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Adult Hodgkin Lymphoma Treatment (PDQ®)

Health Professional Version
Last Modified: 02/28/2014

Stage Information for Adult Hodgkin Lymphoma

Clinical staging for patients with Hodgkin lymphoma (HL) includes a history, physical examination, laboratory studies (including sedimentation rate), and thoracic and abdominal/pelvic computerized tomographic (CT) scans.[1]

Positron emission tomography (PET) scans, usually combined with CT scans, have replaced gallium scans and lymphangiography for clinical staging.[2-4] A prospective, multinational study of 260 newly diagnosed patients with HL obtained PET scans at baseline and after two cycles (four doses) of ABVD (doxorubicin plus bleomycin plus vinblastine plus dacarbazine); with a median follow-up of 2.2 years, the 2-year progression-free survival was 12.8% with a positive PET scan after two cycles and 95% with a negative PET scan after two cycles (P < .0001).[5] In a prospective trial of BEACOPP-based therapy—which includes the drugs bleomycin, etoposide, doxorubicin hydrochloride, cyclophosphamide, vincristine sulfate, procarbazine, and prednisone— for previously untreated patients with advanced-stage HL, patients with residual abnormalities measuring 2.5 cm or more received a PET scan at the end of therapy.[6] A negative PET scan predicted no progression or relapse within 1 year for 94% of patients (confidence interval, 91%–97%). Whether consolidation with radiation therapy can be omitted for PET-negative patients must await overall survival data at 5 years. Only further prospective studies that compare a PET response–adapted strategy versus standard therapy without alteration can assess whether improved outcomes can be achieved by altering the therapeutic strategy based on PET scan results.[7,8]

Bone marrow involvement occurs in 5% of patients; biopsy may be indicated in the presence of constitutional B symptoms or anemia, leukopenia, or thrombocytopenia. In a retrospective review of 454 patients, no patients with a positive bone marrow biopsy had only stage I or II disease on PET-CT scans; omission of the bone marrow biopsy for PET-CT–designated early-stage patients did not change treatment selection.[9] Staging laparotomy is no longer recommended; it should be considered only when the results will allow substantial reduction in treatment. It should not be done in patients who require chemotherapy. If the laparotomy is required for treatment decisions, the risks of potential morbidity should be considered.[10-13] The staging classification that is currently used for HL was adopted in 1971 at the Ann Arbor Conference [14] with some modifications 18 years later from the Cotswolds meeting.[1]

Subclassification of stage

Stages I, II, III, and IV adult HL can be subclassified into A and B categories: B for those with defined general symptoms and A for those without B symptoms. The B designation is given to patients with any of the following symptoms:

  • Unexplained loss of more than 10% of body weight in the 6 months before diagnosis.
  • Unexplained fever with temperatures above 38°C.
  • Drenching night sweats. (Refer to the PDQ summary on Fever, Sweats, and Hot Flashes for more information.)

 [Note: The most significant B symptoms are fevers and weight loss. Night sweats alone do not confer an adverse prognosis. Pruritus as a systemic symptom remains controversial and is not considered a B symptom in the Ann Arbor staging system. (Refer to the PDQ summary on Pruritus for more information.) This symptom is hard to define quantitatively and uniformly, but when it is recurrent, generalized, and otherwise unexplained, and when it ebbs and flows parallel to disease activity, it may be the equivalent of a B symptom.]

The designation E is used when well-localized extranodal lymphoid malignancies arise in or extend to tissues beyond, but near, the major lymphatic aggregates. Stage IV refers to disease that is diffusely spread throughout an extranodal site, such as the liver. If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.

Table 1. Notations for Identifying Sites
N = nodesH = liverL = lungM = bone marrow
S = spleenP = pleuraO = boneD = skin

Current practice is to assign a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on the findings of invasive procedures.

For example, a patient who has disease in the chest and neck, systemic symptoms, and a negative lymphangiogram might be found at laparotomy to have involvement of the spleen, liver, and bone marrow. Thus, the precise stage of such a patient would be CS IIB, PS IVB (S+)(H+)(M+).

The American Joint Committee on Cancer (AJCC) has designated staging using the Ann Arbor classification system to define adult Hodgkin lymphoma.[15]

Table 2. Anatomic Stage/Prognostic Groupsa
Stage Prognostic Groups 
aReprinted with permission from AJCC: Hodgkin and non-Hodgkin lymphomas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 607-11.
IInvolvement of a single lymphatic site (i.e., nodal region, Waldeyer ring, thymus or spleen) (I).
Localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE) (rare in Hodgkin lymphoma).
IIInvolvement of ≥2 lymph node regions on the same side of the diaphragm (II).
Localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with or without involvement of other lymph node regions on the same side of the diaphragm (IIE).
The number of regions involved may be indicated by an arabic numeral, as in, for example, II3.
IIIInvolvement of lymph node regions on both sides of the diaphragm (III), which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE, S).
Splenic involvement is designated by the letter S.
IVDiffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement.
Isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s).
Stage IV includes any involvement of the liver or bone marrow, lungs (other than by direct extension from another site), or cerebrospinal fluid.

Massive mediastinal disease has been defined by the Cotswolds meeting as a thoracic ratio of maximum transverse mass diameter of 33% or more of the internal transverse thoracic diameter measured at the T5/6 intervertebral disc level on chest radiography.[1] Some investigators have designated a lymph node mass measuring 10 cm or more in greatest dimension as massive disease.[16] Other investigators use a measurement of the maximum width of the mediastinal mass divided by the maximum intrathoracic diameter.[17]

Many investigators and many new clinical trials employ a clinical staging system that divides patients into four major groups that are also useful for the practicing physician:[18]

  • Early favorable: Clinical stage I or II without any risk factors.

  • Early unfavorable: Clinical stage I or II with one or more of the following risk factors:
    • Large mediastinal mass (>33% of the thoracic width on the chest x-ray, ≥10 cm on CT scan).
    • Extranodal involvement.
    • Elevated erythrocyte sedimentation rate (>30 mm/h for B stage, >50 mm/h for A stage).
    • Three or more lymph node areas' involvement.
    • B symptoms.

  • Advanced favorable: Clinical stage III or IV with zero to three adverse risk factors listed below. Patients with advanced favorable disease have a 60% to 80% freedom-from-progression at 5 years from treatment with first-line chemotherapy.[19][Level of evidence: 3iiiDiii]

  • Advanced unfavorable: Clinical stage III or IV with four or more adverse risk factors listed below.[19] Patients with advanced unfavorable disease showed a 42% to 51% freedom-from-progression at 5 years from treatment with first-line chemotherapy.[19][Level of evidence: 3iiiDiii]. For patients with advanced-stage HL, the International Prognostic Factors Project has developed an International Prognostic Index with a prognostic score that is based on the following seven adverse factors:[19]
    • Albumin level of <4.0 g/dL.
    • Hemoglobin level of <10.5 g/dL.
    • Male sex.
    • Age of ≥45 years.
    • Stage IV disease.
    • White blood cell (WBC) count of ≥15,000/mm3.
    • Absolute lymphocytic count of <600/mm3 or a lymphocyte count that was <8% of the total WBC count.

References
  1. Lister TA, Crowther D, Sutcliffe SB, et al.: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 7 (11): 1630-6, 1989.  [PUBMED Abstract]

  2. Jerusalem G, Beguin Y, Fassotte MF, et al.: Whole-body positron emission tomography using 18F-fluorodeoxyglucose compared to standard procedures for staging patients with Hodgkin's disease. Haematologica 86 (3): 266-73, 2001.  [PUBMED Abstract]

  3. Naumann R, Beuthien-Baumann B, Reiss A, et al.: Substantial impact of FDG PET imaging on the therapy decision in patients with early-stage Hodgkin's lymphoma. Br J Cancer 90 (3): 620-5, 2004.  [PUBMED Abstract]

  4. Munker R, Glass J, Griffeth LK, et al.: Contribution of PET imaging to the initial staging and prognosis of patients with Hodgkin's disease. Ann Oncol 15 (11): 1699-704, 2004.  [PUBMED Abstract]

  5. Gallamini A, Hutchings M, Rigacci L, et al.: 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 25 (24): 3746-52, 2007.  [PUBMED Abstract]

  6. Kobe C, Dietlein M, Franklin J, et al.: Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin lymphoma. Blood 112 (10): 3989-94, 2008.  [PUBMED Abstract]

  7. Terasawa T, Lau J, Bardet S, et al.: Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin's lymphoma and diffuse large B-cell lymphoma: a systematic review. J Clin Oncol 27 (11): 1906-14, 2009.  [PUBMED Abstract]

  8. Gallamini A, Kostakoglu L: Interim FDG-PET in Hodgkin lymphoma: a compass for a safe navigation in clinical trials? Blood 120 (25): 4913-20, 2012.  [PUBMED Abstract]

  9. El-Galaly TC, d'Amore F, Mylam KJ, et al.: Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography-staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol 30 (36): 4508-14, 2012.  [PUBMED Abstract]

  10. Urba WJ, Longo DL: Hodgkin's disease. N Engl J Med 326 (10): 678-87, 1992.  [PUBMED Abstract]

  11. Sombeck MD, Mendenhall NP, Kaude JV, et al.: Correlation of lymphangiography, computed tomography, and laparotomy in the staging of Hodgkin's disease. Int J Radiat Oncol Biol Phys 25 (3): 425-9, 1993.  [PUBMED Abstract]

  12. Mauch P, Larson D, Osteen R, et al.: Prognostic factors for positive surgical staging in patients with Hodgkin's disease. J Clin Oncol 8 (2): 257-65, 1990.  [PUBMED Abstract]

  13. Dietrich PY, Henry-Amar M, Cosset JM, et al.: Second primary cancers in patients continuously disease-free from Hodgkin's disease: a protective role for the spleen? Blood 84 (4): 1209-15, 1994.  [PUBMED Abstract]

  14. Carbone PP, Kaplan HS, Musshoff K, et al.: Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 31 (11): 1860-1, 1971.  [PUBMED Abstract]

  15. Hodgkin and non-Hodgkin lymphomas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 607-11. 

  16. Bradley AJ, Carrington BM, Lawrance JA, et al.: Assessment and significance of mediastinal bulk in Hodgkin's disease: comparison between computed tomography and chest radiography. J Clin Oncol 17 (8): 2493-8, 1999.  [PUBMED Abstract]

  17. Mauch P, Goodman R, Hellman S: The significance of mediastinal involvement in early stage Hodgkin's disease. Cancer 42 (3): 1039-45, 1978.  [PUBMED Abstract]

  18. Jost LM, Stahel RA; ESMO Guidelines Task Force: ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of Hodgkin's disease. Ann Oncol 16 (Suppl 1): i54-5, 2005.  [PUBMED Abstract]

  19. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 339 (21): 1506-14, 1998.  [PUBMED Abstract]