Hospital Medicine

Hodgkins Lymphoma

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Hodgkins Lymphoma

I. What every physician needs to know.

Hodgkin lymphoma (HL) is a malignant proliferation of B lymphoid cells that contain Reed-Sternberg (RS) cells, which are typically scarce in number and seen in a background of nonmalignant, reactive cells. The disease is subcategorized according to the pattern of RS cell type (classical or lobulated "popcorn" cells in NLPHL) and the pattern of the cellular background.

The two main types are classic HL (composed of nodular sclerosis, mixed cellular, lymphocyte-rich, and lymphocyte-depletion subtypes) and nodular lymphocyte predominance HL. The disease typically begins in a single group of lymph nodes before moving on to other nodes in a predictable contiguous pattern, before finally becoming more aggressive, invading vessels and organs.

Hodgkin lymphoma remains highly curable (80% of all cases) with well-established treatment regimens consisting of chemotherapy and radiotherapy. Confirmation of this diagnosis should prompt rapid referral to an appropriate hematologist/oncologist provider.

II. Diagnostic Confirmation: Are you sure your patient has hodgkins lymphoma?

Biopsy is the required for confirmation of diagnosis. In an effort to maintain node architecture, excisional biopsy should be pursued. If lymph nodes are deep-seated, core needle biopsy may be helpful, but it may not provide definitive diagnosis.

A. History Part I: Pattern Recognition:

Patients usually present with non-tender, movable peripheral lymphadenopathy (particularly cervical, supraclavicular, or axillary), in young adults. Symptoms of mass-effect from nodes, mediastinal mass, or organ involvement may be present. Patients can describe B symptoms:

- fevers > 38 C, characteristically occurring at erratic intervals for days or weeks

- drenching night sweats

- loss of more than 10% body weight within the prior six months

B. History Part 2: Prevalence:

HL accounts for approximately 10% of all lymphomas and less than 1% of all cancers in the US yearly. HL has a bimodal peak in incidence, with the higher pear in the third decade and the smaller peak after the age of 50. Men have a significantly higher incidence than women for all HL subtypes. It occurs more frequently in those of European ancestry. There is evidence for genetic predisposition as well as viral association, particularly Epstein-Barr Virus (EBV). Patients with immunosuppressive conditions such as HIV or having received organ transplant are 10 times more likely to develop HL than the general population.

C. History Part 3: Competing diagnoses that can mimic hodgkins lymphoma.

Lymphadenopathy and B symptoms can be caused by a litany of infectious and malignant etiologies. EBV/CMV infections in particular should be strongly considered and work up should be pursued prior to biopsy. Numerous other lymphoid malignancies can also mimic HL including non-Hodgkin’s lymphoma, myeloma, and other aggressive lymphomas such as Burkitt’s lymphoma. Patients with HL often describe a waxing and waning course of symptoms and enlarged nodes, further confounding diagnosis. Biopsy therefore is required to confirm diagnosis.

D. Physical Examination Findings.

Patients usually present with enlarged firm, non-tender lymph nodes, often in the cervical, supraclavicular or axillary areas. Examine for splenomegaly, which is present in about a fourth of patients at presentation. Attention should be given to jugular venous pressure (JVP) and to facial or upper extremity edema in consideration of obstruction of the superior vena cava.

B symptoms, which include fever, night sweats, and weight loss (see above) can signify worse prognosis. Symptoms of dyspnea, cough, pruritis, fatigue, or pain after drinking alcohol may also be present.

Focal neurologic symptoms or pain may suggest epidural invasion, a rare presentation.

E. What diagnostic tests should be performed?

Because architecture is essential in diagnosis, excisional biopsy of the largest palpable lymph node is required. If lymph nodes are deep-seated, core needle biopsy may be helpful, but may not provide definitive diagnosis. Surgery should be consulted to perform an excisional biopsy. Cervical lymph nodes are preferable to inguinal nodes. Biopsy should be reviewed preferably by an experienced hematopathologist. Immunohistochemistry is also often necessary, particularly in the case of fine-needle or core biopsies. Fine-needle biopsies are strongly discouraged given need for evaluation of nodal architecture.

Staging is largely clinical and radiographic, with various radiographic modalities used to determine the extent of disease.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

To quickly examine for infectious etiologies, EBV and CMV serologies should be checked. Viral load levels may also be useful if serologies are indeterminate. Labs may suggest extranodal involvement, including complete blood count (CBC) with differential and liver function tests. Erythrocyte sedimentation rate (ESR) and serum lactate dehydrogenase (LDH) are used in determining prognosis. Renal function, electrolytes, and uric acid may suggest tumor lysis and may affect chemotherapy dosing. Bone marrow biopsy and aspiration is necessary for staging in most cases, particularly in the setting of cytopenias and a negative PET-CT.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Computed tomography (CT) scans with contrast of the chest, abdomen, and pelvis are used for staging. Contrast is needed to better evaluate for lymphadenopathy. The ratio of mass-to-thorax on chest X-ray (CXR) helps determine "bulky disease," which is a poor prognostic feature. Positron emission tomography (PET) scan can be used to help detect disease not seen on conventional CT. PET scan can also aid in follow-up after chemotherapy in distinguishing residual fibrotic masses from persistent lymphoma.

Imaging results are interpreted using the Cotswolds Staging classification (a modification of the Ann Arbor classification), which is based on the number of lymphoid sites and their locations. Differentiation between lymph node and extralymphatic lymphoid structures is designated with an "E". In addition, each stage also gets a designation of A or B, depending on the presence (B) or absence (A) of B symptoms.

  • Stage I: Single lymph region or one extranodal site (IE).

  • Stage II: Two or more node regions on the same side of the diaphragm, or local extra lymphatic extension plus one or more lymph nodes on the same side of the diaphragm (IIE).

  • Stage III: Nodal regions of both sides of the diaphragm.

  • Stage IV: Dissemination to extra-lymphatic sites.

Echocardiogram or MUGA scan is needed to assess heart function prior to initiation of anthracycline. Pulmonary function tests, particularly vital capacity and DLCO, are needed before bleomycin chemotherapy.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Fine-needle aspiration of a lymph node is strongly discouraged as nodal architecture is key to establishing diagnosis.

III. Default Management.

Management involves a multidisciplinary team, including oncology, radiation oncology, and surgery. Treatment plan is determined by the stage of disease and presence of poor prognostic markers. The potential for cure calls for swift action. Therefore, staging work-up should be initiated immediately after diagnosis, along with assessment of organ function to enable prompt initiation of chemotherapy.

Early stage (I and II) HL is treated with two cycles of chemotherapy and involved-field radiation. Disease with associated B symptoms or advanced-stage disease is treated with six to eight cycles of chemotherapy, with or without radiation.

The standard chemotherapy regimen is ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). Other chemotherapy regimens include Stanford V (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone) or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone).

Consider referral for sperm-banking as well.

A. Immediate management.

Immediate management in HL is typically related to staging and coordination of outpatient care. Treatment of HL consists of radiation alone for select early stage patients, combined chemotherapy and radiation for other early stage disease, and chemotherapy alone for advanced disease.

B. Physical Examination Tips to Guide Management.

With bulky disease, monitoring for signs and symptoms of tumor lysis syndrome may be considered.

If facial edema, syncope, and elevated JVP are noted, consider superior vena cava syndrome, which requires steroids and possibly emergent radiotherapy.

Symptoms or signs of coronary artery disease, pericarditis, cardiomyopathy, valve abnormalities, or arrhythmias may suggest the cardiovascular complications of doxorubicin or mediastinal radiation.

Cough, dyspnea, inspiratory crackles, fever, or infiltrates can be manifestations of the pulmonary toxicities of radiation therapy or bleomycin, including pneumonitis and lung fibrosis.

Fever, chills, myalgias, may be a sign of medication toxicity or fever related to neutropenia, which can result in infection or sepsis.

Peripheral or autonomic neuropathy can be caused by chemotherapy. Acute paresthesias down dorsal extremities with neck flexion (Lhermitte's sign) can be a complication appearing within the first few months of mantle irradiation.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Uric acid, potassium, phosphate, and calcium, as well as creatinine, should be monitored during treatment. Monitor CBC to check for bone marrow suppression. Neutropenic fever should be treated accordingly. CXR and Pulmonary functional tests (PFTs) can be monitored before cycles of chemotherapy. PET scans are preferred for monitoring response to treatment, and will presumably be scheduled by the treating oncologist.

D. Long-term management.

ABVD chemotherapy is given on day 1 and 15 of a 28-day cycle. The number of cycles given depends upon stage and prognostic features. The dose of radiation and fields involved depend on location and stage of disease and will begin within a month of completion of chemotherapy when combined modality is used.

Follow-up after completion of therapy includes evaluation by the oncologist with labs and radiography every few months for the first few years.

E. Common Pitfalls and Side-Effects of Management

Radiation pneumonitis may occur 1-6 months after mantle irradiation, and radiation therapy may also lead to hypothyroidism in almost 1/3. While the risk is greatest in the first 5 years after treatment, new cases can occur up to 20 years later. Breast cancer incidence is also increased with mantle field irradiation, with the risk in women increasing to one in three.

Infertility is a more typically transient with the ABVD regimen than prior chemotherapy regimens, but may occur.

Pulmonary toxicity, including pulmonary fibrosis, alveolitis, and pneumonitis, can be a consequence of bleomycin or radiation therapy.

Treated patients may have a predisposition to coronary artery disease, although doxorubicin-related cardiotoxicity is uncommon, due to the low cumulative dose.

Acute leukemia most frequently occurs within the first 10 years of treatment. The risk was highest with the use of alkylating agents such as mechlorethamine and procarbazine, which were part of the MOPP regimen, and is lower with the ABVD regimen. The risk of acute leukemia at 10 years following therapy with ABVD is < 1%.

Intermediate or high-grade non-HL (NHL) occur as secondary process to treatment, or occasionally as transformation of the HL itself. Solid tumors occur at an increased rate in treated patients, without plateau over time. At a 15-year follow-up, the risk of second solid tumors is approximately 13%, at a 20-year follow-up, the risk if approximately 17%, and at a 25-year follow-up the risk is approximately 22%.

Lhermitte's sign may occur 6-18 weeks following mantle irradiation.

Herpes zoster is a common complication.

IV. Management with Co-Morbidities

A. Renal Insufficiency.

Dose adjustments of the chemotherapeutic regimen will be required. In addition, fluid balance compromise may make tumor lysis syndrome a prominent consideration.

B. Liver Insufficiency.

Dose adjustments of the chemotherapeutic regimen will be required.

C. Systolic and Diastolic Heart Failure

Alternative chemotherapy regimens or adjustments must be considered. Also, the patient with these comorbidities may be at increased risk for development of other heart conditions during therapy.

D. Coronary Artery Disease or Peripheral Vascular Disease

Antiplatelet and anticoagulant therapies may increase morbidity with thrombocytopenia resulting from therapy. Additionally, the accelerated CAD noted with treatment should be taken under advisement. Finally, hypertension is a common side effect of chemotherapy.

E. Diabetes or other Endocrine issues

Radiation may affect thyroid function.

F. Malignancy

Treatment increases the chance of future malignancy (see above).

G. Immunosuppression (HIV, chronic steroids, etc).

HIV positive patients more often present with advanced disease, with unusual sites of disease, and have a worse response to treatment. Management should include HAART, prophylaxis against opportunistic infections, and growth factor support.

H. Primary Lung Disease (COPD, Asthma, ILD)

Underlying lung disease may prevent the use of bleomycin.

I. Gastrointestinal or Nutrition Issues

Patients are likely to experience nausea or vomiting. Anti-emetics should be offered. Constipation from vinblastine requires prophylactic bowel regimen.

J. Hematologic or Coagulation Issues

Myelosuppression may lead to severe thrombocytopenia, anemia, and leukopenia. Chemotherapy may potentiate anticoagulants. G-CSF should be administered prophylactically to prevent neutropenia, maintain dose intensity, and prevent delayed cycles of chemotherapy. It should be given after discussion with patient’s oncologist.

K. Dementia or Psychiatric Illness/Treatment

Neuropathy, both sensory and autonomic, can be prominent in some treatment regimens. This may affect tolerability in patients who have pre-existing neuropathy. Also, drugs may interfere with some neurologic and neuroleptic agents, so dose modifications or alternate treatments may be considered.

V. Transitions of Care

A. Sign-out considerations while Hospitalized.

In all patients, and particularly those with a large tumor burden, arrhythmia or altered mental status should lead to repeating labs to check for tumor lysis syndrome, which requires emergent nephrology consult for hemodialysis.

B. Anticipated Length of Stay.

Patients can typically by discharged after diagnosis is confirmed, depending on availability of rapid follow-up.

C. When is the Patient Ready for Discharge.

With a diagnosis, decisions regarding staging work-up should be based on discussions with the oncologist who will be assuming care. Evaluation by surgery for indwelling line for chemotherapy should be considered. Discharge planning should be centered around the idea that HL is potentially curable.

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

Patients should be seen by an oncologist in clinic shortly after staging work-up, preferably within a matter of days. Close surgery follow-up for line placement may also be scheduled within a week. Radiation oncology should also evaluate the patient within a week, particularly for early stage disease.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

If initial oncology evaluation will be done as an outpatient, staging work-up, including CT of the chest, abdomen, and pelvis, PET scan, as well as CBC, LDH, ESR, and CMP are the appropriate baseline.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

CBC, BMP, and LFTs on the day of clinic visit.

E. Placement Considerations.

Patients with indwelling lines will require line care depending on the type of line and institution protocols.

F. Prognosis and Patient Counseling.

As in NHL, pathologic subtype carries prognostic significance. Lymphocyte-deplete pathologic subtype has poor prognosis, while lymphocyte-rich has a good prognosis. Nodular lymphocyte predominant has a good prognosis, but frequently relapses.

Unfavorable prognosis in early stage is associated with B symptoms, bulky disease, an ESR over 50, and more than three sites of disease. In advanced disease, the international prognostic score (IPI) notes age over 45, male gender, leukocytosis or lymphopenia, anemia, and low albumin as poor prognostic factors. Prognosis depends upon the number of factors, including, prominently, histologic subtype.

Generally, favorable early-stage HL may have cure rates over 90%. Advanced disease with 0 IPS has a 5-year progression-free survival of over 80%, but with additional poor-risk features declines to above 40% with all 5 features.

Hodgkin lymphoma is treated with a goal of cure.

VI. Patient Safety and Quality Measures

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

While DVT prophylaxis with low-molecular weight heraprin is preferred, decisions regarding DVT prophylaxis may be affected by cytopenias.

Tumor lysis prophylaxis should be considered in some circumstances.

Patients should be monitored for infections related to neutropenia.

Patients who receive splenic irradiation should receive appropriate vaccinations for encapsulated organisms.

What's the evidence?

Aleman, BMP, Raemaekers, JMM, Tirelli, U. "Involved field radiotherapy for advanced Hodgkin lymphoma". N Engl J Med. vol. 348. 2003. pp. 2396-2406.

Bhatia, S, Robison, LL, Oberlin, O. "Breast cancer and other second neoplasms after childhood Hodgkin disease". N Engl J Med. vol. 334. 1996. pp. 745-751.

Canellos, GP, Anderson, JR, Propert, KJ. "Chemotherapy of advanced Hodgkin disease with MOPP ABVD, or MOPP alternating with ABVD". N Engl J Med. vol. 327. 1992. pp. 1478-1484.

Diehl, V, Franklin, J, Pfreundschuh, M. "Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin disease [published correction appears in N Engl J Med. 2005;353:744]". N Engl J Med. vol. 348. 2003. pp. 2386-2395.

Engert, A, Pluetschow, A, Eich, HT. "Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma". N Engl J Med. vol. 363. 2010. pp. 640-652.

Federico, M, Bellei, M, Brice, P. "High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin lymphoma responding to front-line therapy". J Clin Oncol. vol. 21. 2003. pp. 2320-2325.

Gallamini, A, Hutchings, M, Rigacci, L. "Early interim 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study". J Clin Oncol. vol. 25. 2007. pp. 3746-3752.

Hasenclever, D, Diehl, V. "A prognostic score for advanced Hodgkin disease". N Engl J Med. vol. 339. 1998. pp. 1506-1514.

Horning, SJ, Hoppe, RT, Breslin, S, Bartlett, NL, Brown, BW, Rosenberg, SA. "Stanford V and radiotherapy for locally extensive and advanced Hodgkin disease: mature results of a prospective clinical trial". J Clin Oncol. vol. 20. 2002. pp. 630-637.

Meyer, RM, Gospodarowicz, MK, Connors, JM. "ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma". N Engl J Med. vol. 366. 2012. pp. 399-408.

Viviani, S, Zinzani, PL, Rambaldi, A. "ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned". N Engl J Med. vol. 365. 2011. pp. 203-212.

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