Hodgkin lymphoma

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Hodgkin lymphoma? What are the typical findings for this disease?

Hodgkin Lymphoma (HL) is a malignant neoplasm arising from lymphoid cells. HL is a common cancer in adolescents and young adults. Typically HL occurs in lymph nodes in the neck and anterior mediastium but can occur throughout the body. Patients will present with lymphadenopathy or B-symptoms such as fever, night sweats, and weight loss. Patients are treated with multiagent systemic chemotherapy with or without radiation therapy. Most patients will survive this disease so close attention needs to be paid to long-term effects of chemotherapy including organ damage and secondary malignancy.

Typical findings

Painless lymphadenopathy
Fever
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Night sweats
Weight loss

What other symptoms and signs can occur?

Respiratory distress (from mediastinal mass)

Cough (from mediastinal mass)

Superior vena cava compression syndrome (from mediastinal mass)

Severe itching

Pain with consumption of alcohol

Thrombosis

Autoimmune hemolytic anemia

Nephrotic syndrome

What other disease/condition shares some of these symptoms?

Infection:

Lymphadenitis

Tuberculosis

Histoplasmosis

HIV/AIDS

Cat Scratch Disease (Bartonella Infection)

Infectious Mononucleosis (EBV or CMV primary infection)

Other malignancies:

Non-Hodgkin Lymphoma

Burkitt Lymphoma

Diffuse Large B-cell Lymphoma

Anaplastic Large Cell Lymphoma

Lymphoblastic Lymphoma

Other rare Non-Hodgkin Lymphoma

Leukemia:

Acute Lymphoblastic Leukemia

Acute Myeloblastic Leukemia

Sarcomas:

Rhabdomysarcoma

Ewing Sarcoma (Askin’s tumor)

Other rare soft tissue sarcomas:

Thymoma

Germ cell tumor

Rheumatologic conditions:

Systemic lupus erythematosus

Sarcoidosis (SLE)

Autoimmune Lymphproliferative Syndrome (ALPS)

What caused this disease to develop at this time?

Most cases do not have an identifiable cause
Prior EBV infection
Immunodeficency

Common Variable Immune Deficiency

HIV infection
Autoimmune Lymphoproliferative Syndrome (ALPS)

Specifically associated with nodular lymphocyte predominant Hodgkin Lymphoma
Familial (very rare)

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Markers of disease activity

ESR — elevated

Ferritin — elevated

Copper — elevated

Albumen — decreased
Complete blood count – evaluates bone marrow involvement or autoimmune cellular destruction

Anemia

Thrombocytopenia

Neutropenia
Chemistries –

Albumen (when low associated with poor prognosis)

Alkaline phosphatase (elevation may indicated bone metastasis)

Evaluate renal function

BUN and creatinine
Evaluate liver function

AST, ALT, and bilirubin total and direct
Evaluate for tumor lysis syndrome

Uric acid, potassium, calcium, phophorus

Uncommon in HL

Helps differentiate HL from T-cell Non-Hodgkin Lymphoma which may present with similar clinical picture
Infectious studies — evaluates for alternative diagnosis

Order Monospot, EBV titers

If HIV risk factors: Order HIV

If cat exposure: Order Bartonella titers

If TB risk factors: Place PPD
Biopsy of suspicious lesion
Staging evaluation after diagnosis confirmed

Bone marrow biopsy — bilateral

Would imaging studies be helpful? If so, which ones?

Initial studies — lowest radiation exposure and cost

Chest X-Ray for mediastinal mass

Ultrasound of lymph nodes to evaluate for architecture and blood flow
Confirmatory studies

Confirmatory studies are indicated whenever bulky lymphadenopathy that can not be fully explained by another non-malignant etiology is identified by clinical exam or initial imaging

Computed tomography (CT) neck and chest

Assess extent of disease

CT or magnetic resonance imaging (MRI) of abdomen and pelvis

Assess extent of disease

Positron Emission Tomography (PET)/CT

Allows identification of active tumor

Uptake of FDG-labeled glucose

Will be followed for response to therapy

Can be expensive

Bone scan

Typically replaced by PET/CT imaging

Previously used to identify metastatic bone disease

Gallium scan

No longer routinely used (replaced by PET)
Echocardiogram useful to assess baseline cardiac function prior to chemotherapy

Confirming the diagnosis

How do you stage pediatric Hodgkin lymphoma?

Hodgkin lymphoma demonstrates orderly, predictable spread from one lymph node group to the next.

Ann Arbor staging system:

Stage I Single lymph node region or single localized extra nodal site
Stage II Multiple lymph node regions on same side of diaphragm
Stage III Multiple lymph node regions on both sides of diaphragm
Stage IV Multifocal extranodal involvement

Most commonly bone, bone marrow, lungs, or liver

B symptoms (any of the following in the last six months):

Fever –

Unexplained, recurrent
Greater than 38 degrees C

Weight loss –

Unexplained
Greater than 10% body weight within 6 months

Night sweats –

Drenching

Extranodal disease:

Extension of tumor to non-nodal tissue
Contiguous with nodal disease

Bulk disease:

Lymph node group –

One lymph node group (other than mediastinal mass) greater than 6 cm in diameter

Mediastinal mass –

Mediastinal ratio measured on chest radiograph (not CT) greater than 33%

How do you risk-stratify pediatric Hodgkin lymphoma?

Risk stratification for treatment purposes is specific for each treatment cooperative group. In the American and European cooperative groups, three risk categories are used. There are differences between the groups. The outline below includes the definitions used by the major American cooperative group, Children’s Oncology Group, in their recently completed clinical trials.

Low risk:

Stage I or II

No B symptoms

No bulky disease

No extranodal disease

Intermediate risk:

Stage I or II with B symptoms and/or bulky disease and/or extranodal disease

Stage III or IV without B symptoms

Can have bulk disease and extranodal disease

High risk:

Stage III or IV with B symptoms

What will the biopsy show?

An involved lymph node will include the following:

Reed-Sternburg cells (R-S cells)

Multi-nucleated giant cells

Inflammatory milieu — majority of tumor

Includes lymphocytes, histiocytes, neutrophils, eosinophils, plasma cells, and fibroblasts

R-S cells are clonal

Pathologic subtypes:

Classical Hodgkin lymphoma

Four subtypes

Nodular sclerosis
Mixed cellularity
Lymphocyte rich
Lymphocyte depleted

Nodular sclerosis most common in adolescents followed by mixed cellularity

Outcomes for mixed cellularity in children and adolescents are better than for Nodular Sclerosis

Newer regimens will take this into account

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL)

What is Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL or LP Hodgkin)?

Different pathology and immunophenotype than classical Hodgkin Lymphoma

Lymphcytic and Histiocytic cells (L&H cells)

Large mononuclear cells

Different epidemiology than classical Hodgkin Lymphoma

More common in boys

More common in children less than 10 years

Typically presents with asymptomatic peripheral lymphadenopathy

Localized and nonbulky

Does not usually involve the mediastinum

Excellent prognosis with minimal treatment

Complete resection of single involved lymph node may be adequate therapy

Chemotherapy for more advanced disease

Radiation only for persistent disease

Adult-onset NLPHL is a separate entity

Response to treatment different

Adult-onset NLPHL minimal sensitive to chemotherapy and very responsive to radiation therapy

If you are able to confirm that the patient has Hodgkin lymphoma, what treatment should be initiated?

Immediate management

All children suspected of having Hodgkin Lymphoma should be referred to a pediatric oncology specialist.

If available, all children should be offered participation in a therapeutic clinical trial.

Consider inpatient admission for rapid evaluation and management

Depends on severity of symptoms, particularly respiratory distress or orthopnea

Urgency required if large mediastinal mass due to concern for superior vena cava syndrome

Superior vena cava syndrome occurs when return of blood flow to the heart from the head and neck is compromised by compression of the great vessels by tumor

Common symptoms include dyspnea, cough, arm and face swelling, and sensation of head fullness

Cerebral edema can develop leading to headache, confusion, and coma

Avoid administration of corticosteroids until after diagnosis is confirmed
Disease-directed treatment depends on risk stratification

Typically includes multiagent systemic chemotherapy with or without radiation therapy

Ongoing therapy based on response

Resolution of FDG_PET avidity

Improvement in lesion size by CT

Normalization of ESR and other laboratory markers of disease

Length of therapy 3-6 months

What are the treatment options for newly diagnosed Hodgkin Lymphoma?

At most centers in the United States, treatment for Hodgkin Lymphoma includes three to five cycles of multiagent chemotherapy depending on initial risk categorization and response to treatment.

Chemotherapy agents typically include (ABVE-PC):

Doxorubicin (A)

Bleomycin (B)

Vincristine (V)

Etoposide (E)

Prednisone (P)

Cylcophosphamide (C)

Brentuximab Vedotin is a promising new targeted agent

Anti-CD30 monoclonal antibody linked to a cytotoxic agent
Currently in clinical trials for frontline and relapsed HL

Patients with slow initial response to chemotherapy may have treatment intensified with additional cycles of chemotherapy or alterative regimens which have shown activity in relapsed or refractory patients depending on the protocol.

Radiation therapy:

Low dose involved field radiation

Radiation directly only at lymph node areas shown to be involved with disease at diagnosis

Dose between commonly between 15 and 25 cGy — usually 21 cGy —

Used in most pediatric clinical trials

Dose and volume of radiation therapy highly protocol specific due to ongoing research objectives

Recent approaches will use involved nodal radiation and may be restricted to areas with bulky or persistent disease.

Recent clinical studies from the Children’s Oncology Group are evaluating for which patients radiation therapy can be safely omitted.

What are the treatment options for relapsed or refractory Hodgkin Lymphoma?

If available, all children should be offered participation in a therapeutic clinical trial.

Additional chemotherapy:

Any standard regimens not used for the patient with initial disease may be considered.

Gemcitabine and Vinorelbine

Brentuximab Vedotin as single agent or in combination with other agents

Regimens including etoposide (e.g., ifosphamide, cisplatin, and etoposide (ICE)) are not preferred prior to stem cell harvest as the risk of secondary malignancy may be increased.

Radiation therapy:

Particularly useful if patient has not been radiated previously or disease is outside original radiation field.

Hematopoietic stem cell transplant:

Should be considered for all patients who achieve good response to retrieval therapy.

Event free survival of 50-70% if patient has chemotherapy sensitive disease.

Event free survival of about 20% if patient has chemotherapy resistant disease.

Typically includes high dose chemotherapy followed by autologous stem cell rescue.

Interest in immune-modulation or reduced intensity allogeneic transplantation to improve outcome for those with resistant disease.

Ongoing clinical trials and laboratory investigations are looking for new agents and therapeutic approaches.

What are the adverse effects associated with each treatment option?

Chemotherapy –

Immediate effects of chemotherapy:

Common side effects of chemotherapy include nausea/vomiting, alopecia, and hematologic suppression. Hematologic suppression can result in fatigue (anemia), bleeding (thrombocytopenia), and risk for infection (neutropenia).

Other short-term effects of these agents include peripheral neuropathy, constipation, mucositis, hypertension, hyperglycemia, allergy, cardiac arrhythmia, rigors, and hypotension.

Long term effects of chemotherapy:

Complications of therapy which can occur years after therapy is complete.

Ongoing clinical trials to decrease cumulative exposure to agents with known serious late effects.

Dependent on exact agent and cumulative dose of agent received:

Doxorubicin — cardiac dysfunction or failure

Bleomycin — pulmonary fibrosis

Vincristine — peripheral neuropathy

Prednisone — osteonecrosis, obesity

Cyclophosphamide — hematuria, electrolyte wasting, secondary malignancy (acute myeloid leukemia, bladder carcinoma), male infertility

Etoposide — secondary malignancy (acute myeloid leukemia).

Radiation therapy –

Side effects depend on organ or tissue area radiated and dose received.

Immediate effects of radiation include skin irritation and burns, nausea, and fatigue.

Long term effects of radiation are dependent on tissue exposed:

Thyroid – hypothyroidism, thyroid cancer

Cardiac – accelerated coronary artery disease, carditis, myopathy

Lung – pulmonary fibrosis

Ovary – infertility, premature ovarian failure

Breast – breast cancer

Reducing risk for late effects of both chemotherapy and radiation therapy is one of the major foci of current pediatric clinical trials.

What are the possible outcomes of Hodgkin lymphoma?

Over 90% of childhood with newly diagnosed Hodgkin Lymphoma will be cured. Careful attention needed to long-term risks for organ toxicity and secondary malignancy.

Most children who experience recurrent disease can be cured with intensive treatment. Increased risk for late effects of treatment.

Refractory Hodgkin Lymphoma is very difficult to treat.

What causes this disease and how frequent is it?

Cause typically unknown.
Lymphoma is third most common childhood cancer

Hodgkin Lymphoma is the most common childhood lymphoma

Hodgkin Lymphoma represents 6% of all childhood cancers

Hodgkin Lymphoma is most common in adolescents (age 15-19).
Highest incidence in adolescent girls

During adolescence male:female ratio 0.8

During childhood strong male predominance (male:female ratio 5.3).
Hodgkin Lymphoma associated with higher social economic status in adolescent and young adults but with lower socioeconomic status in those under age 10 years

Possible protective effect of exposure to more children during young childhood.

What complications might you expect from the disease or treatment of the disease?

Mediastinal mass –

Hodgkin Lymphoma can present as superior vena cava syndrome:

Airway compression, vena cava compression, cardiac tamponade

Symptoms include facial swelling and plethora, syncope, cough or progressive respiratory distress

Can be life-threatening

Need to obtain diagnosis by quickest and least invasive method possible

In extreme situations, empiric treatment (most commonly with corticosteroids) may be indicated prior to obtaining tissue for pathology.

How can Hodgkin lymphoma be prevented?

There are no known preventive strategies for pediatric Hodgkin lymphoma.

What is the evidence?

“National Cancer Institute: PDQ Childhood Hodgkin Lymphoma Treatment”. (This is a website maintained by the National Cancer Institute to provide up-to-date information on pediatric Hodgkin Lymphoma and its treatment written for both patients and health professionals. Information on this site is reviewed and updated frequently by national experts in the field.)

Schwartz, CL. “The management of Hodgkin disease in the young child”. Curr Opin Pediatr. vol. 15. 2003. pp. 10-6. (This paper reviews current thoughts on management of Hodgkin Lymphoma in pediatric patients with a focus on both improving efficacy and reducing long term effects of chemotherapy.)

Kelly, KM, Hodgson, D, Appel, B, Chen, L, Cole, PD, Horton, T, Keller, FG. “COG Hodgkin Lymphoma Committee: Children's Oncology Group's 2013 blueprint for research: Hodgkin lymphoma”. Pediatr Blood Cancer. vol. 60. 2013 Jun. pp. 972-8. (This paper presents the most recent Children's Oncology Group strategy for evaluation, treatment, and research in pediatric Hodgkin lymphoma including reduction in exposure to radiation therapy, a new prognostic factor score, and novel retrieval regimens.)

Nachman, JB, Sposto, R, Herzog, P. “Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy”. J Clin Oncol. vol. 20. 2002. pp. 3765-71. (This paper reports results from a Children's Cancer Group study which treated patients with combination chemotherapy and randomized them to radiation or no radiation. Patients treated without radiation had a slightly increased risk of relapse, but no survival benefit to radiation has been shown. This study is one of the basis for continuing investigation in the Children's Oncology Group on the appropriate role of radiation therapy for children with Hodgkin Lymphoma.)

Schwartz, CL, Constine, LS, Villaluna, D. “A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425”. Blood. vol. 114. 2009. pp. 2051-9. (This paper reports results from a Pediatric Oncology Group study which treated patients with novel combination chemotherapy designed to minimize risk for late effects of therapy and low dose involved field radiation therapy. Patients treated with this regimen enjoyed excellent outcomes while receiving cumulative doses of key chemotherapy agents below thresholds usually associated with significant long-term toxicity. This chemotherapy backbone continues to be used in ongoing Children's Oncology Group studies.)

Akhtar, S, El Weshi, A, Rahal, M. “High-dose chemotherapy and autologous stem cell transplant in adolescent patients with relapsed or refractory Hodgkin's lymphoma”. Bone Marrow Transplant. vol. 45. 2010. pp. 476-82. (This paper describes one center's experience with autologous stem cell transplant with adolescents with relapsed and refractory Hodgkin Lymphoma.)

Hutchings, M, Loft, A, Hansen, M. “FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma”. Blood. vol. 107. 2006. pp. 52-9. (This paper provides one example of utilizing FDG-PET response to therapy as part of risk stratification for treatment decisions. These investigators found that early (after two cycles of chemotherapy) PET response was associated with improved event free and overall survival.)

Mauz-Körholz, C, Gorde-Grosjean, S, Hasenclever, D. “Resection alone in 58 children with limited stage, lymphocyte-predominant Hodgkin lymphoma-experience from the European network group on pediatric Hodgkin lymphoma”. Cancer. vol. 110. 2007. pp. 179-85. (This article reviews the recent European experience with management of localized LP Hodgkin Lymphoma with surgery alone. Approximately 60% of patients were apparently cured with surgery alone, while those with progressive disease were typically able to be salvaged without significant toxicity.)

Constine, LS, Tarbell, N, Hudson, MM. “Subsequent malignancies in children treated for Hodgkin's disease: associations with gender and radiation dose”. Int J Radiat Oncol Biol Phys. vol. 72. 2008. pp. 24-33. (This article reviews the experience of five centers with children and young adults who developed secondary malignancies after treatment for Hodgkin Lymphoma. 11% of survivors experienced a secondary malignancy with an increased risk in girls and those who received higher radiation doses.)

Chen, X, Soma, LA, Fromm, JR. “Targeted therapy for Hodgkin lymphoma and systemic anaplastic large cell lymphoma: focus on brentuximab vedotin”. Onco Targets Ther. vol. 19. 2013. pp. 45-56. (This paper discusses targeted immunotherapy against CD30 for HL and anaplastic large cell lymphoma using brentuximab vedotin. Included is information on the United States Food and Drug Administration approval of brentuximab vedotin for the treatment of relapsed and refractory HL.)

Ongoing controversies regarding etiology, diagnosis, treatment

Clinical trials to optimally treat pediatric Hodgkin Lymphoma are ongoing through the Children’s Oncology Group and other international pediatric oncology cooperative groups. Work continues on improved risk stratification, reduction of radiation exposure, development of new chemotherapy agents and strategies particularly for recurrent or refractory disease, and minimization of long-term effects of therapy.

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