Hodgkin's disease


Malignant Lymphoma
Definition : malignant tumor that originate in the reticuloendothelial system : two major subgroups
1. Hodgkin's diesase
2. Non-hodgkin's lymphoma.

Epidemiology : only 0.75% of all cancer diagnosed in the US each year.
: about 7 of every 100,000 people annually
: incidence in Chulalongkorn hospital in 1992 is 0.21% of all cancer and HD : NHL ratio is 1:17
: Age - median age - 26 years - bimodal peak, 25-30 years and 75-80 years
- rare in children under age 10 years
: Sex - slight male predominance

Etiology and Risk Factors
1. Relationship with Epstein-Barr Virus (EBV)
2. Other unexplained factors
-Occupational exposure : increase risk among wood worker
-Familial association and linkage with certain HLA antigen

Natural History & Clinical Presentation
- Always begin in lymph nodes
- Isolated extralymphatic involvement in the absence of nodal disease is exceedingly rare
- Spreading pattern
: Concept of Unifocal origin followed by predictable route of spread
: Spreading mainly by lymphatic pathway by the theory of contiguity of spread
: Evidence of vascular dissemination about 10%
- Usually present with painless lymphadenopathy, more common at cervical and mediastinal lymph nodes
: 80% of HD present with cervical lymph node involvement
: more than 50% have mediastinal disease, most often involve superior mediastinal nodes and hilar nodes, respectively
: Patient with clinical stage I confined to upper neck almost never has positive laparotomy
- Abdominal disease
: more common in spleen, splenic hilar and paraaortic nodes
: mesenteric nodes is rather rare
: spleen involvement does not correlate well with splenomegaly and likelihood of disseminated disease increases as the extent of disease in the spleen increase
: liver invasion is rare without splenic involvement
: rarely involve gut-associated lymphoid tissue
- CNS are rarely involved
- Systemic symptom : B symptoms - unexplained fever more than 38° c
- night sweat
- weight loss more than 10% of body weight in the last 6 months B symptoms often correlated with more extensive disease and natural history is generally worse than in asymptomatic patient. Weight loss and fever are particularly poor prognosis.
- Bone marrow involvement associated with extensive tumor and usually with systemic symptoms.
Fig. 1 Anatomic staging sites for lymph nodes.

Diagnostic work up

1. History
2. Physical Examination
3. Laboratory studies
- CBC and Other blood chemistry
- Serum ESR and Copper level
4. Radiographic studies
- Chest x-ray : to evaluate extent of mediastinal adenopathy
: Bulky mass is defined by ratio of maximum mediastinal mass and maximum intrathoracic diameter exceed 1:3
- Bipedal lymphangiography
: most accurate for evaluation of retroperitoneal lymph nodes
: abnormalities not only in size but also in the internal architecture
: overall accuracy is around 95%
: can't evaluate celiac, perihepatic, perisplenic, mesenteric and internal iliac nodes
- CT scan of abdomen, pelvis or thorax
- Gallium scan
- Bone scan ( if indicated )
5. Bone marrow biopsy
6. Complementary : Percutaneous liver biopsy
: Peritoneoscope
: Staging laparotomy

Diagnostic cell of Hodgkin's disease is Reed-Sternberg cell ( Large cell with two or more mirror-imaged nuclei, each containing a single prominent nucleolus, well demarcated nuclear membrane with eosinophilic cytoplasm ) Majority of the cells are lymphoid cell, eosinophil, plasma cell and other normal cells.
Fig 2 Reed-Sternberg cell. Note the prominent inclusion-like nucleoli with a clear halo around them. ( Courtesy of Dr. Patrick Ward, Department of Pathology and Laboratory Medicine, University of Minnesota School of Medicine, Duluth, Minnesota. )

Clinical differences between Hodgkin's and Non-hodgkin's lymphoma

Hodgkin's Disease

Non-hodgkin's Lymphoma

-More often localized to a single axial group of nodes ( cervical, mediastinal, paraaortic )

-Orderly spread by contiguity

-Mesenteric nodes and Waldeyer's ring rarely involved

-Uncommon extranodal involvement

-More often with early stage presentation

-Usually favorable histopathology in pediatric

-More frequent involvement of multiple peripheral nodes

-Noncontiguous spread

-Waldeyer's ring and mesenteric nodes commonly involved

-Common extranodal involvement

-More often with advanced stage presentation

-Usually high grade in pediatric

Pathologic Classification

According to Rye modification of the Lukes and Butler system, there are 4 histologic subtypes with different prognosis and spreading pattern. As the disease advanced, there is progressive loss of lymphocyte and increase number of malignant cell.

1. Lymphocyte Predominance Hodgkin's Disease ( LPHD ) - 15 %

-characterized by abundance of normal-appearing lymphocyte and scarcity of abnormal cells
-most favorable natural history
-often young people with early stage disease, uncommon systemic symptom

2. Nodular Sclerosis Hodgkin's Disease ( NSHD ) - 70 %

-most common histologic subtype
-natural history is less favorable than LPHD
-often involve mediastinum
-B symptom in 1/3 of patients

3. Mixed Cellularity Hodgkin's Disease ( MCHD ) - 10 %

-relative abundant atypical mononuclear and RS cell
-natural history is less favorable than NSHD
-slightly older patient with advanced disease
-62% chance of abdominal disease

4. Lymphocyte Depletion Hodgkin's Disease ( LDHD ) - 5 %

-characterized by paucity of normal appearing cell with abundance of abnormal cell and RS cell
-least common histologic subtype
-worst prognosis of all histologic subtype
-more likely associate with advanced disease, subdiaphragmatic disease and B symptoms

Ann Arbor Staging Classification

Stage I : Involvement of a single lymph node region
Stage II : Involvement of two or more lymph node regions on the same side of diaphragm (II), or localized involvement of an extralymphatic organ or site and of one or more lymph node regions on the same side of diaphragm ( IIE )
Stage III : Involvement of lymph node regions on both sides of diaphragm ( III ) which may also be accompanied by involvement of the spleen ( IIIS ) or by localized involvement of an extralymphatic organ or site ( IIIE ) or both ( IIISE )
Stage IV : Diffuse or disseminated involvement of one or more extralymphatic organs or tissue with or without associated LN involvement

Note : A - no symptom
           B - fever, night sweat, weight loss


Treatment modalities :
-Radiation therapy
-Combined modality treatment
: Because of the excellent therapeutic results of the single modality approach for the properly selected patient group, it has been difficult to prove the value of combined modality program.
: The most accepted value of the combined modality approach is in the management of children with Hodgkin's Disease. This approach cures over 90% of children without interfering with their growth and development.
: The concern about combined modality approach has been additive or greater spectrum of acute and late complication.

Stage I, II
-Only 10 % of stage I limit to subdiaphragmatic site
-15-20% of stage I, II have B symptoms
-Majority of the cases can be managed with RT alone.
-Combined treatment in pathologic St I, II will improve free from relapse but equivalent survival, reserve for patient with unfavorable disease ( bulky mediastinal mass, systemic B symptoms especially both fever and weight loss or intraabdominal disease )
-Subdiaphragmatic disease with splenic involvement may considered systemic chemotherapy.

Stage IIIA
-RT alone ( Total nodal irradiation ) in cases with involvement of splenic hilar, celiac or portal nodes with uninvolved spleen or limited splenic involvement
-Combined modalities treatment
-Combination chemotherapy

Stage IIIB, IV
-Systemic chemotherapy is the mainstay of treatment of advanced disease.

Radiation Treatment Technique

Principal objective of the irradiated program is to treat the contiguous lymphatic chains to tumor eradicating dose. It requires meticulous treatment planning, simulation and frequent verification by portal films.

Radiation treatment field

1. Local or Involved Field Irradiation
2. Mantle Field Irradiation

-Target volume - cover supradiaphragmatic lymph node include cervical nodes, axillary nodes, hilar nodes and mediastinal nodes.
-Superior margin from inferior portion of the mandible and mastoid tip
-Inferior margin to the level of insertion of diaphragm or T9

3. Inverted Y Field Irradiation
-Target volume - cover subdiaphragmatic lymph nodes include paraaortic nodes, splenic pedicle nodes, spleen, pelvic nodes, inguinal nodes and femoral nodes
- Superior margin from T11

4. Total Nodal Irradiation
-Mantle field plus Inverted Y field Irradiation

5. Subtotal Nodal Irradiation
-Not included pelvis in TNI

6. Total Lymphoid Irradiation
-TNI plus waldeyer's ring and whole abdomen

Fig.3 Simulator film of a template for " mantle field irradiation "

Fig.4 Template for " inverted Y technique " showing bilateral nephrograms and lead shielding to testes

Radiation Dose and Beam
-Megavoltage photon beam : Co-60, 4-10 MV Linac
-Fractionation : 150-200 cGy/F, 5F/wk
-Involved area : 3500-4400 cGy
-Subclinical disease : 3000-3600 cGy
-Combined modalities : Involved area 2500 cGy
: Subclinical disease 2000 cGy

Systemic Chemotherapy

-Single-agent chemotherapy plays a small role in the treatment
-Combination chemotherapy : use of multiple non-cross resistant agent with additive antitumor effect but without additive toxicity

M: Nitrogen mustard 6 mg/m2 IV Day 1,8
O: Vincristine 1.4 mg/m2 IV Day 1,8
P: Procarbazine 100 mg/m2 PO Day 1-14
P: Prednisolone 40 mg/m2 PO Day 1-14

A: Doxorubicin 25 mg/m2 IV Day 1,15
B: Bleomycin 10 mg/m2 IV Day 1,15
V: Vinblastine 6 mg/m2 IV Day 1,15
D: Dacarbazine 375 mg/m2 IV Day 1,15

-A standford study, initiated in 1974 used six cycle of MOPP chemotherapy as an adjuvant to involved-field irradiation in favorable laparotomy-staged patients. This randomized study demonstrated that the chemotherapy was as effective as irradiation in controlling occult disease. However, six cycles of MOPP proved to be leukemogenic in a small percentage of patients and to induce sterility in the majority of young patients who survived. 5
-ABVD provide similar complete remission rate when compare with MOPP and succes in salvage patients with recurrence after MOPP
-Alternating cycle MOPP/ABVD give superior result when compare to MOPP alone, significant difference in relapse-free survival but no significant difference in CR and OS ( Milan gr. )
-At least 6 cycles of chemotherapy is generally approach or until achieve CR then administer two additional cycles.

Prognostic Factors

Patient related : Age -young has better prognosis
: Sex -slightly worse outcome for men
: Intercurrent disease

Disease related : Staging
: Histopathology
: Disease extent - bulky disease
- number of involved sites
- extent of splenic involvement
: B symptoms - relate with more extensive disease
: Serum marker of disease activity

Result of Treatment

Stage I, II A 10 yr SR 90%
10 yr RFS 75-80%
Stage I, II B 10 yr SR 80-90%
10 yr RFS 70-80%
Stage IIIA 5 yr SR 70-80%
Stage IIIB, IV 5 yr SR 50-60%

Treatment of relapse

-depend on initial disease charactor, initial treatment, relapse site and general performance status of the patient
-Initial treatment :
: RT alone - primary salvage treatment is chemotherapy with or without local radiation
: Chemotherapy - common approach is systemic chemotherapy with drugs which are not included in primary treatment with or without irradiation
- if multiple relapse or unfavorable characteristic, aggressive treatment e.g.Autologous bone marrow transplantation should be considered.

Hodgkin's Disease in Childhood

-HD in childhood has particular good prognosis ( favorable histology, earlier stage )
-Laparotomy has minor impact on overall treatment program
-Splenectomy should not be performed in a child younger than 5 years
-most effective treament is combined chemotherapy ( MOPP, MOPP-like, ABVD, MOPP/ABVD ) plus low dose involved field irradiation ( limit to 1500-2500 cGY )
-goal of treatment: cure with maximum quality of life and minimal complication

Hodgkin's Disease in HIV patient

-HIV does not increase risk of HD but tend to present in more advanced stage, systemic symptom and unusual pattern of involvement


Acute complication : skin reaction, occipital hair loss, sore throat, N/V, dry cough, transient dysphagia from RTesophagitis, altered sense of taste

Late complication :
-Radiation Pneumonitis
-Cardiac Complication
-Neurologic Complication
-Subclinical hypothyroidism
-Herpes Zoster Infection

Fig.5 A. Chest x-ray film of a 20 year-old male with massive nodular sclerosis Hodgkin's disease, stage IIAe.
        B. Chest x-ray film at 10 years after radical radiation 4000 rads in 9 weeks with 2 splits to the entire left hemithorax with an additional 1000 rads to residual mass.Patient developed progressive dyspnea on exertion. An unsuccessful attempt was made to resect the left lung, which was encased in fibrous tissue.Thoracoplasty was only slight helpful. Patient is able to work, but has shortness of breath with mild exertion.

       - Kanjana Shotelersuk, MD
       - Radiation Oncology Division
       - Department of Radiology
       - Chulalongkorn Hospital


1. Cox JD : Lymphoma and Leukemia In: James D. Cox, Moss Radiation Oncology seventh edition : Missouri, Mosby, 1994 ; 795-826
2. Hoppe RT, Glatstein E, Wasserman TH : Hodgkin's Disease In : Carlos A.Perez,Luther W. Brady, Principle and Practice of Radiation Oncology second edition :Philadelphia, J.B. Lippincott Company, 1992 ; 1307-28
3. Lymphomas In : Jane Dobbs, Ann Barrett, Daniel Ash, Practical Raidotherapy Planning second edition : Great Britain, Edward Arnold, 1991 ; 174-83
4. Million RR : The Lymphomatous Diseases In : Gilbert H. Fletcher, Textbook of Radiotherapy : Philadelphia, LEA & FEBIGER ; 584-636
5. Rosenberg SA : Modern combined modality management of Hodgkin's Disease, Current Opinion in Oncology 1994,6 ; 470-2
6. The hematopoietic and lymphoid system In: Kumar V, Cotran RS, Robbins SL, Basic Pathology fifth edition : USA, W.B. Saunders, 1992 ; 333-84
7. Tumor Registry Statistical Report 1992, Faculty of Medicine, Chulalongkorn Univeristy and Chulalongkorn Hospital, The Thai Red Cross Society, Bangkok, Thailand