Hodgkin lymphoma

HODJKIN 2019

1. Hodgkin’s Lymphoma Dr. Shivaom Chaurasia Resident Internal Medicine

2. INTRODUCTION Hodgkin’s lymphoma (HL) is a malignancy of mature B lymphocytes. It represents ~10% of all lymphomas diagnosed each year. The majority of HL diagnoses are classical HL ( cHL ). It was named after Thomas Hodgkin who first described it in 1832. Dorothy Reed and Carl Sternberg first described the malignant cells of Hodgkin lymphoma called Reed Sternberg cells.

3. Classical HL is one of the success stories of modern oncology. Radiation therapy cured some patients with early stage disease, and the introduction of multi-agent chemotherapy in the 1970s resulted in further improved cure rates, both for patients with early and advanced stage disease. Cure rates now are >85%. The new challenge in the treatment of HL is late therapy-related toxicity, including a high rate of secondary malignancies and cardiovascular disease.

4. Natural history Hodgkin lymphoma arises in a single node or chain of nodes and spreads first to anatomically contiguous lymphoid tissue. Visceral involvement by hodgkin lymphoma may be secondary to extension from adjacent lymph nodes . Hematogenous spread occurs to liver or multiple bony sites. Mechanism of spleen involvement is unclear but all patients with hepatic and bone involvement are associated with splenic involvement.

5. What is the Lymphatic System? Made up of organs, such as the tonsils, spleen, liver, bone marrow and a network of lymphatic vessels that connect to lymph nodes Lymph nodes located throughout the body Lymph nodes filter foreign particles out of the lymphatic fluid Contain B and T lymphocytes Immature lymphocytes that travel to the thymus differentiate into T-Cells Immature lymphocytes that travel to the spleen or lymph nodes differentiate into B cells

6. pathogenesis

7. EPIDEMIOLOGY HL is of B-cell origin. Race: HL is more common in whites than in blacks and more common in males than in females . Age: A bimodal distribution of age at diagnosis has been observed, with one peak incidence occurring in patients in their twenties and the other in those in their eighties . Patients in the younger age groups diagnosed in the United States largely have the nodular sclerosing subtype of HL. Elderly patients, patients infected with HIV, and patients in Third World countries more commonly have mixed-cellularity HL or lymphocyte-depleted HL.

8. Reed-Sternberg (HRS) cells are the malignant cells in HL. Infection by HIV is a risk factor for developing HL. Viral oncogenesis appears to play a greater role in HIV-related cHL : EBV can be detected in nearly all cases of HIV-associated cHL , compared to only one-third of cases of non-HIV-associated cHL. HRS cells in HIV-associated cHL express the EBV-transforming protein latent membrane protein 1 (LMP-1), and the EBV genomes.

9. Histologically, the HRS cell is diagnostic of cHL These cells are large cells with abundant cytoplasm with bilobed and/or multiple nuclei .

10. RS cell and variants Popcorn cell Lacunar cell Classic RS cell (mixed cellularity) ( N odular sclerosis) ( L ymphocyte predominance)

11. By immunohistochemistry they are often PAX-5 positive but have low to no expression of other B-cell antigens like CD19 and CD20. They express CD15 and CD30 in 85 and 100% of cases, respectively. The HRS cell interacts with its microenvironment via cell-cell contact and elaboration of growth factors and cytokines, that protects it from host immune attack. The surrounding environmental cells likewise support the HRS cells via cell-cell signaling and cytokine production which provides signals that promote proliferation and survival of the HRS cell itself.

12. APPROACH TO THE PATIENT Evaluation of patients with HL will typically begin with a careful history and physical examination . Lymphadenopathy Most patients with cHL present with palpable lymphadenopathy that is nontender ; in most patients, these lymph nodes are in the neck, supraclavicular area, and axilla . More than half of the patients will have mediastinal adenopathy at diagnosis, and this is sometimes the initial manifestation. Subdiaphragmatic presentation of cHL is unusual and more common in older males.

13. One third of patients present with “B” symptoms Fever Occasionally, HL can present as a fever of unknown origin. This is more common in older patients who are found to have mixed-cellularity HL in an abdominal site. Rarely , the fevers persist for days to weeks, followed by afebrile intervals and then recurrence of the fever. This pattern is known as Pel-Ebstein fever . night sweats, and/or weight loss >10% of body weight in 6 months.

14. HL can occasionally present with unusual manifestations . These include severe and unexplained itching, cutaneous disorders such as erythema nodosum and ichthyosiform atrophy, paraneoplastic cerebellar degeneration and other distant effects on the CNS, nephrotic syndrome, immune hemolytic anemia and thrombocytopenia, hypercalcemia, and pain in lymph nodes on alcohol ingestion. Patients should be asked about the presence or absence of “B” symptoms. Comorbid diagnoses that may impact therapy should be reviewed, including a history of pulmonary disease and congestive heart failure given the use of chemotherapy drugs that can cause both lung and heart toxicity. A physical examination should pay attention to the peripherally accessible sites of lymph nodes and to the liver and spleen size.

15. Treatment of HL depends on the stage at presentation; investigations therefore aim not only to diagnose lymphoma but also to determine the extent of disease. FBC may be normal. If a normochromic, normocytic anaemia or lymphopenia is present , this is a poor prognostic factor. An eosinophilia or a neutrophilia may be present. ESR may be raised. Renal function tests are required to ensure function is normal prior to treatment. Liver function may be abnormal in the absence of disease or may reflect hepatic infiltration. An obstructive pattern may be caused by nodes at the porta hepatis . LDH measurements showing raised levels are an adverse prognostic factor. HIV and hepatitis virus testing. Laboratory evaluation

16. Imaging Chest X-ray may show a mediastinal mass . CT scan of chest, abdomen and pelvis permits staging. Bulky disease (> 10 cm in a single node mass) is an adverse prognostic feature. Positron emission tomography (PET) scanning identifies nodes involved with HL, which are 18fluorodeoxyglucose (FDG)-avid, and this allows more accurate staging and monitoring of response . Lymph node biopsy may be undertaken surgically or by percutaneous needle biopsy under radiological guidance

17. The differential diagnosis of a lymph node biopsy suspicious for HL includes inflammatory processes, mononucleosis, NHL, phenytoin-induced adenopathy , and nonlymphomatous malignancies. Staging for cHL is anatomically based given the propensity of the disease to march from one lymph node group to the next group, often contiguous to the first. Staging is important for selecting therapy of appropriate intensity, but the outcome of optimal therapy for all the stages is excellent.

18. Patients are stratified based on whether they have early stage, stage I or II, or advanced stage, stage III or IV, disease. Patients with early stage disease have a better prognosis overall but are further classified as favorable or unfavorable based on a variety of factors. These factors vary from study to study but include bulky disease, number of lymph node areas involved, an elevated ESR (>30 if B symptoms are present; >50 if B symptoms are absent), and age.

19. Management:

20. TREATMENT The overwhelming majority of patients with HL will be cured with either chemotherapy alone, or a combination of chemotherapy and radiation therapy. For early stage disease, however, treatment with combined modality therapy has been associated with a small decrease in risk of relapse but with an increased risk of late toxicity including secondary malignancies , thyroid disease, and premature cardiovascular disease and stroke resulting in minimal or no improvement in long-term survival . Much of this risk can be attributed to radiation therapy. Thus, investigation into the treatment of early stage HL at present is aimed at trying to maximize treatment outcome without using radiotherapy . This is an area of controversy in the treatment of HL.

21. EARLY STAGE DISEASE The most common chemotherapy regimen used to treat HL in the United States is ABVD ( adriamycin , bleomycin , vinblastine, and dacarbazine ). This regimen is given every other week, with each cycle including two treatments. In patients with low-risk, or favorable disease , the use of 4–6 cycles of ABVD alone, without radiation therapy , results in progression-free and overall survivals of 88–92% and 97–100% at 5–7 years. This may be associated with a slightly increased risk of relapse when compared with abbreviated chemotherapy (ABVD x4 cycles) followed by involved field radiation therapy (30 Gy ), but with no difference in overall survival owing to the excellent salvage strategies used for relapsed HL and to the late toxicities seen following radiation therapy to the chest. Finally, the use of an early interim PET/CT scan can aid decisions on the duration and extent of therapy.

22. For unfavorable risk disease, the omission of radiation therapy following chemotherapy is associated with a more significant increased risk of relapse compared to favorable risk disease, but again with no change in overall survival. For these patients, treatment options would include ABVD x 4 cycles followed by involved field radiation therapy or ABVD alone for 6 cycles. Combined modality therapy has typically been used for patients with bulky disease, although patients with bulky disease who have a negative PET/CT scan after chemotherapy may not benefit from additional radiation therapy. Alternative chemotherapy regimens to ABVD have been developed and include the Stanford V regimen and escalated BEACOPP. Neither of these regimens has resulted in improved outcomes inpatients with early stage disease.

23. ADVANCED STAGE DISEASE Patients with advanced stage disease do not benefit from the addition of radiation therapy after a complete response to chemotherapy alone and should be treated with chemotherapy alone. The most common regimen used in the United States is ABVD x6 cycles . Again, Stanford V and escalated BEACOPP have been evaluated in advanced stage disease and are not associated with an improvement in overall survival but are associated with increased toxicity. The small fraction of patients who do not achieve complete remission with chemotherapy alone (partial responders with persistent PET scan positivity account for <10% of patients) may benefit from the addition of involved field radiotherapy . Newer drugs- antibody drug conjugate brentuximab ( an antibody against CD30 conjugated to the microtubule inhibitor MMAE) pembrolizumab and nivolumab ( Drugs that target the PD-1/PD-L1 ) In case of relapse

24. RELAPSED DISEASE Patients who relapse after primary therapy of Hodgkin’s lymphoma can frequently still be cured . Patients who relapse after an effective chemotherapy regimen are usually not curable with subsequent chemotherapy administered at standard doses. For patients who respond completely or nearly so, autologous bone marrow transplantation can cure over half of patients. Standard salvage chemotherapy regimens include ICE ( ifosfamide , carboplatin, etoposide ) or GND (gemcitabine, navelbine , doxil ).

25. For patients with early stage disease who do not respond sufficiently to salvage chemotherapy, radiation therapy can be very effective to achieve a remission; whether to consolidate such a remission with an autologous stem cell transplant is debated. For patients with advanced stage disease in whom salvage chemotherapy fails, the antibody drug conjugate brentuximab vedotin , a CD30-directed antibody linked to the microtubule toxin MMAE, is active and can be tried as a bridge to allogeneic transplant. The anti-PD-1 immune checkpoint inhibitors, nivolumab and pembrolizumab , have efficacy in relapsed HL , and many responses are durable.

26. SURVIVORSHIP Because of the very high cure rate in patients with HL, long-term complications have become a major focus for clinical research. In fact, in some series of patients with early-stage disease, more patients died from late complications of therapy than from HL itself . This is particularly true in patients with localized disease. The most serious late side effects include second malignancies and cardiac injury . Patients are at risk for the development of acute leukemia in the first 10 years after treatment with combination chemotherapy regimens that contain alkylating agents plus radiation therapy . The risk of development of acute leukemia after treatment for HL is also related to the number of exposures to potentially leukemogenic agents (i.e ., multiple treatments after relapse) and the age of the patient being treated, with those aged >60 years at particularly high risk .

27. The development of carcinomas as a complication of treatment for HL is a major problem. ( ≥10 years after treatment) For this reason, young women treated with thoracic radiotherapy for HL should institute screening mammograms 5–10 years after treatment . Mediastinal radiation also accelerates coronary artery disease, and patients should be encouraged to minimize risk factors for coronary artery disease such as smoking and elevated cholesterol levels. Cervical radiation therapy increases the risk of carotid atherosclerosis and stroke and thyroid disease , including cancer.

28. Patients who receive thoracic radiotherapy are at very high risk for the eventual development of hypothyroidism. Lhermitte’s syndrome occurs in ~15% of patients who receive thoracic radiotherapy. This syndrome is manifested by an “electric shock” sensation into the lower extremities on flexion of the neck. Because of the young age at which HL is often diagnosed , infertility is a concern for patients undergoing treatment for HL.

29. Common Chemotoxicities

30. NODULAR LYMPHOCYTE-PREDOMINANT HODGKIN LYMPHOMA NLPHL is now recognized as an entity distinct from cHL. Previous classification systems recognized that biopsies from a small subset of patients diagnosed as having HL contained a predominance of small lymphocytes and rare Reed-Sternberg-like cells; tumors have a nodular growth pattern and a clinical course that varied from that of patients with cHL. This is an unusual clinical entity and represents <5 % of cases of HL and defines NLPHL . NLPHL has a number of characteristics that suggest its relationship to NHL, rather than cHL.

31. The HRS-like cell, or L&H (lymphocyte and histiocyte ) or “popcorn” cell, is a clonal proliferation of B cells that are positive for B cell markers CD45, CD79a, CD20, CD19, and BCL2. They do not express two markers normally found on HRS cells, CD30 and CD15. This lymphoma tends to have a chronic, relapsing course and sometimes transforms to diffuse large B-cell lymphoma.

32. More commonly male (75%). Like cHL , the age distribution of patients with this disease has two peaks, but unlike cHL these peaks include children and adults ages 30–40 years, respectively. The majority of patients diagnosed have stage I or II disease (75%), with a minority having advanced stage disease at diagnosis. B symptoms are uncommon.

33. Patients with early stage disease at diagnosis should be treated with definitive radiotherapy. This is associated with a 15-year non-relapse survival of 82%. The treatment of patients with advanced stage NLPHL is controversial. For patients who need therapy due to symptoms or signs of organ function impairment, both cHL regimens and B-cell NHL regimens have been used, including ABVD and R-CHOP. ( R)  rituximab (C )   cyclophosphamide (H)  doxorubicin hydrochloride (O )  vincristine ( P)  prednisolone

34. References Harrison’s Principles of Internal Medicine Twentieth Edition Davidsons Principles and Practice of Medicine 23rd ed

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