Diagnosis and Staging
Establishing the Diagnosis of Hodgkin Lymphoma
Ann Arbor Staging Classification for Hodgkin Lymphoma
Interim response assessment
End of chemotherapy response assessment
Staging and evaluation of disease status is undertaken at diagnosis and performed again early in the course of chemotherapy and at the end of chemotherapy.Pretreatment Staging
- Detailed history of systemic symptoms.
- Physical examination.
- Laboratory studies.
- Anatomic imaging including chest x-ray and computed tomography (CT) scan of the neck, chest, abdomen, and pelvis.
- Functional imaging including positron emission tomography (PET) scan.
The following three specific constitutional symptoms (B symptoms) correlate with prognosis and are considered in assignment of stage:
- Unexplained fever with temperatures above 38.0°C orally.
- Unexplained weight loss of 10% within the 6 months preceding diagnosis.
- Drenching night sweats.
Additional Hodgkin-associated constitutional symptoms without prognostic significance include the following:
- Alcohol-induced nodal pain.
- All node-bearing areas, including the Waldeyer ring, should be assessed by careful physical examination.
- Enlarged nodes should be measured to establish a baseline for evaluation of therapy response.
- Hematological and chemical blood parameters show nonspecific changes that may correlate with disease extent.
- Abnormalities of peripheral blood counts may include neutrophilic leukocytosis, lymphopenia, eosinophilia, and monocytosis.
- Acute-phase reactants such as the erythrocyte sedimentation rate and C-reactive protein, if abnormal at diagnosis, may be useful in follow-up evaluation.
Anatomic information from CT is complemented by PET functional imaging, which is sensitive in determining initial sites of involvement, particularly sites too small to be considered abnormal by CT criteria.Definition of bulky disease
The posteroanterior chest radiograph remains important since the criterion for bulky mediastinal lymphadenopathy used in North American protocols is defined by the ratio of the diameter of the mediastinal lymph node mass to the maximal diameter of the rib cage on an upright chest radiograph; a ratio of 33% or higher is considered bulky. This definition is no longer used in some European protocols because it does not influence risk classification.
The criteria for bulky peripheral (nonmediastinal) lymphadenopathy have varied per cooperative group study protocols from aggregate nodal masses exceeding 4 to 6 cm. This disease characteristic has not been consistently used among all groups for risk stratification.Criteria for lymphomatous involvement by CT
Defining strict CT size criteria for the establishment of lymphomatous nodal involvement is complicated by a number of factors, such as overlap between benign reactive hyperplasia and malignant lymphadenopathy and obliquity of node orientation to the scan plane. Additional difficulties more specific to children include greater variability of normal nodal size with body region and age and the frequent occurrence of reactive hyperplasia.
General concepts to consider in regard to defining lymphomatous involvement by CT include the following:
- Contiguous nodal clustering or matting is highly suggestive of lymphomatous involvement.
- Any focal mass lesion large enough to characterize in a visceral organ is considered lymphomatous involvement unless the imaging characteristics indicate an alternative etiology.
- North American protocols have used a consistent size criteria: A measurable lesion by CT is defined as one that can be accurately measured in two orthogonal dimensions, which typically requires a lesion at least 1 cm in diameter for extranodal sites; lymph nodes are considered abnormal if the long axis is 1.5 cm or greater or between 1.1 cm and 1.5 cm with a short axis of at least 1.0 cm.
- Criteria for nodal involvement may vary by cooperative group or protocol. For example, in the Society for Paediatric Oncology and Haematology (Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH]) completed study (GPOH-HD-2002), nodal involvement was defined if the node was greater than 2 cm in largest diameter. The node was not involved if it was less than 1 cm and was considered questionably involved if it was between 1 cm and 2 cm. Involvement decision was then based on all further clinical evidence available.
The recommended functional imaging procedure for initial staging is now PET.[4,5] In PET scanning, uptake of the radioactive glucose analog, 18-fluoro-2-deoxyglucose (FDG) correlates with proliferative activity in tumors undergoing anaerobic glycolysis. PET-CT, which integrates functional and anatomic tumor characteristics, is often used for staging and monitoring of pediatric patients with Hodgkin lymphoma. Residual or persistent FDG avidity has been correlated with prognosis and the need for additional therapy in posttreatment evaluation.[6-9]
General concepts to consider in regard to defining lymphomatous involvement by FDG-PET include the following:
- Concordance between PET and CT data is generally high for nodal regions, but may be significantly lower for extranodal sites. In one study specifically analyzing pediatric Hodgkin lymphoma patients, assessment of initial staging comparing PET and CT data demonstrated concordance of approximately 86% overall. Concordance rates were significantly lower for the spleen, lung nodules, bone/bone marrow, and pleural and pericardial effusions.
- Integration of data acquired from PET scans can lead to significant changes in staging. In the previously mentioned study, PET findings resulted in a change in staging in 50% of patients (with a nearly equal number of patients up- and down-staged), and subsequent adjustments in involved-field radiation therapy treatment volumes in 70% of patients (more likely an addition rather than exclusion).
- Staging criteria using PET and CT scan information is protocol dependent, but generally areas of PET positivity that do not correspond to an anatomic lesion by clinical examination or CT scan size criteria should be disregarded in staging.
- A suspected anatomic lesion which is PET-negative should not be considered involved unless proven by biopsy.
FDG-PET has limitations in the pediatric setting. Tracer avidity may be seen in a variety of nonmalignant conditions including thymic rebound commonly observed after completion of lymphoma therapy. FDG-avidity in normal tissues, for example, brown fat of cervical musculature, may confound interpretation of the presence of nodal involvement by lymphoma.Establishing the Diagnosis of Hodgkin Lymphoma
After a careful physiologic and radiographic evaluation of the patient, the least invasive procedure should be used to establish the diagnosis of lymphoma.
Key issues to consider in choosing the diagnostic approach include the following:
- If possible, the diagnosis should be established by biopsy of one or more peripheral lymph nodes. Aspiration cytology alone is not recommended because of the lack of stromal tissue, the small number of cells present in the specimen, and the difficulty of classifying Hodgkin lymphoma into one of the subtypes.
- An image-guided biopsy may be used to obtain diagnostic tissue from intra-thoracic or intra-abdominal lymph nodes. Based on the involved sites of disease, alternative noninvasive procedures that may be considered include thoracoscopy, mediastinoscopy, and laparoscopy. Thoracotomy or laparotomy is rarely needed to access diagnostic tissue.
- Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation. After careful planning with anesthesia, peripheral lymph node biopsy or image-guided core-needle biopsy of mediastinal lymph nodes may be feasible using light sedation and local anesthesia before proceeding to more invasive procedures. Care should be taken to keep patients out of a supine position. Most procedures, including CT scans, can be done with the patient on his or her side or prone.
- If airway compromise precludes the performance of a diagnostic operative procedure, preoperative treatment with steroids or localized radiation therapy should be considered. Since preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risks associated with general anesthesia or heavy sedation are alleviated.
- Because bone marrow involvement is relatively rare in pediatric Hodgkin lymphoma patients, bilateral bone marrow biopsy should be performed only in patients with advanced disease (stage III or stage IV) and/or B symptoms.
Stage is determined by anatomic evidence of disease using CT scanning in conjunction with functional imaging. The staging classification used for Hodgkin lymphoma was adopted at the Ann Arbor Conference held in 1971  and revised in 1989. Staging is independent of the imaging modality used.Table 1. Ann Arbor Staging Classification for Hodgkin Lymphomaa
|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.|
|I||Involvement of a single lymphatic site (i.e., nodal region, Waldeyer's ring, thymus, or spleen) (I); or localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE).|
|II||Involvement of two or more lymph node regions on the same side of the diaphragm (II); or 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).|
|III||Involvement 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).|
|IV||Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement; or 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.|
|Designations applicable to any stage|
|B||Fever (temperature >38ºC), drenching night sweats, unexplained loss of >10% of body weight within the preceding 6 months.|
|E||Involvement of a single extranodal site that is contiguous or proximal to the known nodal site.|
Extralymphatic disease resulting from direct extension of an involved lymph node region is designated E. Extralymphatic disease can cause confusion in staging. For example, the designation E is not appropriate for cases of widespread disease or diffuse extralymphatic disease (e.g., large pleural effusion that is cytologically positive for Hodgkin lymphoma), which should be considered stage IV. If pathologic proof of noncontiguous involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed. Current practice is to assign a clinical stage on the basis of findings of the clinical evaluation; however, pathologic confirmation of noncontiguous extralymphatic involvement is strongly suggested for assignment to stage IV.Risk Stratification
After the diagnostic and staging evaluation data are acquired, patients are further classified into risk groups for the purposes of treatment planning. The classification of patients into low-, intermediate-, or high-risk categories varies considerably among the various pediatric research groups, and often even between different studies conducted by the same group, as summarized in Table 2.Table 2. Criteria Used for the Classification of Risk Groups in Childhood Hodgkin Lymphoma Clinical Trialsa
|Trial||Low Risk||Intermediate Risk||High Risk|
|Children's Oncology Group|
|AHOD0031 ||IA bulk or E; IB; IIA bulk or E; IIB; IIIA, IVA|
|AHOD0431 ||IA, IIA with no bulk|
|C5942 ||IA, IB, IIA with no bulk, no hilar nodes and <4 sites||IA, IB, IIA with bulk, hilar nodes or ≥4 sites; III||IV|
|C59704 ||IIB/IIIB with bulk, IV|
|P9425/P9426 ||IA, IIA with no bulk||IB, IIA, IIIA1 with bulk; IIIA2||IIB, IIIB, IV|
|GPOH-HD 95; GPOH-HD 2002; PHL-C1 [3,22,23]||1A/B, IIA||IEA/B;IIEA; IIB; IIIA||IIEB; IIIEA/B; IIIB; IV|
|Stanford/St. Jude/Dana-Farber Cancer Institute Consortium|
|HOD05||IB, IIIA, IA/IIA with E, ≥3 sites or bulk|
|HOD08||IA, IIA with no bulk, E and <3 sites|
|HOD99||IIB, IIIB, IV|
|E = extralymphatic.|
|aAdapted from Kelly.|
Although all major research groups classify patients according to clinical criteria, such as stage and presence of B symptoms, extranodal involvement, or bulky disease, comparison of outcomes across trials is further complicated because of differences in how these individual criteria are defined.Response Assessment
Further refinement of risk classification may be performed through assessment of response after initial cycles of chemotherapy or at its completion.Interim response assessment
The interim response to initial therapy, which may be assessed on the basis of volume reduction of disease, functional imaging status, or both, is an important prognostic variable in both early- and advanced-stage pediatric Hodgkin lymphoma.[24,25] Definitions for interim response are variable and protocol specific, but can range from volume reductions of greater than 50% to the achievement of a complete response with a volume reduction of greater than 95% by anatomic imaging or resolution of FDG-PET avidity.[3,18,21]
The rapidity of response to early therapy has been used in risk stratification to tailor therapy in an effort to augment therapy in higher-risk patients or to reduce the late effects while maintaining efficacy.Results of selected trials using interim response to titrate therapy
- The Pediatric Oncology Group used a response-based therapy approach consisting of dose-dense ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide-prednisone, cyclophosphamide) for unfavorable advanced-stage patients in combination with 21 Gy involved-field radiation therapy (IFRT). The dose-dense approach permitted reduction in chemotherapy exposure in 63% of patients who achieved a rapid early response after three ABVE-PC cycles. Five-year event-free survival (EFS) was comparable for rapid early responders (86%; treated with three cycles of ABVE-PC) and slow early responders (83%; treated with five cycles of ABVE-PC) followed by 21 Gy IFRT.
- The Children's Cancer Group (CCG) (CCG-59704) evaluated response-adapted therapy featuring four cycles of the dose-intensive BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) regimen followed by a gender-tailored consolidation for pediatric patients with stage IIB, IIIB with bulky disease, and IV Hodgkin lymphoma. For rapid early responding girls, an additional four courses of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vinblastine) (without IFRT) was given in an effort to reduce breast cancer risk. Rapid early responding boys received two cycles of ABVD followed by IFRT. Slow early responders received four additional courses of BEACOPP and IFRT. Rapid early response (defined by resolution of B symptoms and >70% reduction in tumor volume) was achieved by 74% of patients after four BEACOPP cycles and 5-year EFS among the cohort was 94% (median follow-up, 6.3 years).
Restaging is carried out upon the completion of all planned initial chemotherapy and may be used to determine the need for consolidative radiation therapy. Key concepts to consider include the following:
- Defining complete response.
- Although complete response can be defined as absence of disease by clinical examination and/or imaging studies, complete response in Hodgkin lymphoma trials is often defined by a greater than 70% to 80% reduction of disease and a change from initial positivity to negativity on functional imaging. This definition is necessary in Hodgkin lymphoma because fibrotic residual disease is common, particularly in the mediastinum. In some studies, such patients are designated as having an unconfirmed complete response.
- The definition of complete response varies by protocol/cooperative group. GPOH studies use very stringent criteria of at least 95% reduction in tumor volume or less than 2 mL residual volume on CT. Consideration of this difference in complete response criteria compared with that used in North American protocols is an important consideration for the omission of radiation therapy, which is stipulated in GPOH trials among favorable-risk patients achieving these strict complete-response criteria.
- Timing of PET scanning after completing therapy.
- Timing of PET scanning after completing therapy is an important issue. For patients treated with chemotherapy alone, PET scanning should be performed a minimum of 3 weeks after the completion of therapy, while patients whose last treatment modality was radiation therapy should not undergo PET scanning until 8 to 12 weeks postradiation.
- Use of anatomic and functional imaging to assess response.
- Response assessment using anatomic and functional imaging appears to be superior to that of anatomic imaging alone.
- A review of the revised International Workshop Criteria comparing Hodgkin lymphoma response evaluation by CT imaging alone or CT together with PET imaging demonstrated that the combination of CT and PET imaging was more accurate than CT imaging alone.[27,28] While the International Harmonization for assessment of FDG-PET response has been attempted in adults, it has yet to be evaluated in pediatric populations.[29,30]
- A Children's Oncology Group study evaluated surveillance CT and detection of relapse in intermediate-stage and advanced-stage Hodgkin lymphoma. The majority of relapses occurred within the first year after therapy or were detected based on symptoms, laboratory, or physical findings. The method of detection of late relapse, whether by imaging or clinical change, did not affect overall survival. Routine use of CT at the intervals used in this study did not improve outcome. The concept of reduced frequency of imaging was supported by a review of imaging studies on 99 patients from a single institution.
- Caution should be used in making the diagnosis of relapsed or refractory disease based solely on anatomic and functional imaging because false-positive results are not uncommon.[33-37] Consequently, pathologic confirmation of refractory/recurrent disease is recommended before modification of therapeutic plans.
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- Friedberg JW, Canellos GP, Neuberg D, et al.: A prospective, blinded comparison of positron emission tomography (PET) with gallium/SPECT scintigraphy in the staging and follow-up of patients (pts) with de novo Hodgkin's disease. [Abstract] Leuk Lymphoma 42 (Suppl 1): P-123, 64, 2001.
- Mauz-Körholz C, Hasenclever D, Dörffel W, et al.: Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: the GPOH-HD-2002 study. J Clin Oncol 28 (23): 3680-6, 2010. [PUBMED Abstract]
- Hudson MM, Krasin MJ, Kaste SC: PET imaging in pediatric Hodgkin's lymphoma. Pediatr Radiol 34 (3): 190-8, 2004. [PUBMED Abstract]
- Hernandez-Pampaloni M, Takalkar A, Yu JQ, et al.: F-18 FDG-PET imaging and correlation with CT in staging and follow-up of pediatric lymphomas. Pediatr Radiol 36 (6): 524-31, 2006. [PUBMED Abstract]
- Naumann R, Vaic A, Beuthien-Baumann B, et al.: Prognostic value of positron emission tomography in the evaluation of post-treatment residual mass in patients with Hodgkin's disease and non-Hodgkin's lymphoma. Br J Haematol 115 (4): 793-800, 2001. [PUBMED Abstract]
- Hutchings M, Loft A, Hansen M, et al.: FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107 (1): 52-9, 2006. [PUBMED Abstract]
- Lopci E, Burnelli R, Guerra L, et al.: Postchemotherapy PET evaluation correlates with patient outcome in paediatric Hodgkin's disease. Eur J Nucl Med Mol Imaging 38 (9): 1620-7, 2011. [PUBMED Abstract]
- Sucak GT, Özkurt ZN, Suyani E, et al.: Early post-transplantation positron emission tomography in patients with Hodgkin lymphoma is an independent prognostic factor with an impact on overall survival. Ann Hematol 90 (11): 1329-36, 2011. [PUBMED Abstract]
- Robertson VL, Anderson CS, Keller FG, et al.: Role of FDG-PET in the definition of involved-field radiation therapy and management for pediatric Hodgkin's lymphoma. Int J Radiat Oncol Biol Phys 80 (2): 324-32, 2011. [PUBMED Abstract]
- Anghelescu DL, Burgoyne LL, Liu T, et al.: Clinical and diagnostic imaging findings predict anesthetic complications in children presenting with malignant mediastinal masses. Paediatr Anaesth 17 (11): 1090-8, 2007. [PUBMED Abstract]
- Simpson CD, Gao J, Fernandez CV, et al.: Routine bone marrow examination in the initial evaluation of paediatric Hodgkin lymphoma: the Canadian perspective. Br J Haematol 141 (6): 820-6, 2008. [PUBMED Abstract]
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- 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]
- Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010.
- Kelly KM: Management of children with high-risk Hodgkin lymphoma. Br J Haematol 157 (1): 3-13, 2012. [PUBMED Abstract]
- Friedman DI, Wolden S, Constine L, et al.: AHOD0031: A phase III study of dose intensive therapy for intermediate risk Hodgkin lymphoma: a report from the Children’s Oncology Group. [Abstract] Blood 116 (22): A-766, 2010.
- Keller FG, Nachman J, Constine L: A phase III study for the treatment of children and adolescents with newly diagnosed low risk Hodgkin lymphoma (HL). [Abstract] Blood 116 (21): A-767, 2010.
- Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002. [PUBMED Abstract]
- Kelly KM, Sposto R, Hutchinson R, et al.: BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: a report from the Children's Oncology Group. Blood 117 (9): 2596-603, 2011. [PUBMED Abstract]
- Schwartz CL, Constine LS, Villaluna D, et al.: A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 114 (10): 2051-9, 2009. [PUBMED Abstract]
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