Hodgkin's lymphoma

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

Hodgkin’s lymphoma was first described by Thomas Hodgkin, a British physician, in 1832. Since then, the tremendous efforts of many researchers have continued to provide more precise and comprehensive information regarding the pathology, staging, and treatment of Hodgkin’s lymphoma. Hodgkin’s lymphoma is a potentially curable tumor, in which malignancy originates from lymphocytes. According to the World Health Organization (WHO), Hodgkin’s lymphoma (HL) can be classified into two major subgroups: nodular lymphocyte predominant and classic Hodgkin’s lymphoma. Classic Hodgkin’s lymphoma is further divided into four subtypes: nodular sclerosis classic HL (NSHL), mixed cellularity classic HL (MCHL), lymphocyte rich classic HL (LRHL), and lymphocyte depleted classic HL (LDHL). According to the Lugano classification and Cotswolds modifications of the original Ann Arbor staging system, there are 4 stages of Hodgkin’s Lymphoma based on clinical features gathered from history and physical examination and findings on positron emission tomography/computed tomography (PET/CT) scan of the chest, abdomen, and pelvis. Each stage is assigned one letter and one number that designate the number of lymph node regions involved and the presence/absence of systematic symptoms or of bulky or extended disease. On gross pathology, white-grey, uniform, and enlarged lymph nodes are characteristic findings of Hodgkin’s lymphoma. On microscopic histopathological analysis, Reed-Sternberg cells, reactive cell infiltrate, and complete or partial effacement of the lymph node architecture are characteristic findings of Hodgkin’s lymphoma. Hodgkin’s lymphoma must be differentiated from sarcoidosis, lymphocytic lymphoma, miliary tuberculosis, infectious mononucleosis, thoracic aortic aneurysm, substernal goiter, thymoma, actinomycosis, chronic lymphocytic leukemia, superior vena cava syndrome, unicentric castleman disease, adult still disease, small cell lung carcinoma, and malignant histiocytosis. Hodgkin’s lymphoma has a bi-modal age distribution that differs geographically and ethnically in industrialized countries with the first peak occurring in the middle-to-late 20’s and the second peak occurring after age 50. In developing countries, the early peak instead occurs before adolescence. In 2015, the incidence of Hodgkin’s lymphoma was estimated to be 3 cases per 100,000 individuals in the United States with a higher incidence among patients with HIV/AIDS. However, in contrast to many other lymphomas associated with HIV infection, Hodgkin’s lymphoma occurs most commonly in patients who do not have severe immunosupression. The most common risk factors in the development of Hodgkin’s lymphoma are the Epstein-Barr virus, family history, and HIV infection. Other possible risk factors include genetics, infectious mononucleosis, autoimmune diseases, immunodeficiency, tobacco usage, and socio-economic status. The 5-year survival rate of patients with Hodgkin’s lymphoma varies with the stage of the disease, however the early stage is associated with the most favorable prognosis. The most common symptoms of classic Hodgkin’s lymphoma include painless localized peripheral lymphadenopathy, B symptoms (fever, night sweats, and weight loss), and pruritus. Less common symptoms of Hodgkin’s lymphoma include cough, chest pain, breathing problems, pain or feeling of fullness below the ribs, pain in lymph nodes after drinking alcohol, skin blushing or flushing, bone pain, and leg swelling. Common physical examination findings of Hodgkin’s lymphoma include fever, lymphadenopathy, petechiae, jaundice, chest tenderness, wheezing, superior vena cava syndrome, abdominal tenderness, hepatomegaly, splenomegaly, fracture, peripheral lymphadenopathy, and central lymphadenopathy. The diagnostic study of choice for Hodgkin’s lymphoma is lymph node biopsy. The presence of Reed-Sternberg cell is diagnostic for classic Hodgkin’s lymphoma. In addition to light microscopy evaluation of the biopsy samples, the immunophenotypic analysis with immunohistochemistry helps to determine Hodgkin’s lymphoma subtypes and distinguish Hodgkin’s lymphoma from T cell rich large B cell lymphoma and anaplastic large cell lymphoma. Laboratory tests for Hodgkin’s lymphoma include complete blood count (CBC), blood chemistry studies, HIV blood test, immuno histochemistry, erythrocyte sedimentation rate, and immunophenotyping. On ultrasound, Hodgkin’s lymphoma is characterized by hepatomegaly and splenomegaly. The optimal therapy for Hodgkin’s lymphoma depends on the stage at diagnosis, age, type, and size of tumor but the predominant therapy for Hodgkin’s lymphoma is chemotherapy. Adjunctive radiation therapy and stem cell transplant may also be required.

Hodgkin’s lymphoma was first described by Thomas Hodgkin, a British physician, in 1832. Since then, tremendous efforts of many scientists have been continuing to provide more precise and comprehensive with pathology, staging, and treatment of Hodgkin’s lymphoma. Since 1997 the World Health Organisation (WHO) has been involved in a project with committees of international hematopathologists and oncologists, who have developed lists and definitions of disease entities to ensure that the classification will be helpful to clinicians. They proposed their first approach in 2000 and after that, the relevant Clinical Advisory Committee (CAC) updates its latest revision every few years.

According to World Health Organization (WHO) Hodgkin’s lymphoma (HL) may be classified classification into two major subgroups: nodular lymphocyte predominant and classic Hodgkin’s lymphoma. Classic Hodgkin’s lymphoma is further divided into four subtypes: nodular sclerosis classic HL (NSHL), mixed cellularity classic HL (MCHL), lymphocyte rich classic HL (LRHL), and lymphocyte depleted classic HL (LDHL).

According to the Ann Arbor Staging System with Cotswolds modifications, there are 4 stages of Hodgkin’s Lymphoma based on clinical features gathered from history and physical examination, and findings on positron emission tomography/computed tomography (PET/CT) scan of the chest, abdomen, and pelvis. Each stage is assigned one letter and one number that designate the number of involved lymph node regions and the presence/absence of systematic symptoms or of bulky or extended disease.

On gross pathology, white-grey, uniform, and enlarged lymph nodes are characteristic findings of Hodgkin’s lymphoma. On microscopic histopathological analysis, Reed-Sternberg cells, reactive cell infiltrate, and complete or partial effacement of the lymph node architecture are characteristic findings of Hodgkin’s lymphoma.

There are no established causes for Hodgkin’s lymphoma.

Hodgkin’s lymphoma must be differentiated from sarcoidosis, lymphocytic lymphoma, miliary tuberculosis, infectious mononucleosis, thoracic aortic aneurysm, substernal goiter, thymoma, actinomycosis, chronic lymphocytic leukemia, superior vena cava syndrome, unicentric castleman disease, adult still disease, small cell lung carcinoma, and malignant histiocytosis.

Hodgkin’s lymphoma has a bimodal age distribution that differs geographically and ethnically in industrialized countries where the early peak occurs in the middle-to-late 20’s and the second peak after the age of 50. In developing countries, the early peak occurs before adolescence. In 2015, the incidence of Hodgkin’s lymphoma was estimated to be 3 cases per 100,000 individuals in the United States with the incidence of Hodgkin’s lymphoma being higher among patients with HIV/AIDS. However, in contrast to many other lymphomas associated with HIV infection, Hodgkin’s lymphoma occurs most commonly in patients who do not have severe immunosupression.

The common risk factors in the development of Hodgkin’s lymphoma are the Epstein-Barr virus, family history, and HIV infection. Other possible risk factors include genetics, infectious mononucleosis, autoimmune diseases, immunodeficiency, tobacco, socio-economic status and family features.

Screening for Hodgkin’s lymphoma is not recommended.

Hodgkin’s lymphoma has a bimodal age distribution and both children and adult may be affected. The early peak occurs in the middle-to-late 20’s and the second peak after the age of 50. Treatment outcomes of Hodgkin’s lymphoma are excellent and five-year survival rates are more than 80%. Due to modern therapies, the natural history of untreated Hodgkin’s lymphoma is actually difficult to determine. Survivors are at risk for relapse, second primary malignancies, cardiovascular complications and other treatment-related toxicities. Prognosis is based on the stage of the disease and other prognostic factors but the early stage of the Hodgkin’s lymphoma is associated with the most favorable prognosis. The 5-year survival rate of patients with Hodgkin’s lymphoma varies with the stage of the disease.

According to the Lugano classification and Cotswold’s modification of the original Ann arbor staging system, there are four stages of Hodgkin’s lymphoma based on the number of nodes and extra nodal involvement.

The most common symptoms of Hodgkin’s lymphoma include fatigue, fever and chills, itching, loss of appetite, soaking night sweats, weight loss, and painless swelling of the lymph nodes in the neck, axilla, or groin (swollen glands). Less common symptoms of Hodgkin’s lymphoma include cough, chest pain, or breathing problems, pain or feeling of fullness in abdomen, pain in lymph nodes after drinking alcohol, skin blushing or flushing, bone pain, and leg swelling.

Common physical examination findings of Hodgkin’s lymphoma include fever, pruritus, petechiae, jaundice, chest tenderness, wheezing, superior vena cava syndrome, abdominal tenderness, hepatomegaly, splenomegaly, fracture, peripheral lymphadenopathy, and central lymphadenopathy.

Laboratory tests for Hodgkin’s lymphoma include complete blood count (CBC), blood chemistry studies, HIV blood test, immunohistochemistry, erythrocyte sedimentation rate, and immunophenotyping.

Chest, spine, pelvic, and long bone x ray may be helpful in the diagnosis of Hodgkin’s lymphoma.

Chest, abdomen, and pelvis CT scan may be helpful in the diagnosis of Hodgkin’s lymphoma.

Chest, abdomen, and pelvic MRI scan may be helpful in the diagnosis of Hodgkin’s lymphoma.

On ultrasound, Hodgkin’s lymphoma is characterized by hepatomegaly and splenomegaly.

Lymph node or extra nodal tissue biopsy is diagnostic of Hodgkin’s lymphoma.

Chest, abdomen, and pelvis PET scan may be helpful in the diagnosis of Hodgkin’s lymphoma. In some cases a Gallium Scan may be used instead of a PET scan.

Other diagnostic studies for the diagnosis of Hodgkin’s lymphoma include bone marrow biopsy, bone scan, lymphangiogram, or laparotomy.

Hodgkin lymphoma is considered a curable cancer, however, treatment-related toxicities for this disease can be associated with significant long-term complications. Selection of treatment protocol for Hodgkin’s lymphoma depends on the type, the stage at diagnosis, age, and size of the tumor. Combined modality therapy including use of chemotherapy and radiation therapy (RT) is the treatment of choice in patients with early-stage classic Hodgkin’s Lymphoma.

Surgical intervention is not recommended for the management of Hodgkin’s lymphoma.

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

Hodgkin’s lymphoma was first described by Thomas Hodgkin, a British physician, in 1832. Since then, tremendous efforts of many scientifics have been continuing to provide more precise and comprehensive with pathology, staging, and treatment of Hodgkin’s lymphoma.

• Hodgkin’s lymphoma was first described by Thomas Hodgkin, a British physician, in 1832.Although earliest description for this disease was provided by Marcello Malpighi in 1666.^[1][2]
• Dr. Hodgkin’s report of macroscopic description entitled “On some morbid appearances of the absorbent glands and spleen”, was presented to the Medical and Chirurgical Society in London in 1832.^{[1] [3]}
• In 1856, Samuel Wilks independently reported on a series of patients with the same disease that Hodgkin had previously described.^[3] Wilks, a successor to Hodgkin at Guy’s Hospital, was unaware of Hodgkin’s prior work on the subject. Bright made Wilks aware of Hodgkin’s contribution and in 1865, Wilks published a second paper, entitled “Cases of enlargement of the lymphatic glands and spleen”, in which he called the disease “Hodgkin’s disease” in honor of his predecessor.^[3]
• Theodor Langhans and WS Greenfield first described the microscopic characteristics of Hodgkin’s lymphoma in 1872 and 1878, respectively.^[1]
• The cytogenetic characteristics of the malignant cells of Hodgkin’s lymphoma which now is known as Reed–Sternberg cells, were described by Carl Sternberg, and Dorothy Reed in 1898 and 1902, respectively.^[1][4]
• In 1944, Jackson and Parker classified Hodgkin’s lymphoma into three subtypes: early Hodgkin’s disease or paragranuloma, granuloma, and sarcoma. In 1956, Smetana and Cohen proposed a histopathological variant for granulomatous Hodgkin’s disease, with sclerotic changes and better prognosis. ^[5]
• In 1964 , Lukes, Butler, and Hicks termed this form as nodular sclerosis Hodgkin’s disease. Their categorization system, simplified at the Rye conference in 1965 and has been used commonly from then on. ^[6]
• In 1993 the International Lymphoma Study Group (ILSG) in Berlin, provided a new lymphoma classification system and their consensus released as revised European–American lymphoma (REAL) classification In 1994, and subdivided Hodgkin’s lymphoma into two main types: lymphocyte predominant Hodgkin’s lymphoma and common Hodgkin’s lymphoma. ^[7]

• Since 1997 The World Health Organisation (WHO) has been starting a project with committees of international hematopathologists and oncologists, who have developed lists and definitions of disease entities to ensure that the classification will be helpful to clinicians. They proposed their first approach in 2000 and after that, the relevant Clinical Advisory Committee (CAC) updates its latest revision every few years. ^[8]

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

Hodgkin’s lymphoma (HL) may be classified according to World Health Organization (WHO) classification into two major subgroups: nodular lymphocyte predominant and classic Hodgkin’s lymphoma. classic Hodgkin’s lymphoma is further divided into four subtypes: nodular sclerosis classic HL (NSHL), mixed cellularity classic HL (MCHL), lymphocyte rich classic HL (LRHL), and lymphocyte depleted classic HL (LDHL).

According to the Ann Arbor Staging System with Cotswolds modifications, there are 4 stages of Hodgkin’s Lymphoma based on clinical features gathered from history and physical examination, and findings on positron emission tomography/computed tomography (PET/CT) scan of the chest, abdomen, and pelvis. Each stage is assigned one letter and one number that designate the number of involved lymph node regions and the presence/absence of systematic symptoms or of bulky or extended disease .

Hodgkin’s lymphoma may be classified according to World Health Organization (WHO) classification into two major subgroups based upon the appearance and immunophenotype of the tumor cells:^[1]

• Nodular lymphocyte predominant Hodgkin’s lymphoma
• Classical Hodgkin’s lymphoma

Classic Hodgkin’s lymphoma is further divided into four subtypes:

1. Nodular sclerosis classic HL (NSHL)
2. Mixed cellularity classic HL (MCHL)
3. Lymphocyte rich classic HL (LRHL)
4. Lymphocyte depleted classic HL (LDHL)

Classic Hodgkin’s lymphoma classification

Name	Description
Nodular sclerosing	Most common subtype and is composed of large tumor nodules showing scattered lacunar classical Reed–Sternberg cells set in a background of reactive lymphocytes, eosinophils, and plasma cells with varying degrees of collagen fibrosis/sclerosis.
Mixed-cellularity	Common subtype and is composed of numerous classic Reed-Sternberg cells admixed with numerous inflammatory cells including lymphocytes, histiocytes, eosinophils, and plasma cells without sclerosis. This type is most often associated with Epstein–Barr virus (EBV) infection and may be confused with the early, so-called ‘cellular’ phase of nodular sclerosing classical Hodgkins lymphoma.
Lymphocyte rich	Rare subtype, show many features which may cause diagnostic confusion with nodular lymphocyte predominant B-cell Non-Hodgkin’s Lymphoma (B-NHL). This form also has the most favorable prognosis.
Lymphocyte depleted	Rare subtype, composed of large numbers of often pleomorphic Reed-Sternberg cells with only few reactive lymphocytes, which may easily be confused with diffuse large cell lymphoma. Many cases previously classified within this category would now be reclassified under anaplastic large cell lymphoma.

• According to the Ann Arbor Staging System with Cotswolds modifications^[2], there are 4 stages of Hodgkin’s Lymphoma based on clinical features gathered from history and physical examination, and findings on positron emission tomography/computed tomography (PET/CT) scan of the chest, abdomen, and pelvis. Each stage is assigned one letter and one number that designate the number of involved lymph node regions and the presence/absence of systematic symptoms or of bulky or extended disease . The stages of Hodgkin’s Lymphoma are shown in the table below:

Hodgkin’s Lymphoma Ann Arbor Staging with Cotswolds Modifications
Stage	Definition
I	Involvement of a single lymph node (I) or single extranodal site (IE)
II	Involvement of two or more lymph node ereas on the same side of the diaphragm alone (II) or with involvement extralymphatic organ (IIE)
III	Involvement of lymph node ereas or lymphoid structures on both sides of the diaphragm
IV	Disseminated or multiple involvement of the extranodal organs

In the Ann Arbor Staging System with Cotswolds modifications, letters A and B indicate the absence (A) or presence (B) of one or more of the following systemic symptoms:

• Fevers with temperatures above 38°C (>100.4°F) during the previous month

• Drenching night sweats

• Unexplained weight loss exceeding 10 percent of body weight during the six months prior to diagnosis

The subscript “X” in this staging system denotes bulky disease for treatment purposes.^[3] Bulky mass is determined as a single mass of 10 cm or greater than one-third of the transthoracic diameter at any level of thoracic vertebrae as determined by computed tomography.^[4]

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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] Mohsen Basiri M.D.

Hodgkin lymphoma (HL) is a neoplasm characterized by involving lymph nodes and the lymphatic system, and is classified according to WHO classification into two major subgroups: nodular lymphocyte predominant and classic Hodgkin’s lymphoma. Classic Hodgkin’s lymphoma is further divided into four subtypes: nodular sclerosis , mixed cellularity , lymphocyte rich, and lymphocyte . Hodgkin lymphoma is characterized by the presence of multinucleated giant cells Reed-Sternberg cells, derived from germinal center or postgerminal center B cells. In all four subtypes of classic Hodgkin lymphoma the Reed-Sternberg cells have a similar immunophenotype. Whereas in the NLPHL the Reed-Sternberg cells have a distinctive B-cell immunophenotype. On gross pathology, white-grey, uniform, and enlarged lymph nodes are characteristic findings of Hodgkin’s lymphoma. On microscopic histopathological analysis, Reed-Sternberg cells, reactive cell infiltrate, and complete or partial effacement of the lymph node architecture are characteristic findings of Hodgkin’s lymphoma.

Hodgkin’s lymphoma is a potentially curable cancer, in which malignancy originates from lymphocytes.^[1][2] Hodgkin lymphoma is characterized by the presence of multinucleated giant cells Reed-Sternberg cells, derived from germinal center or postgerminal center B cells. In all four subtypes of classic Hodgkin lymphoma the Reed-Sternberg cells have a similar immunophenotype. Whereas in the NLPHL the Reed-Sternberg cells have a distinctive B-cell immunophenotype.

• Most Reed-Sternberg cells are of B-cell origin, derived from lymph node germinal centers. Molecular analysis of single isolated Reed-Sternberg cells and variants has been determined the origin of the neoplastic Reed-Sternberg cells.^[3][4]
• Despite having the genetic signature of a B cell, the Reed-Sternberg cells of classical HL fail to express most B-cell–specific genes, including the Ig genes and no longer able to produce antibodies. The Ig genes of Reed-Sternberg cells have undergone both V(D)J rearrangements and somatic hypermutation.
• Growth and survival of classic RS cells are dependent to the activation of the nuclear factor kappa B (NF-kB) transcription factor-signaling pathway. This activation can occur by several mechanisms:
  • NF-κB may be activated either by EBV infection or by some other mechanism and turns on genes that promote lymphocyte survival and proliferation. The constitutive nuclear activity of NF-kB can both prevent apoptosis and promote cell proliferation.
  • EBV+ tumor cells express viral latent membrane protein-1 (LMP-1), a protein encoded by the EBV genome that transmits signals leads to NF-kB activation.
  • NF-kB is degraded normally by the “I kappa B (IkB)” family in order to prevent the unwanted stimulation and neoplasm formation. However, there are specific cellular proteins which lead to inactivation of the (IkB). So, by inactivating the (IkB), the NF-kB transcription factors will not be degraded and leads to gene transcriptions activation.^[3]
• In Hodgkin’s lymphoma, there are elevated levels of the NF-kB proteins especially c-REL and REL-A.^[5]
• Unstopped activation of (NF-kB):
  • Active (NF-kB) will lead to constituent gene activation and eventually no apoptosis takes place. Moreover, uninhibited proliferation of Reed-Sterburg cells.
  • Activation of (NF-kB) occurs due to the following causes:^[6][7]
    • Loss of function Mutation of the IkB protein which is responsible for inhibiting NF-kB
    • Alteration in the NF-kB itself protecting it from inhibition by IkB
    • Gain of function mutation of the MAP3K14 gene which is an activator of NF-kB
  • NF-kB leads to activation of many genes which appear to be related to HL. Some examples of the genes expressed in HL include the following:^[8]
    • (ICAM-1) gene
    • GM-CSF gene
    • IL-6 gene
    • IKBA gene
• Besides NF-kB signaling pathway, Hodgkin’s lymphoma can be caused by mutations in JAK-STAT pathway. Alterations in JAK tyrosine kinases signaling lead to high levels of activated STAT pathway which is considered an observed feature in some cases of HL.^[9]

Reports from countries like Honduras,^[10] China,^[11] Mexico,^[12] Peru,^[13] and Malaysia^[14] suggest an association between EBV infection and Hodgkin’s lymphoma, an association that is more evident in the pediatric population^[15] and in the subtype of mixed cellularity.^[16]

On gross pathology, affected lymph nodes (most often, latero cervical lymph nodes) are enlarged, but their shape is preserved because the capsule is not invaded. Usually, the cut surface is white-grey and uniform. In some histological subtypes (e.g. nodular sclerosis), the cut surface may have a nodular aspect.

Microscopic examination of the lymph node biopsy reveals complete or partial effacement of the lymph node architecture by scattered large malignant cells known as Reed-Sternberg cells (typical and variants) admixed within a reactive cell infiltrate composed of variable proportions of lymphocytes, histiocytes, eosinophils, and plasma cells. The Reed-Sternberg cells are identified as large often bi-nucleated cells with prominent nucleoli and an unusual CD45-, CD30+, and CD15+/- immuno phenotype. In approximately 50% of cases, the Reed-Sternberg cells are infected by the Epstein-Barr virus.

Reed-Sternberg cells (RSC) (Classical and variants)

Type of cell	Characteristics
Classic
Reed-Sternberg cells (RSC)	Include large size (20–50 micro metres), abundant, amphophilic, finely granular/homogeneous cytoplasm; two mirror-image nuclei (owl eyes) each with an eosinophilic nucleolus and a thick nuclear membrane (chromatin is distributed close to the nuclear membrane).
Variants
Hodgkin cells (Atypical mononuclear Reed-Sternberg cell)	Have the same characteristics as Reed-Sternberg cells (RSC), but is mono nucleated.
Lacunar Reed-Sternberg cells	Have a single hyper lobulated nucleus, multiple, small nucleoli and eosinophilic cytoplasm which is retracted around the nucleus, creating an empty space (“lacunae”).
Pleomorphic Reed-Sternberg cells	Have multiple irregular nuclei.
“Popcorn” Reed-Sternberg cells (Lympho-histiocytic variant)	Have a very lobulated nucleus and small nucleoli.
“Mummy” Reed-Sternberg cells	Have a compact nucleus with no nucleolus and basophilic cytoplasm.

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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 Hodgkin’s lymphoma.

There are no established causes for Hodgkin’s lymphoma.

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Hodgkin’s lymphoma must be differentiated from sarcoidosis, lymphocytic lymphoma, miliary tuberculosis, infectious mononucleosis, thoracic aortic aneurysm, substernal goiter, thymoma, actinomycosis, chronic lymphocytic leukemia, superior vena cava syndrome, unicentric castleman disease, adult still disease, small cell lung carcinoma, and malignant histiocytosis.

Differentiating diagnosis of Lymphoma	Symptoms					Signs			Diagnosis	Additional Findings
	Fever	Rash	Diarrhea	Abdominal pain	Weight loss	Painful lymphadenopathy	Hepatosplenomegaly	Arthritis	Lab Findings
Lymphoma	✔	✘	✘	✔	✔	✘	✔	✘	Increase ESR, increased LDH	Night sweats, constant fatigue
Brucellosis	✔	✔	✘	✔	✔	✔	✔	✔	Relative lymphocytosis	Night sweats, often with characteristic smell, likened to wet hay
Typhoid fever	✔	✔	✘	✔	✘	✘	✔	✔	Decreased hemoglobin	Incremental increase in temperature initially and than sustained fever as high as 40°C (104°F)
Malaria	✔	✘	✔	✔	✘	✘	✔	✔	Microcytosis, elevated LDH	“Tertian” fever: paroxysms occur every second day
Tuberculosis	✔	✔	✘	✔	✔	✔	✘	✔	Mild normocytic anemia, hyponatremia, and hypercalcemia	Night sweats, constant fatigue
Mumps	✔	✘	✘	✘	✘	✔	✘	✘	Relative lymphocytosis, serum amylaseelevated	Parotidswelling/tenderness
Rheumatoid arthritis	✘	✔	✘	✘	✘	✘	✘	✔	ESR and CRP elevated, positive rheumatoid factor	Morning stiffness
SLE	✘	✔	✘	✔	✔	✘	✘	✔	ESR and CRP elevated, positive ANA	Fatigue
HIV	✘	✘	✘	✔	✔	✔	✘	✔		Constant fatigue

The differentials include the following:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]}

Category of Disease	Diseases	Signs and symptoms										Laboratory findings
		Fever	Fatigue	Arthralgia	Myalgia	Soft tissue swelling/serositis	Skin rash	Weight loss	Dyspnea	Sore throat	Lymphadenopathy	Complete blood count (CBC)	Liver function tests (LFTs)	Inflammatory markers		Autoantibodies						Diagnostic tests
														Erythrocyte sedimentation rate (ESR)	C- reactive protein (CRP)	Anti-nuclear antibodies (ANA)	Rheumatoid factor (RF)	Anti- glomerular basement membrane (anti-GBM)	Anti-dsDNA	Anti-Jo1/ Anti Mi2	ANCA
Infections	HIV	+	+	+	+	+/-	–	+	+/-	+ /-	+	Leukopenia Anemia Thrombocytopenia	ALT↑ AST↑	↑	↑	–	–	–	–	–	–
	Herpesviridae	+	+	+	+	+	Papular or vesicular Erythematous base Painful	–	–	+/-	+	Leukocytosis	–	↑	↑	–	–	–	–	–	–
	Measles	+	+	+	+	–	3-5 days after fever Erythematous maculopapular rash starts on face spreads to trunk and extremities (centrifugal)	–	–	+	+	Leukocytosis	–	↑	↑	–	–	–	–	–	–
	Viral hepatitis	+	+	–	+/-	–	–	+/-	–	–	+/-	Leukocytosis	ALT↑ AST↑	↑	↑	–	–	–	–	–	–
	Parvovirus B19	+	+	+	+/-	–	Slapped cheek rash	–	–	–	+	Leukopenia Aplastic anemia (low reticulocyte count) Thrombocytopenia	ALT↑ AST↑	↑	↑	–	–	–	–	–	–
	Infective endocarditis	+	+	+	+/-	–	Purpuric	+/-	+	–	+	Leukocytosis	–	↑	↑	–	–	–	–	–	–	Blood cultures, ultrasonography
	Borreliosis, Brucellosis, Yersiniosis	+	+	+	+	–	Target rash (Borrelia) Diffuse maculopapular (Brucellosis) Erythema nodosum (Yersiniosis)	–	–	–	+	Leukocytosis	ALT↑ AST↑	↑	↑	–	–	–	–	–	–	Serology, PCR
	Syphilis and Jarisch-Herxheimer reaction	+	+	+	+	–	Non-pruritic Macular On palms and soles Round Seen in secondary syphilis Penile ulceration (painless)	–	–	+	+	Leukocytosis	ALT↑ (Uncommon) AST↑ (Uncommon)	↑	↑	–	–	–	–	–	–	Serology, PCR
	Toxoplasmosis	+	+	–	+	–	Maculopapular Palms and soles	–	–	+	+	Leukocytosis (eosinophilia)				–	–	–	–	–	–	Serology, PCR
Neoplasia	Malignant lymphoma	+	+	–	+/-	+/-	Purplish scaly rash in cases of cutaneous lymphoma	+	+	–	+	Anemia of chronic disease	In case of liver metastasis (Non-Hodgkin lymphoma): ALT↑ AST↑	↑	↑	–	–	–	–	–	–	CT, PET/CT, Bone marrow examination, lymph node biopsy
	Multicentric Castleman disease	+	+	–	–	+	–	+	+	–	+	Anemia Thrombocytopenia	–	↑	↑	–	–	–	–	–	–	Lymph node biopsy
	Angioimmunoblastic T cell lymphoma	+	+	–	–	–	Maculopapular eruption on the trunk mimicking toxic erythema	+	–	–	+	Lymphocytosis	ALT↑ AST↑	↑	↑	–	–	–	–	–	–	Lymph node biopsy
Drug hypersensitivity	Drug reaction with eosinophilia and systemic symptoms	+	+	+	+	+/-	Utricaria (Immediate type) Maculopapular (Delayed type)	–	+	–	–	Leukocytosis (eosinophilia)	–	↑	↑	–	–	–	–	–	–	Eosinophil count, skin biopsy
Autoimmune conditions	Systemic lupus erythematosus	+	+	+	+/-	+	Butter-fly shaped erythematous malar rash that spares the nasolabial folds Coin-shaped erythematous rash on extremities or trunk	+	+	–	+/-	Leukopenia Hemolytic anemia Thrombocytopenia	ALT↑ AST↑	↑	↑	+	+	–	+	–	–	Antinuclear autoantibodies
	Inflammatory myositis	+	+	–	+ (weakness > pain)	–	Macular red rash over the back of the fingers, elbows or knees (Grotton’s sign) Macular purpish or reddish rash on the upper chest or back  (Shawl-like, heliotrope rash)	–	–	–	+/-	Leukocytosis	–	↑	↑	+/-	+/-	–	–	+	–	Idem, muscle biopsy
	Rheumatoid arthritis	+	+	+	–	+	Purpura Ulcers	–	+	–	+	Anemia of chronic disease Neutropenia (Felty’s syndrome)	–	↑	↑	+/-	+/-	–	–	–	–	Anti-citrullinated peptids autoantibodies, rheumatoid factor
	Systemic vasculitides	+	+	+	–	+	Nasopharyngeal ulceration (Wegner’s granulomatosis) Erythematous rash on palms and soles (Kawasaki disease)	–	+/-	–	+/-	Leukocytosis	–	↑	↑	–	–	+/-	–	–	+	ANCA, tissue biopsy, arteriography
	Familial Mediterranean fever	+	+	+	+	+	Red rash on lower extremities (ankles and knees)	+	+ (due to pain)	–	+/-	Leukocytosis (during acute flares)	–	↑	↑	–	–	–	–	–	–	Familial history, MEFV gene analysis
	Mevalonate kinase deficiency	+	+	+	+	–	Maculopapular rash Aphthous ulcers (or stomatitis)	+	–	+	+	Leukocytosis (during acute flares)	–	↑	↑	–	–	–	–	–	–	Urinary mevalonic acid, mevalonate kinase analysis
	Reactive arthritis	+	+	+	–	–	Keratoderma blennorrhagica (palms, soles, scrotum) Circinate balanitis (penile)	–	+ (Aortic insufficiency)	–	+	Leukocytosis	–	↑	↑	–	–	–	–	–	–	HLA B27, magnetic resonance imaging
Miscellaneous	Sarcoidosis	+	+	+	–	+	Waxy skin plaques Violaceous facial lesions Erythema nodosum	+	+	–	+	Lymphopenia Eosinophilia	Normal ALT, AST ALP ↑ (infiltrative pattern)	↑	↑	–	–	–	–	–	–	Lymph node/Lung biopsy ACE levels FDG-PET

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

Hodgkin’s lymphoma has a bimodal age distribution that differs geographically and ethnically in industrialized countries; the early peak occurs in the middle-to-late 20s and the second peak after age 50 years. In developing countries, the early peak occurs before adolescence.^[1] In 2015, the incidence of Hodgkins lymphoma was estimated to be 3 cases per 100,000 individuals in the United States.^[1] The incidence of Hodgkin’s lymphoma is higher among patients with HIV/AIDS; however, in contrast to many other lymphomas associated with HIV infection, Hodgkin’s lymphoma occurs most commonly in patients who do not have severe immunosupression.^[2]

• In the United States, the age-adjusted prevalence of Hodgkin’s lymphoma is 35 per 100,000 in 2011.^[3]

• In 2015, the incidence of Hodgkins lymphoma was estimated to be 3 cases per 100,000 individuals in the United States.^[1]

• Hodgkin’s lymphoma has a bimodal age distribution that differs geographically and ethnically in industrialized countries; the early peak occurs in the middle-to-late 20s and the second peak after age 50 years. In developing countries, the early peak occurs before adolescence.^[1]
• The incidence of Hodgkin’s lymphoma is estimated to be 2.9 cases per 100,000 adolescents among ages 15 to 19 years in the United States.
• The incidence of Hodgkin’s lymphoma is estimated to be 0.9 cases per 100,000 children among ages 10 to 14 years in the United States.
• The incidence of Hodgkin’s lymphoma is estimated to be 0.3 cases per 100,000 children among ages 5 to 9 years in the United States.
• The incidence of Hodgkin’s lymphoma is estimated to be 0.09 cases per 100,000 children among 4 years of age in the United States.
• While the overall age-adjusted incidence of Hodgkin’s lymphoma in the United States between 2007 and 2011 is 2.7 per 100,000, the age-adjusted incidence of Hodgkin’s lymphoma by age category is:^[3]
  • Between 20 and 29 years: 4.1-4,5 per 100,000
  • Under 65 years: 2.5 per 100,000
  • 65 and over: 4.2 per 100,000

• In children <5 year, males are more commonly affected with Hodgkin’s lymphoma than females. The male to female ratio is approximately 5.3.^[1]
• In children aged 15 to 19 year, females are more commonly affected with Hodgkin’s lymphoma than males. The male to female ratio is approximately 0.8.
• In the United States, the age-adjusted prevalence of Hodgkin’s lymphoma by gender in 2011 is:^[3]
  • In males: 37.2 per 100,000
  • In females: 33.1 per 100,000
• In the United States, the age-adjusted incidence of Hodgkin’s lymphoma by gender on 2011 is:^[3]
  • In males: 3.11 per 100,000 persons
  • In females: 2.34 per 100,000 persons
• In the United States, the delay-adjusted incidence of Hodgkin’s lymphoma by gender in 2011 is:^[3]
  • In males: 3.22 per 100,000 persons
  • In females: 2.42 per 100,000 persons

Shown below is an image depicting the delay-adjusted incidence and observed incidence of Hodgkin’s lymphoma by gender and race in the United States between 1975 and 2011. These graphs are adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.^[3]

• Shown below is a table depicting the age-adjusted prevalence of Hodgkin’s lymphoma by race in 2011 in the United States.^[3]

	All Races	White	Black	Asian/Pacific Islander	Hispanic
Age-adjusted prevalence	35 per 100,000	40 per 100,000	32.1 per 100,000	12.6 per 100,000	23.6 per 100,000

Shown below is an image depicting the incidence of Hodgkin’s lymphoma by race in the United States between 1975 and 2011.^[3]

API: Asian/Pacific Islander; AI/AN: American Indian/ Alaska Native

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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]

The common risk factors in the development of Hodgkin’s lymphoma are Epstein-Barr virus, family history, and HIV infection. Other possible risk factors include genetics, infectious mononucleosis, autoimmune diseases, immunodeficiency, tobacco, socio-economic status and family features.

The common risk factors in the development of Hodgkin’s lymphoma are Epstein-Barr virus, family history, and HIV infection. Other possible risk factors include genetics, infectious mononucleosis, autoimmune diseases, immunodeficiency, tobacco, socio-economic status and family features.^[1][2][3][4]

Risk factors for Hodgkin’s lymphoma

Risk factors	Possible risk factors
Epstein-Barr virus	Genetics
Family history	Infectious mononucleosis
HIV infection	Autoimmune diseases
	Immunodeficiency
	Tobacco
	Socio-economic status and family features

• Epstein-Barr virus^[5]

• A history of infection with the Epstein-Barr virus (EBV) is a risk factor for Hodgkin’s lymphoma.
• Infection with Epstein-Barr virus is common – more than 90% of adults worldwide are infected.
• In North America, Epstein-Barr virus is found in about 40%–50% of cases of Hodgkin’s lymphoma.

• Family history^[6]

• First-degree relatives of a person with Hodgkin’s lymphoma have an increased risk of developing the disease.
• Siblings of the same sex may have a greater risk of developing Hodgkin’s lymphoma than people in the general population.
• It is unclear whether the increase in risk is due to genetics alone or a combination of genetics and environmental or lifetime exposures.

• HIV infection^[7]

• HIV infection increases a person’s risk of developing Hodgkin’s lymphoma and some other types of cancer. The risk of developing Hodgkin’s lymphoma is 10-times higher in people with HIV than in people who are HIV-negative.

• Genetics

• Although close relatives of people with Hodgkin’s lymphoma are at increased risk of the disease, the reasons for this higher risk are unknown. One explanation is that family members are exposed to the same environmental factors, which may be the reason why several people in a family develop Hodgkin’s lymphoma.

• Autoimmune diseases

• People with certain autoimmune diseases have an increased risk of Hodgkin’s lymphoma. These diseases include:

• Rheumatoid arthritis
• Systemic lupus erythematosus
• Ulcerative colitis
• Immune thrombocytopenic purpura
• Sarcoidosis

• Immunodeficiency^[8]

• People with poor immunity may have a higher risk for Hodgkin’s lymphoma. Poor immunity may be caused by conditions such as:

• Severe combined immunodeficiency (SCID)
• Hypogammaglobulinemia
• Hyperimmunoglobulin M syndrome
• Congenital immunodeficiency
• Organ transplant or allogeneic bone marrow transplant

• Tobacco ^[9]

• Studies suggest that current smokers have a higher risk of developing Hodgkin’s lymphoma. They may also have an increased risk of tumors that contain the Epstein-Barr virus.

• Socio-economic status and family features^[10]

Young adult in family with higher standard of living in early childhood, and fewer siblings and playmates are at the risk of HL . This risk generally is related to the delayed exposure to Epstein-Barr virus (EBV)

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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]

Screening for Hodgkin’s lymphoma is not recommended.

Screening for Hodgkin’s lymphoma is not recommended.

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

Hodgkin’s lymphoma has a bimodal age distribution and both children and adult may be affected. The early peak occurs in the middle-to-late 20’s and the second peak after the age of 50. Treatment outcomes of Hodgkin’s lymphoma are excellent and five-year survival rates are more than 80%. Owing to modern therapies, the natural history of untreated Hodgkin’s lymphoma is actually difficult to determine. Survivors are at risk for relapse, second primary malignancies, cardiovascular complications and other treatment-related toxicities. Prognosis is based on the stage of the disease and other prognostic factors. The early stage of the Hodgkin’s lymphoma is associated with the most favorable prognosis and the 5-year survival rate of patients with Hodgkin’s lymphoma varies with the stage of the disease.

• Hodgkin’s lymphoma has a bimodal age distribution and both children and adult may be affected. The most common symptom of classic Hodgkin’s lymphoma includes painless localized peripheral lymphadenopathy.
• Owing to modern therapies, the natural history of untreated Hodgkin’s lymphoma is actually difficult to determine.

• If left untreated, Hodgkin’s lymphoma develop complications depend on site and size of mass, including breathing problem, hypoxemia, chest pain, significant weight loss, and a tracheoesophageal fistula and eventually significant decrease in the overall survival.^[1]

• The main complications of Hodgkin lymphoma are due to side effects of chemotherapy and/or radiotherapy, table below provides these general side effects:

Complications of Medical Therapy

Complications of Chemotherapy[2]	Complications of Radiotherapy[2]
Skin reactions	Skin changes
Nausea and vomiting	Nausea and vomiting
Sore throat and painful swallowing	Sore mouth
Taste changes	Loss of appetite
Fatigue	Fatigue
Diarrhea	Diarrhea
Bone marrow suppression	Bone marrow suppression
Dental cavities	Constipation
Thyroid problems	Hair loss
Fertility problems	Cystitis
Heart and lung problems	Muscle and joint pain
Second cancers	Second cancers
	Pain at the injection site
	Inflammation of the vein
	Allergic reactions
	Organ damage
	Fluid retention

• Leading complications in Hodgkin lymphoma survivors are second primary malignancies and cardiovascular toxicities. Cardiovascular complications of radiation therapy (RT) include pericarditis, myocardial ischemia or infarction, cardiomyopathy, heart failure, valvular abnormalities, or conduction abnormalities. ^[3][4]
• Breast, lung, and colon cancer are the majority of second cancers in Hodgkin’s lymphoma survivors. ^[5]
• Leukemia and non-Hodgkin lymphoma (NHL) are less common. Most leukemias that occur after the treatment are acute myeloid leukemia (AML) related to alkylating agent exposure. ^[6]

• The relative risk of non-Hodgkin lymphoma increases among Hodgkin lymphoma survivors, and this risk increases with follow-up time. ^{[7] [8]}

• Hodgkin lymphoma is considered as curable cancer, with stages I and II considered early stage. In addition, other clinical features, such as age, absence or presence of B symptoms, number of involved sites, and size of lymphadenopathy are used by experts to stratify Hodgkin’s lymphoma into favorable and unfavorable subtypes.

• Under 50 years old
• No large mediastinal adenopathy
• ESR of less than 50 mm/h and no B symptoms (or an ESR of less than 30 mm/h with B symptoms)
• Disease limited to three or fewer regions of involvement

• No more than two sites of involvement
• No extranodal extension
• No mediastinal mass measuring one-third the maximum thoracic diameter or greater
• ESR less than 50 mm/h (less than 30 mm/h if B symptoms present)

The International Prognostic Score (IPS) is the most commonly used risk stratification system for patients with advanced-stage disease (stages III and IV), which uses the following seven potential unfavorable features at diagnosis: ^[12][13]

• Serum albumin <4 g/dL
• Hemoglobin <10.5 g/dL
• Male gender
• Age >45 years
• Stage IV disease
• White blood cell count ≥15,000/microL
• Absolute lymphocyte count <600/microL and/or <8 percent of the total white blood cell count

Each variable is assigned 1 point and the total score is inversely related to 5-year survival rates as follows:

1. No point : 84 percent
2. One points : 77 percent
3. Two points : 67 percent
4. Three points : 60 percent
5. Four points : 51 percent
6. Five or more points : 42 percent

• Between 2004 and 2010, the 5-year relative survival of patients with Hodgkin’s lymphoma was 87.7%.^[14]

• When stratified by age, the 5-year relative survival of patients with Hodgkin’s lymphoma was 90.5% and 52.8% for patients <65 and ≥ 65 years of age respectively.^[14]

• The survival of patients with Hodgkin’s lymphoma varies with the stage of the disease. Shown below is a table depicting the 5-year relative survival by the stage of Hodgkin’s lymphoma:^[14]

Stage	5-year relative survival (%), (2004-2010)
All stages	85.3%
Localized	90.8%
Regional	92.1%
Distant	76.2%
Unstaged	80.7%

• The survival of patients with Hodgkin’s lymphoma also varies with the subtype of Hodgkin’s lymphoma. Shown below is the 5-year relative survival by the subtype of Hodgkin’s lymphoma:^[14]
  • Classical Hodgkin’s lymphoma: 84.8%
    • Lymphocyte-rich: 87.1%
    • Mixed cellularity: 80%
    • Lymphocyte-depleted: 56.6%
    • Nodular sclerosis: 89.4%
    • Classical Hodgkin’s lymphoma not otherwise specified: 75.2%
  • Nodular lymphocyte predominant Hodgkin’s lymphoma: 95.3%

• Shown below is an image depicting the 5-year conditional relative survival (probability of surviving in the next 5-years given the cohort has already survived 0, 1, 3 years) between 1998 and 2010 of Hodgkin’s lymphoma by stage at diagnosis according to SEER. These graphs are adapted from SEER: The Surveillance, Epidemiology, and End Results Program of the National Cancer Institute.^[14]

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