Hodgkin Lymphoma

Todd M. Blodgett, MD

Alex Ryan, MD

Barry McCook, MD

Key Facts

Terminology

Hodgkin lymphoma (HL); Hodgkin disease (HD)

Imaging Findings

FDG PET/CT: Enlarged, hypermetabolic lymph nodes
PET/CT or PET + CT (side-by-side) is superior to contrast CT or PET alone for staging HD
Ga-67 inferior to FDG PET for initial staging
CECT can help evaluate cortical bone involvement but has low sensitivity in detecting bone marrow disease
Pooled true positive value of PET for HL 90% with upstaging rate ranging from 8-17% and downstaging rate from 2-23%
PET has prognostic value after 1-3 cycles of chemotherapy
After 2-3 cycles of chemo, PET-positive group had 39% 5 year survival vs. PET-negative group at 92%
For tumor response to therapy, low-dose CT PET/CT may be enough
PET has significant influence on staging of HL, upstaging 15-25% of patients with shift to more advanced treatment in 10% of patients
SUV reduction of 60% is used as cutoff to separate treatment responders from nonresponders

Top Differential Diagnoses

Granulomatous Process
Infections
Other Malignancy
Normal Lymphoid Tissue
Reactive Lymph Nodes

Graphic demonstrates a typical appearance of Hodgkin lymphoma in the anterior mediastinum as a fairly homogeneous mass

, typically with low attenuation on CT.

Coronal PET (A), axial CT (B) and fused PET/CT (C) demonstrate an anterior mediastinal mass

with intense FDG activity, compatible with Hodgkin lymphoma.

TERMINOLOGY

Abbreviations and Synonyms

Hodgkin lymphoma (HL)
Hodgkin disease (HD)
Lymph nodes (LN)

Definitions

Malignant neoplasm arising from lymphocytes
Rare variety is derived from histiocytes

IMAGING FINDINGS

General Features

Best diagnostic clue
- FDG PET/CT
  - Enlarged FDG-avid lymph nodes/conglomerate mass
  - In usual location: Anterior mediastinum with other nodal groups
- CT
  - Mediastinal lymphadenopathy presenting as mediastinal mass
  - ± Hepatomegaly, splenomegaly, lung nodules/infiltrates, pleural effusions
Location
- Uncommon spread to extralymphatic locations
  - CNS, spine
- Usual spread is to contiguous lymph nodes
  - Then to viscera or bone marrow
- 30-40% of patients present with splenic involvement
- 5-14% of patients have bone marrow involvement
- Bone involvement
  - Primary bone invasion does not affect staging; rare (1-4%) at presentation
  - Hematogenous spread indicates stage IV disease
  - Stage IV occurs in 5-20% of patients during disease course
- 6% of patients have chest wall involvement
  - Requires more aggressive therapy due to higher relapse rate
- Thymic involvement considered “nodal”
  - Does not count as extranodal disease
  - Not associated with change in disease stage
  - Up to half of patients with thoracic HL may show enlarged thymus
  - Present after successful treatment as a result of rebound thymic hyperplasia
  - Occasionally develop thymic cysts
- Rare locations
  - Peritoneal and omental involvement found only in non-Hodgkin lymphoma
  - Renal parenchyma is rarely involved, although perirenal space may be invaded
  - GI tract uncommon and usually due to nodal extension
Morphology
- Rounded or bulky soft tissue mass due to nodal aggregation
- Large masses may have areas of necrosis, hemorrhage, or cyst formation

Imaging Recommendations

Best imaging tool
- PET/CT
  - Best for staging HD (sensitivity 94-98% and specificity 95-100%)
- MR
  - To delineate soft tissue margins and evaluate spinal cord impingement
Protocol advice
- Baseline FDG PET images should be obtained for initial staging
  - Prior to treatment
- Patient should be kept warm and avoid activity prior to scan
  - Reduces physiologic uptake in muscle and fat
- Low dose CT is acceptable for evaluating response to therapy

CT Findings

CT has replaced more complicated invasive diagnostic procedures
- Method of choice for identification of disease invisible on clinical exam
- Rarely performed anymore: Laparotomy/splenectomy, lymphangiography, and mediastinoscopy
Lymphadenopathy
- Lymph node enlargement and aggregation
  - Appearance of multiple round or bulky soft tissue masses
- Large masses may develop necrosis, hemorrhage, or cyst formation (10-20%)
- Minimal contrast enhancement
- Calcification rare before treatment but 20% prevalence post-radiotherapy
  - Rim calcification
  - Multiple discrete deposits (mulberry)
- CT useful for treatment/radiation planning
Extralymphatic involvement
- Mediastinal structures may show displacement, compression, or invasion
- Cortical bone well evaluated with CT
- Poor sensitivity for bone marrow disease
- Invasion of gallbladder and pancreas usually from adjacent nodal disease
  - Absence of pancreatic capsule hinders diagnosis of invasion vs. contact
- Thymic mass may be discrete or infiltrating
Therapy response
- Tumor masses have low density of malignant cells
- Reduction in volume of lesion is an insensitive predictor of response

Nuclear Medicine Findings

Initial diagnosis
- Involved lymphoid tissue generally shows increased FDG uptake
  - No differentiation of subtypes by SUV has been demonstrated
- Focal, super-physiologic uptake in nodal or extranodal tissue fairly specific indicator of disease
  - Diffuse uptake more difficult to interpret
  - Awareness of common FDG PET false positives is essential
- Uptake may be seen in spleen and liver
  - Focal increased FDG activity generally indicative of malignant involvement
Staging
- For organ staging, PET/CT seems to have no obvious advantage over FDG PET alone
  - Except in reducing false positives by better characterization of lesions using CT
- Pooled true positive rate of FDG PET for HL: 90%
  - Upstaging rate: 8-25%
  - Shift to more advanced treatment: 10%
  - Downstaging: 2-23% (mean less than for upstaging)
  - FDG PET inclusion criteria are more accurate than CT inclusion criteria
  - Size is an insensitive indicator of malignancy
  - Enhancement characteristics are unreliable for inclusion
  - Combined PET/CT is superior for lesion delineation in radiotherapy planning
- Bone marrow involvement
  - Diffuse marrow involvement may be intense
  - May also be indistinguishable from background
  - May be misinterpreted as negative for disease with diffuse marrow activity
  - Increased uptake can be iatrogenic
  - G-CSF, erythropoietin
  - Beta-thalassemia also increases uptake
  - Bone marrow biopsy (BMB) and PET/CT are complementary
  - Similar sensitivity/specificity but discordant findings
  - BMB more sensitive for detection of diffuse disease
  - PET/CT more likely to detect patchy disease
- Spleen and liver
  - Full dose diagnostic CT necessary for adequate evaluation of liver and spleen
  - Splenic involvement may appear as diffusely increased uptake
  - Also seen in “reactive” spleen
  - Liver involvement may appear as diffuse uptake or patchy uptake in portal areas
  - Less commonly as large focal lesions
- Response to therapy
- SUV reduction of 60% is used as cutoff to separate treatment responders from nonresponders
- PET has prognostic value after chemotherapy: 5 year survival after 2-3 cycles of chemo
  - 92% for PET-negative group
  - 39% for PET-positive group
- 2 year progression-free survival after 2 cycles of ABVD-like chemo
  - 94% for PET-negative patients
  - 0-6% for early PET-positive patients
- Study showed no evidence that patients benefit from treatment alteration based on early PET
  - Patients with PET-negative residual mass after chemo who received radiotherapy to original bulky site had 2.5% relapse rate within 18 months vs. 14% relapse in non-radiotherapy arm
  - In contrast, the International Prognostic Index (IPS) poorly predicts improved survival

DIFFERENTIAL DIAGNOSIS

Granulomatous Process

Active disease positive on FDG PET
Infectious and non-infectious etiologies
Will usually resolve over time
More likely bilateral hilar and paratracheal distribution

Infections

Pyogenic, fungal, parasitic, HIV-related, viral (e.g., varicella, zoster, HCV, CMV)
Usually positive on FDG PET

Other Malignancy

Variable enhancement and FDG uptake
History is crucial

Normal Lymphoid Tissue

Physiologic uptake common in Waldeyer ring, thymic tissue, cervical nodes
Asymmetric uptake can occur normally and may be mistaken for malignancy

Reactive Lymph Nodes

Usually much smaller than typical aggressive Hodgkin

PATHOLOGY

General Features

Genetics
- 1% of patients with HD have family history of disease
- Sibling of affected individual has 3-7x increased risk
  - Higher in monozygotic twins
- HLA-DP alleles more common in HD
Etiology
- Unknown
- Infection may be involved in pathogenesis, particularly Epstein-Barr virus (EBV)
  - Tumor cells are EBV-positive in ˜ 50% of HD cases
  - Positivity higher in MCHD (60-70%) than in NSHD (15-30%)
  - ˜ 100% of HIV-related HD are EBV-positive (though HD is not an AIDS-defining condition)
Epidemiology
- 8,000 new cases and 1,000 deaths occur in the USA annually
- Incidence: 3-4/100,000 per year

Gross Pathologic & Surgical Features

Cut surface white-gray and uniform
Affected LN
- Usually enlarged
- Shape is preserved
- Capsule is not invaded
- Surface may be nodular in nodular sclerosis subtype

Microscopic Features

Prominent lymphocytic infiltrate and Reed-Sternberg cells
- Reed-Sternberg cells: Large, binucleate, with characteristic CD15+, CD30+ immunophenotype
Core biopsy preferred over fine needle aspiration
- Malignant cells in HL make up only a very small, scattered proportion of the tumor volume
- Subtyping requires core biopsy
- Tumors pleomorphic
Bone marrow disease is often patchy and focal resulting in low sensitivity of bone marrow biopsy
- If positive on PET, directed biopsy of that area increases true positive yield