Hodgkin Lymphoma

Hodgkin lymphoma (HL) is a malignancy of B lymphocytes B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells originating in the lymph nodes. The pathognomonic histologic finding of HL is a Hodgkin/Reed-Sternberg (HRS) cell (giant multinucleated B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy (neck most commonly involved), night sweats, weight loss, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and at times, splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly and hepatomegaly. Diagnostic testing includes lymph node histologic analysis showing HRS cells, blood tests, and CT and PET scanning. HL is managed with chemotherapy and radiotherapy. The prognosis has improved significantly with the advent of chemotherapeutic regimens.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Hodgkin lymphoma (HL) is a monoclonal B-cell lymphoma (neoplasm) originating in lymph nodes in which the malignant Hodgkin/Reed-Sternberg (HRS) cells are mixed with a heterogeneous population of nonneoplastic inflammatory cells.

Epidemiology

  • Incidence in the United States: 2 to 3 cases per 100,000 population
  • Bimodal age peaks : young adults (15–34 years) and > 55 years of age 
  • Can be seen in children: 
    • Peak age of incidence: 12 years
    • Incidence: 1.1 cases per 100,000 children
    • Pediatric cases: 85% male
  • M > F (3:2) in adults
  • 30% of all lymphomas (remainder are non-Hodgkin)
  • Lowest incidence (United States):
    • American Indians
    • Alaska Natives
    • Asians/Pacific Islanders

Etiology

  • Exact etiology unknown
  • Increased risk with:
    • EBV:
      • Responsible for infectious mononucleosis Mononucleosis Infectious mononucleosis (IM), also known as "the kissing disease," is a highly contagious viral infection caused by the Epstein-Barr virus. Its common name is derived from its main method of transmission: the spread of infected saliva via kissing. Clinical manifestations of IM include fever, tonsillar pharyngitis, and lymphadenopathy. Mononucleosis (IM)
      • Minority of patients infected with EBV will develop HL.
      • EBV DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure found in HRS cells in 50% of patients in North America and Europe.
      • EBV DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure found in HRS cells in 90% of patients in economically developing countries.
    • Immunodeficiency:
      • HIV: 5- to 25-fold increased risk of developing HL
      • Immunotherapy
      • Almost all cases of HL occurring in immunodeficiency conditions are EBV-positive.
    • Obesity Obesity Obesity is a condition associated with excess body weight, specifically with the deposition of excessive adipose tissue. Obesity is considered a global epidemic. Major influences come from the western diet and sedentary lifestyles, but the exact mechanisms likely include a mixture of genetic and environmental factors. Obesity
    • Diet high in meats and sweets
    • Physical inactivity
    • High birth weight
    • Cigarette smoking
  • Aspirin and breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding seem to be protective.
  • Familial predisposition:
    • Unclear if genetic or environmental
    • Risk in close relatives: 3- to 5-fold greater than overall expected rate
    • Risk varies with subtype.
    • Risk stronger in siblings than in parents.

Classification

Based on WHO classification, HLs have the following types and subtypes according to immunophenotype and morphology.

Classic HL (95%):

  • Nodular sclerosis (NSHL):
    • 80% of HLs
    • Male = female
    • Young adults
    • Lacunar cells
    • Classic HRS cells
    • Background cells are mixed
    • Bands of fibrosis
    • Typically stage I or II (mediastinal)
  • Mixed cellularity:
    • 30% of HLs
    • Male > female
    • All ages
    • Histologic type most commonly observed in patients with HIV
    • Typically stage III or IV
    • Mononuclear and classic HRS cells
    • Background cells mixed
    • Eosinophilia present
  • Lymphocyte-rich:
    • 4% of HLs
    • Predominantly men in 30s
    • Mononuclear and classic HRS cells
    • Background cells: T lymphocytes T lymphocytes T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
    • Best prognosis
  • Lymphocyte-depleted:
    • 2% of HLs
    • Associated with advanced age
    • Classic HRS cells along with variants
    • Few background cells
    • Some diffuse fibrosis
    • Typically older men
    • HIV association
    • Abdominal lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
    • Worst prognosis

Nodular lymphocyte–predominant HL (NLPHL):

  • 5% of HLs
  • Distinct clinical entity and not considered part of the classical HL type
  • Males > females: 3:1
  • Typical presentation is chronic asymptomatic peripheral lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy.
  • Strong genetic component
  • Lymphocytic and histiocytic (L&H) (popcorn) neoplastic cells:
    • Express CD20 antigen
    • Negative for CD15 and CD30
  • Typical HRS cells are either infrequent or absent.
  • B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells and dendritic cells are the background cells.
  • More common in younger patients
  • Cervical and axillary involvement typical

Pathophysiology

Hodgkin/Reed-Sternberg cells

  • Neoplastic cells in classic Hodgkin lymphoma (cHL)
  • Bilobed nuclei with prominent nucleoli (owl’s-eye appearance)
  • cHL expresses CD15 (Leu-M1) and CD30 (Ki-1) antigens 
  • Comprise only 1%–2% of the total tumor cell mass
  • Produce cytokines (e.g., interleukins Interleukins Interleukins are a type of cytokines (signaling proteins) that communicate messages between different parts of the immune system. The majority of interleukins are synthesized by helper CD4 T lymphocytes along with other cells such as monocytes, macrophages, and endothelial cells. Interleukins and tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF))), which stimulate cell proliferation
  • Result from clonal transformation of cells of B-cell origin:
    • Derived from germinal lymph node centers 
    • Origin cells acquire multiple mutations
  • Lose the ability to undergo apoptosis:
    • Latent membrane protein 1 (LMP-1), which is expressed by Epstein-Barr–infected cells, is responsible for activation of nuclear factor kappa-B (NF-kappaB) pathway, which is apoptotic.
    • NF-kappaB is translocated to the nucleus of RS cells.
    • NF-kappaB is also responsible for proliferation of the HRS cells and secretion of proinflammatory cytokines that are responsible for the systemic features of cHL.
  • No longer able to produce antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
  • Some HRS cells show evidence of EBV infection and frequent cytogenetic abnormalities:
    • EBV is an oncogenic virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview associated with HL.
    • EBV is believed to be responsible for production of signals that render cells immortal (i.e., they no longer undergo apoptosis).
    • Detection of EBV in HRS cells varies with histologic subtype, geography, and immunocompetence.

Surrounding inflammatory stroma

  • Benign reactive cells that are attracted to and proliferate with the expression of cytokines by HRS cells.
  • Comprise the bulk of the tumor
  • Mixture of macrophages, lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes, mast cells, neutrophils, eosinophils, and plasma cells
  • HRS cells also activate fibroblasts and collagen deposition.

Genetic mutations

  • Affect proliferation and survival of malignant cells
  • Mutations producing abnormalities of intracellular signaling:
    • NF-kappaB
    • JAK-STAT 
    • NOTCH
  • Mutations producing immune evasion: PD-1 related genes

Dissemination

  • Proceeds from a single lymph node to adjacent nodes via lymphatic channels
  • Distant spread later

Clinical Presentation

Time course:

  • cHL generally progresses slowly.
  • Some variability 

Most common presentations:

  • Asymptomatic lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy:
    • 66% of cHL cases
    • Nontender
    • Firm
    • Rubbery consistency
    • Neck most common site
    • Axillary and inguinal nodes less common
    • Retroperitoneal node involvement in 30% of patients
  • Chest mass on imaging:
    • Mediastinal nodes involved in over 50% of patients.
    • Not detectable on physical exam
Prominent cervical lymphadenopathy

Hodgkin lymphoma:
Prominent cervical lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy

Image: “Hodgkin’s Disease (Essentials of Medicine)” by Charles Phillips Emerson, Nellie Gates Brown. License: Public Domain

“B” symptoms (constitutional) present in 40% of cases:

  • Fever
  • Night sweats
  • Unintended weight loss
  • Fatigue

Other symptoms:

  • Pruritus (10%–15%)
  • Alcohol-associated pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain (rare): alcohol consumption induces pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain in lymph nodes (pathognomonic).
  • Skin lesions (ichthyosis, acrokeratosis, erythema nodosum Erythema nodosum Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. Erythema Nodosum, urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives), erythema multiforme Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). Erythema Multiforme)
  • Bone pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain (if there is bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones involvement)
  • Paraneoplastic syndromes Paraneoplastic syndromes Paraneoplastic syndromes are a heterogeneous group of disorders caused by an abnormal immune response to a neoplasm. The substances produced are not due to the direct effect of the tumor, such as metastasis, mass effect, or invasion. Antibodies, hormones, cytokines, and other substances are generated and affect multiple organ systems. Paraneoplastic Syndromes:
    • Neurologic
    • Nephrotic

Diagnosis and Staging

History

  • Lymphadenopathy:
    • Painless
    • Most common symptom
    • Contiguous spread or single node
    • Unilateral 
    • Cervical/supraclavicular → axillary → inguinal
    • Nontender, rubbery 
  • Constitutional B symptoms:
    • Low-grade fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Night sweats
    • Weight loss
  • Pruritus
  • Back or bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Pel-Ebstein fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever: waves of fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever for weeks 
  • Alcohol pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Family history: particularly helpful in NSHL

Physical exam

  • Lymph nodes:
    • Palpable nodes
    • Painless
    • Neck: 60%–80%
    • Axilla Axilla The axilla is a pyramid-shaped space located between the upper thorax and the arm. The axilla has a base, an apex, and 4 walls (anterior, medial, lateral, posterior). The base of the pyramid is made up of the axillary skin. The apex is the axillary inlet, located between the 1st rib, superior border of the scapula, and clavicle. Axilla and Brachial Plexus: 6%–20%
    • Inguinal: 6%–20%
  • Superior vena cava Superior vena cava The venous trunk which returns blood from the head, neck, upper extremities and chest. Mediastinum and Great Vessels (SVC) syndrome:
    • If sufficient physical obstruction of SVC by mediastinal node infiltration
    • Venous distention of the upper limbs and neck 
    • Facial swelling and congestion
    • Pleural effusion Pleural Effusion Pleural effusion refers to the accumulation of fluid between the layers of the parietal and visceral pleura. Common causes of this condition include infection, malignancy, autoimmune disorders, or volume overload. Clinical manifestations include chest pain, cough, and dyspnea. Pleural Effusion: shortness of breath
    • Cough
  • Rare, extranodal manifestations:
    • Hepatomegaly
    • Splenomegaly
    • Diminished breath sounds and tachypnea (pleural effusion)
    • Bony tenderness 

Diagnostic testing

Laboratory studies:

  • CBC with differential:
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • Lymphopenia
    • Neutrophilia
    • Eosinophilia
  • Erythrocyte sedimentation rate (ESR):
    • General marker for inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
    • May be elevated
    • Associated with worse prognosis
  • Serum chemistries:
    • Serum calcium elevation
    • Serum sodium elevation
    • Serum creatinine increased in nephrotic syndrome Nephrotic syndrome Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminemia, and peripheral edema. In contrast, the nephritic syndromes present with hematuria, variable loss of renal function, and hypertension, although there is sometimes overlap of > 1 glomerular disease in the same individual. Nephrotic Syndrome
  • Liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests:
    • Alkaline phosphatase (ALP) may be increased with involvement of:
      • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
      • Bone
    • LDH increased
    • May correlate with disease extent and bulk
  • Albumin
  • HIV testing
  • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus and C testing

Imaging:

  • Chest X-ray (masses or mediastinal widening)
  • CT scanning to evaluate:
    • Lymph node enlargement
    • Hepatomegaly
    • Splenomegaly
    • Lung:
      • Nodules
      • Effusions
      • Infiltrates
  • PET scanning:
    • Considered essential to the initial staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis of HL:
    • Injection of fluorodeoxyglucose (FDG), which is an analogue of glucose:
      • Taken up by tumor cells
      • Emits gamma rays
      • Gamma rays are detected by scanner.
    • Ability to distinguish between viable tumor and necrosis or fibrosis
    • Often performed in conjunction with CT scanning
    • Guides the need for further treatment
Chest x-ray showing mediastinal lymphadenopathy in hodgin lymphoma

Chest X-ray showing mediastinal lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy in Hodgin lymphoma

Image: “Hodgkin’s lymphoma presenting with markedly elevated IgE: a case report” by Ellis AK AK Actinic keratosis (AK) is a precancerous skin lesion that affects sun-exposed areas. The condition presents as small, non-tender macules/papules with a characteristic sandpaper-like texture that can become erythematous scaly plaques. Actinic Keratosis (AK), Waserman S. License: CC BY 2.0

Biopsy:

  • Excisional biopsy of a peripheral lymph node (preferred):
    • Mandatory testing
    • Microscopy: 
      • RS cells
      • Pleomorphic inflammatory cell infiltrate
      • Fibrosis
    • Immunophenotype: 
      • CD30 (classical HL)
      • CD15 (classical HL)
      • CD20 (NLPHL)
      • Absence of CD45 and CD3
  • Bone marrow biopsy: to determine extent of disease

Staging

Staging is based on the Ann Arbor classification.

  • Stage I:
    • 1 group of lymph nodes (I): primarily cervical or
    • A single extralymphatic site (Ie)
  • Stage II:
    • ≥ 2 lymph nodes on 1 side of diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm (II) or
    • Localized extranodal foci and infestation of ≥ 1 lymph nodes on 1 side of diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm (IIe)
  • Stage III:
    • Lymph node involvement on both sides of the diaphragm Diaphragm The diaphragm is a large, dome-shaped muscle that separates the thoracic cavity from the abdominal cavity. The diaphragm consists of muscle fibers and a large central tendon, which is divided into right and left parts. As the primary muscle of inspiration, the diaphragm contributes 75% of the total inspiratory muscle force. Diaphragm (III), which may include the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen (IIIs) or
    • Limited contiguous extralymphatic organ or site (IIIe, IIIes)
  • Stage IV: disseminated involvement of ≥ 1 extralymphatic organs without lymph node involvement
  • “A” indicates the absence of systemic symptoms.
  • “B” indicates the presence of systemic symptoms.

Management and Prognosis

Management

  • Goals of therapy:
    • Maximize cure for all stages.
    • Minimize both short- and long-term complications.
    • Minimize risks of toxicity.
  • Primarily guided by clinical stage
  • Stage IA:
    • Chemotherapy with ABVD (doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine)
    • Followed by localized or regional radiotherapy
  • Stage IB/II:
    • 4–6 courses of ABVD
    • Radiotherapy to bulky nodes
  • Stages III and IV: 
    • 6–8 courses of ABVD
    • Radiotherapy for residual bulky lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
  • Refractory cases: 
    • Autologous stem cell transplantation
    • Different chemotherapeutics
    • Antibodies to block PD-L1
    • Antibodies against CD30

Prognosis

  • International Prognostic Score (IPS): based on 7 unfavorable features at diagnosis:
    • Male sex
    • Age > 45 years
    • Stage IV disease
    • Hypoalbuminemia: serum albumin < 4 g/dL
    • Hemoglobin < 10.5 g/dL
    • Lymphocyte count < 600/µL and/or < 8% of the WBC
    • WBC ≥ 15,000/µL
  • Freedom of progression at 5 years:
    • 0 factors: 84% (7% of patients)
    • 1 factors: 77% (22% of patients)
    • 2 factors: 67% (29% of patients)
    • 3 factors: 60% (23% of patients)
    • 4 factors: 51% (12% of patients)
    • 5 or more factors: 42% (7% of patients)

Complications

  • Radiotherapy complications:
    • Myelodysplasia 
    • Acute leukemia 
    • Sarcoma
    • Increased risk of lung cancer Lung cancer Lung cancer is the malignant transformation of lung tissue and the leading cause of cancer-related deaths. The majority of cases are associated with long-term smoking. The disease is generally classified histologically as either small cell lung cancer or non-small cell lung cancer. Symptoms include cough, dyspnea, weight loss, and chest discomfort. Lung Cancer or fibrotic lung disease, particularly in smokers
  • Chemotherapy complications: 
    • Adriamycin is cardiotoxic.
    • Bleomycin causes pneumonitis.
    • Congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure and increased risk of coronary artery disease
    • Long-term immunodeficiency
    • Neuropathy and muscle atrophy

Differential Diagnosis

  • Reactive processes: infectious, autoimmune, and other inflammatory processes may result in lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, organomegaly, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and other systemic symptoms. Reactive processes have a polymorphous infiltrate but lack Reed-Sternberg cells. Diagnosis is by histologic analysis, blood tests, and imaging studies. Treatment is tailored to the underlying disease.
  • Non-Hodgkin lymphoma (NHL): composes all forms of lymphocyte malignancies that do not have the HRS cells histologically. Signs and symptoms include lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, and constitutional symptoms. Diagnosis is by histologic examinations of lymphoid tissue or bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow. Imaging is performed to assist with staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis. Management is with chemotherapy, radiation therapy, and stem cell transplantation. 
  • Anaplastic large cell lymphoma: neoplasm of T-cell origin that produces inflammatory responses and tissue fibrosis (a subtype of NHL). Signs and symptoms include lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, but constitutional symptoms are rare. Anaplastic large cell lymphoma has an aggressive course. Diagnosis is made by a combination of morphologic and immunophenotypic evaluations. Management is with chemotherapy and stem cell transplantation.
  • EBV-positive mucocutaneous ulcer: disorder characterized by isolated circumscribed ulcerative lesions that occur in older patients or in the setting of immunosuppression. Lesions are commonly in the oropharynx, but skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin or GI sites can be involved. The lesions contain polymorphous inflammatory infiltrates with scattered EBV-infected B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells that resemble HRS cells. EBV-positive mucocutaneous ulcer has an extranodal presentation, benign course, and frequent spontaneous regressions, and it is responsive to conservative treatment.

References

  1. LaCasce, A., Ng, A., Aster, I. (2021). Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults. In Freedman, A. (Ed.), UpToDate. Retrieved April 18, 2021, from https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-classic-hodgkin-lymphoma-in-adults
  2. Canellos, G., Ng, A. (2021). Overview of the treatment of classic Hodgkin Lymphoma in adults. In Freedman, A. (Ed.), UpToDate. Retrieved April 18, 2021, from https://www.uptodate.com/contents/overview-of-the-treatment-of-classic-hodgkin-lymphoma-in-adults
  3. Lash, B. (2020). Hodgkin Lymphoma. In Besa, E. (Ed.), Medscape. Retrieved April 18, 2021, from https://reference.medscape.com/article/201886-overview
  4. Engert, A., Plütschow, A., Eich, H.T., et al. (2010). Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med 363:640–652. https://doi.org/10.1056/NEJMoa1000067
  5. Radford, J., Illidge, T., Counsell, N., et al. (2015). Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med 372:1598–1607. https://doi.org/10.1056/NEJMoa1408648
  6. Shimabukuro-Vornhagen, A., Haverkamp, H., Engert, A., et al. (2005). Lymphocyte-rich classical Hodgkin’s lymphoma: clinical presentation and treatment outcome in 100 patients treated within German Hodgkin’s Study Group trials. J Clin Oncol 23:5739–5745. https://pubmed.ncbi.nlm.nih.gov/16009944/
  7. Mauch, P.M., Kalish, L.A., Kadin, M., et al. (1993). Patterns of presentation of Hodgkin disease. Implications for etiology and pathogenesis. Cancer 71:2062–2071. https://pubmed.ncbi.nlm.nih.gov/8443755/

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