Although the exact aetiology of HL has not yet been elucidated, patients infected with the Epstein-Barr virus (more common in the mixed cellularity and lymphocyte depleted subtypes) as well as those living with autoimmune and immunosuppressive diseases are at an increased risk.²

Patients living with HIV are at high risk of several types of cancer collectively called ‘non-AIDS defining cancers’. Apart from HL, patients living with HIV are also at higher risk of anus, liver, oral cavity/pharynx, and lung cancer. Patients living with HIV commonly present with a more advanced HL stage, unusual lymph nodes sites, and have a poor prognosis.^2,3

Studies also found there is a ten-fold increase of developing HL in same-sex siblings of patients with HL, suggesting a gene-environment interaction role in predisposition.²

Incidence of Hodgins lymphoma in South Africa

Classic HL (cHL) is more common in young adults, whereas mixed cellularity HL tends to affect older adults. The incidence of cHL subtypes is as follows:²

• Nodular sclerosis classical HL (70%)
• Mixed cellularity classical HL (25%)
• Lymphocyte-rich classical HL (5%)
• Lymphocyte-depleted classical HL (<1%)
• Nodular lymphocyte-predominant HL (5%).

According to a 2023 report by Statistics South Africa, HL is more common in younger men, compared to older men, and women. In 2019, HL accounted for 9.2% of diagnoses in men ≤20-years. In men between 20- to 29-years, HL accounted 6.6% of diagnoses and 6.2% in women. It should be noted that in this age cohort, HL accounted for 4.8% of all deaths in men due to cancer.³

The incidence of HL also varies by race. In the United States, White and Black individuals have equal incidences (3.1 cases per 100 000 males), while locally, Black individuals have at least three-fold increased risk compared to the other ethnic groups.¹

What are the symptoms of Hodgkin lymphoma and how it is diagnosed?

The most common presentation is enlarged lymph nodes, which increase in size over a period of several months and are usually painless. The three most common sites of disease presentation include the mediastinum,  or lcervical (neck) nodal enlargement , seen in about 60% of patients (not mutually exclusive). Other sites of enlarged nodes include axillary, abdominal, hilar or inguino-femoral in descending order of frequency. The spleen is also commonly involved. ⁴

In patients with advanced or bulky disease (tumour mass exceeding 10cm) symptoms such as fevers, chills, night sweats or unexplained weight loss >10% of body weight are common. These patients have a poorer prognosis.⁴

Severe unremitting pruritus without obvious skin pathology on exam can be resistant to topical and systemic agents and can be an early clue to the presence of clinically occult HL. Excisional biopsy of the involved node (or less commonly an involved extra-nodal site or bone) is recommended to establish a definitive diagnosis.⁴

Role of PET/CT in the management of Hodgkin’s lymphoma

Treatment of HL depends on the histologic characteristics of the disease, the stage of the disease, and the presence or absence of prognostic factors. The goal of treatment is to cure the disease with control of short- and long-term complications. The modified Ann Arbor system is the most used for staging. The system divides the disease into four stages (see Table 1).²

Chemotherapy (ChT) and radiotherapy (RT) are the mainstays of treatment for cHL. Before the advent of combination chemotherapy, cHL was fatal, with a five-year survival rate of <10%. However, advances in understanding the biology of the disease and improvement in modalities of ChT and RT have led to significant improvements in survival.⁴

The five-year relative survival for patients diagnosed with cHL at <19-years is 96.4%, and 89.8% for those diagnosed between the ages of 20- to 64 -years. This means that cHL is now considered a highly curable malignancy.

The outlook for patients with cHL is very good, and with early diagnosis and treatment, most patients can achieve long-term remission.⁴

International guidelines recommended 18-fluoro-2-deoxy-D-glucose (¹⁸FDG) PET-CT for routine staging. The advantage of performing the staging scan is that it increases the accuracy of response assessment following treatment.

This is particularly important to determine whether the patient has partial metabolic response, no metabolic response, or progressive metabolic disease by comparing the intensity of residual glucose analogue fluorodeoxyglucose (FDG) uptake with the pre-therapy tumour uptake.^2,5,6,7

Mid-treatment scanning, also known as iPET-CT, is a method of monitoring the response of lymphoma patients to treatment. It involves using PET to measure the uptake of FDG by tumor cells.⁵

Studies have shown that a rapid decline in FDG uptake during iPET-CT is predictive of an excellent prognosis. Conversely, patients with persistent FDG uptake have an inferior prognosis.⁵

In patients with HL, iPET-CT has been shown to be an accurate predictor of progression-free survival (PFS). PFS rates of around 85%-90% have been reported in patients with HL who have a good response on iPET-CT.⁵

However, the predictive accuracy of iPET-CT has decreased in recent years, due to improved treatment outcomes in patients treated with rituximab and better supportive care. Despite this, PET/CT remains superior to CT assessment in the setting of mid-treatment imaging. This is because PET/CT can provide more accurate information about the location and extent of disease, as well as the response to treatment.⁵

Overall, iPET-CT scanning is a valuable tool for monitoring the response of lymphoma patients to treatment. It can help to identify patients who are not responding to treatment and who may need to have their therapy modified.⁵

To assess response to treatment, guidelines recommend using a 5-point scale, the so-called Deauville criteria. The scale ranges from 1 to 5, where 1 is best and 5 is the worst. Each FDG-avid (or previously FDG-avid) lesion is rated independently (see Table 2).⁷

What does the CMS recommend?

The CMS recommends the following:¹

• Once the diagnosis of cHL is confirmed, the disease should be staged using a PET-CT scan to be able to determine the Ann Arbor stage of the disease. FDG PET-CT has very high sensitivity and specificity in HL
• The use of a PET-CT for response assessment after two cycles of ChT is a good prognostic indicator in patients with early disease. For patients with advanced disease (stage III-IV), interim response assessment with PET should be conducted after two to four cycles of ChT depending on the regimen used.
• A diagnostic contrast-enhanced CT scan of the neck, chest and the abdomen are PMB level of care (if a PET-CT scan is unavailable).
• PET-CT scans are PMB level of care for staging, interim assessments and follow-up surveillance.
• A bone marrow biopsy is PMB level of care.
• Chest x-ray is PMB level of care for HL.
• Electrocardiogramand echocardiogram are PMB level of care and should also be performed prior to receiving ChT.

REFERENCES

1. Council for Medical Schemes. PMB Benefit Definition Guideline: Hodgkin Lymphoma Version 2. December 2022. [Internet]. Available at: https://www.medicalschemes.co.za/wpfd_file/pmb-benefit-definition-guideline-for-hodgkins-lymphoma/
2. Kaseb H, Babiker HM. Hodgkin Lymphoma. [Updated 2022 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK499969/
3. Statistics South Africa. Cancer in South Africa (2008 – 2019). 2023. [Internet]. Available at: https://www.statssa.gov.za/publications/03-08-00/03-08-002023.pdf
4. Shanbhag S, Ambinder RF. Hodgkin lymphoma: A review and update on recent progress. CA Cancer J Clin,
5. Barrington SF, Kirkwood AA, Franceschetto A, et al. PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study. Blood, 2016.
6. Al-Ibraam A, Mottaghy FM, Juweid ME, et al. PET/CT in Hodgkin Lymphoma: An Update. Seminars in Nuclear Medicine, 2023.
7. Pfleger R, Worsley C, Bell D, et al. Deauville five-point scale. Reference article, Radiopaedia.org (Accessed on 21 Jul 2023) https://doi.org/10.53347/rID-32555.
8. Vangu MDT, Momodu JI. Imaging Lymphoma With F-18 Fluorodeoxyglucose PET-CT: What Should Be Known About Normal Variants, Pitfalls, and Artifacts? Front. Nucl Med, 2022.