchful waiting is often the initial course of action. This is carried out because the harms and risks of treatment outweigh the benefits.[48] If a low-grade lymphoma is becoming symptomatic, radiotherapy or chemotherapy are the treatments of choice; although they do not cure the lymphoma, they can alleviate the symptoms, particularly painful lymphadenopathy. People with these types of lymphoma can live near-normal lifespans, but the disease is incurable. Some centers advocate the use of single agent rituximab in the treatment of follicular lymphoma rather than the wait and watch approach. Watchful waiting is not a good strategy for everyone, as it leads to significant distress and anxiety in some people. It has been equated with watch and worry.[49]

High-grade

Treatment of some other, more aggressive, forms of lymphoma can result in a cure in the majority of cases, but the prognosis for people with a poor response to therapy is worse.[50] Treatment for these types of lymphoma typically consists of aggressive chemotherapy, including the CHOP or R-CHOP regimen. A number of people are cured with first-line chemotherapy. Most relapses occur within the first two years, and the relapse risk drops significantly thereafter.[51] For people who relapse, high-dose chemotherapy followed by autologous stem cell transplantation is a proven approach.[52]

Hodgkin lymphoma

Hodgkin lymphoma typically is treated with radiotherapy alone, as long as it is localized.[53]

Advanced Hodgkin disease requires systemic chemotherapy, sometimes combined with radiotherapy.[54] Chemotherapy used includes the ABVD regimen, which is commonly used in the United States. Other regimens used in the management of Hodgkin lymphoma include BEACOPP and Stanford V. Considerable controversy exists regarding the use of ABVD or BEACOPP. Briefly, both regimens are effective, but BEACOPP is associated with more toxicity. Encouragingly, a significant number of people who relapse after ABVD can still be salvaged by stem cell transplant.[55]

Palliative care

Palliative care, a specialized medical care focused on the symptoms, pain, and stress of a serious illness, is recommended by multiple national cancer treatment guidelines as an accompaniment to curative treatments for people suffering from lymphoma.[56][57] It is used to address both the direct symptoms of lymphoma and many unwanted side effects that arise from treatments.[58][59] Palliative care can be especially helpful for children who develop lymphoma, helping both children and their families deal with the physical and emotional symptoms of the disease.[58][60][61][62] For these reasons, palliative care is especially important for people requiring bone marrow transplants.[63][64]

Prognosis

Five-year relative survival by stage at diagnosis[65]
Stage at diagnosis Five-year relative
survival (%)		 Percentage
of cases (%)
Localized (confined to primary site) 82.3 26
Regional (spread to regional lymph nodes) 78.3 19
Distant (cancer has metastasized) 62.7 47
Unknown (unstaged) 68.6 8

Epidemiology

Deaths from lymphomas and multiple myeloma per million persons in 2012
  0-13
  14-18
  19-22
  23-28
  29-34
  35-42
  43-57
  58-88
  89-121
  122-184

Lymphoma is the most common form of hematological malignancy, or "blood cancer", in the developed world.

Taken together, lymphomas represent 5.3% of all cancers (excluding simple basal cell and squamous cell skin cancers) in the United States and 55.6% of all blood cancers.[66]

According to the U.S. National Institutes of Health, lymphomas account for about 5%, and Hodgkin lymphoma in particular accounts for less than 1% of all cases of cancer in the United States.

Because the whole system is part of the body's immune system, people with a weakened immune system such as from HIV infection or from certain drugs or medication also have a higher number of cases of lymphoma.[67]

History

Thomas Hodgkin

Thomas Hodgkin published the first description of lymphoma in 1832, specifically of the form named after him.[68] Since then, many other forms of lymphoma have been described.

The term "lymphoma" is from latin lympha ("water") and from greek -oma ("morbid growth, tumor").[69]

Research

The two types of lymphoma research are clinical or translational research and basic research. Clinical/translational research focuses on studying the disease in a defined and generally immediately applicable way, such as testing a new drug in people. Studies may focus on effective means of treatment, better ways of treating the disease, improving the quality of life for people, or appropriate care in remission or after cures. Hundreds of clinical trials are being planned or conducted at any given time.[70]

Basic science research studies the disease process at a distance, such as seeing whether a suspected carcinogen can cause healthy cells to turn into lymphoma cells in the laboratory or how the DNA changes inside lymphoma cells as the disease progresses. The results from basic research studies are generally less immediately useful to people with the disease,[71] but can improve scientists' understanding of lymphoma and form the foundation for future, more effective treatments.

Other animals

References

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    50% for limited stage: Leitch HA, Gascoyne RD, Chhanabhai M, Voss NJ, Klasa R, Connors JM (October 2003). "Limited-stage mantle-cell lymphoma". Ann. Oncol. 14 (10): 1555–61. doi:10.1093/annonc/mdg414. PMID 14504058.
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