Subclassification of Stage
Stage I
Stage II
Stage III
Stage IV
End of Chemotherapy Re-evaluation
Current Clinical Trials

Stage is a critical determinant in the selection of treatment. Evaluation of the child with Hodgkin lymphoma includes history, physical examination, anatomic imaging (including chest x-rays; computed tomographic [CT] scans of chest, abdomen, and pelvis; functional imaging including gallium scan and/or positron emission tomography [PET] scan),[1-4] and laboratory studies. The posteroanterior and lateral chest radiograph remains important since the criterion for bulky mediastinal lymphadenopathy is defined by the ratio of the measurement of the mediastinal lymph nodes to the maximal measurement of the chest cavity on an upright chest radiograph; mediastinal ratios 33% or higher are considered bulky. CT scans help delineate the status of intrathoracic lymph node groups (including the hila and cardiophrenic angle), lung parenchyma, pericardium, pleura, and the chest wall, demonstrating abnormalities in about one-half of patients with unremarkable chest radiographs. Definition of disease involvement of intrathoracic tissues by CT will often dictate more aggressive therapy than would otherwise have been administered. Distinguishing normal (or hyperplastic) thymus from nodes in children can be problematic. Bone marrow biopsy should be performed in patients with advanced disease (stage III or stage IV) and/or symptoms (fever, weight loss, or night sweats).[5] Bone scans are performed in patients with bone pain or elevated alkaline phosphatase. In the past, lymphangiograms were commonly used to evaluate involvement of the abdominal lymph nodes in patients with Hodgkin lymphoma; however, more false-positives occur in children than in adults, and the studies are technically more difficult to perform.[6] Lymphangiography is no longer used in the staging of children. Gallium scanning is sensitive in determining initial sites of involvement, particularly in the neck and mediastinum. It is also helpful in determining whether residual mass lesions in the chest following chemotherapy represent active disease or scarring.[7] Fluorodeoxyglucose (FDG)-PET has advantages over gallium-67 because the scan is a 1-day procedure with higher resolution, better dosimetry, and less intestinal activity.[1,2,8] FDG-PET is now the recommended functional imaging procedure for initial staging and to evaluate therapy response, though gallium scan remains an acceptable alternative.[9,10] FDG-PET detects more disease sites above and below the diaphragm on staging compared to gallium scan and may have particular utility in the evaluation of the spleen.[11]

A negative posttherapy PET scan is predictive for continuing remission; however, there is a significant incidence of false-positive or equivocal PET scans following completion of treatment.[12,13] In addition, following a negative end-of-therapy PET scan, a subsequent positive PET scan has poor predictive value.[14] When standard-dose radiation therapy was an acceptable treatment strategy for patients with early-stage Hodgkin lymphoma, exploratory laparotomy with splenectomy was performed to determine the presence and extent of abdominal involvement. There is generally no role for staging laparotomies in the current treatment of pediatric Hodgkin lymphoma patients.

Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation.[15-18] Although this is less likely to be problematic in Hodgkin lymphoma than in non-Hodgkin lymphoma, appropriate planning of the surgical approach is essential. After a careful physiologic and radiographic evaluation of the patient has been carried out, the least invasive procedure should be used to establish the diagnosis of lymphoma. If at all possible, the diagnosis should be established by lymph node biopsy. 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. When the diagnostic procedures described above are not fruitful, a CT or ultrasound-guided core needle biopsy should be considered. This procedure can frequently be carried out using light sedation and local anesthesia, before more invasive procedures are undertaken. If a significant pleural effusion is present, thoracentesis should be considered, though cytologic diagnosis is rarely made in Hodgkin lymphoma. Mediastinoscopy, anterior mediastinotomy, or thoracoscopy are the procedures of choice when other diagnostic modalities fail to establish the diagnosis. A formal thoracotomy is rarely indicated for the diagnosis of Hodgkin lymphoma. If a diagnostic operative procedure cannot be performed because of the risk of general anesthesia or heavy sedation and if needle biopsy is not feasible, then preoperative treatment with localized radiation therapy should be considered. Because preoperative treatment may hinder an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risks of general anesthesia or heavy sedation are thought to be alleviated.

The staging classification currently used for Hodgkin lymphoma was adopted at the Ann Arbor Conference held in 1971 [19] and revised in 1989.[20]

Hodgkin lymphoma can be subclassified into A and B categories: A is for those patients who are asymptomatic, and B is for those patients with any of the following specific symptoms:

• Unexplained loss of more than 10% of body weight in the 6 months before diagnosis.



• Unexplained fever with temperatures above 38° C for more than 3 days.



• Drenching night sweats.

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.

Involvement of a single lymph node region or, in the case of stage I(E), direct extension from that node to an adjacent extralymphatic region.

Involvement of two or more lymph node regions (number to be stated) on the same side of the diaphragm, or extension from any one of these lymph nodes to an extralymphatic adjacent organ, or stage II(E).

Involvement of lymph node regions on both sides of the diaphragm, which may also be accompanied by extension to an adjacent extralymphatic organ, [stage III(E)], involvement of the spleen [stage III(S+)], or both [stage III(E+S)].

Noncontiguous involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement.

Restaging is carried out at the end of chemotherapy. The purpose of restaging is to assess the degree of response to initial chemotherapy. 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 more than a 70% to 80% reduction of disease and a change from initial positivity to negativity on either gallium or PET scanning.[21,22] This definition is necessary in Hodgkin lymphoma because fibrotic residual is common, particularly in the mediastinum. In some studies such patients are designated as having an unconfirmed complete response.

Recently, many centers have switched functional imaging from gallium to PET scanning.[1,2,8] There is a growing consensus from adult studies that PET scanning may identify more sites of initial disease than gallium scans, and that PET scanning is more accurate than gallium scanning in detecting viable Hodgkin lymphoma in posttherapy residual masses. 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 post therapy completion. For patients whose last treatment modality was radiation therapy, PET scanning should be performed 8 to 12 weeks post radiation.[23] A study testing the sensitivity and specificity of conventional imaging (CT or magnetic resonance imaging) and PET scans in children with Hodgkin lymphoma showed that side-by-side comparison or image fusion could improve the staging accuracy over either modality alone. [4] Currently, either PET or gallium scanning is acceptable; however, caution should be used in making the diagnosis of relapsed disease based solely on imaging because false-positive results are not uncommon.[12-14,24]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Hueltenschmidt B, Sautter-Bihl ML, Lang O, et al.: Whole body positron emission tomography in the treatment of Hodgkin disease. Cancer 91 (2): 302-10, 2001.  [PUBMED Abstract]
   
   
2. Wiedmann E, Baican B, Hertel A, et al.: Positron emission tomography (PET) for staging and evaluation of response to treatment in patients with Hodgkin's disease. Leuk Lymphoma 34 (5-6): 545-51, 1999.  [PUBMED Abstract]
   
   
3. 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. 
   
   
4. Furth C, Denecke T, Steffen I, et al.: Correlative imaging strategies implementing CT, MRI, and PET for staging of childhood Hodgkin disease. J Pediatr Hematol Oncol 28 (8): 501-12, 2006.  [PUBMED Abstract]
   
   
5. Mahoney DH Jr, Schreuders LC, Gresik MV, et al.: Role of staging bone marrow examination in children with Hodgkin disease. Med Pediatr Oncol 30 (3): 175-7, 1998.  [PUBMED Abstract]
   
   
6. Dudgeon DL, Kelly R, Ghory MJ, et al.: The efficacy of lymphangiography in the staging of pediatric Hodgkin's disease. J Pediatr Surg 21(3): 233-235, 1986. 
   
   
7. Castellani MR, Cefalo G, Terenziani M, et al.: Gallium scan in adolescents and children with Hodgkin's disease (HD). Treatment response assessment and prognostic value. Q J Nucl Med 47 (1): 22-30, 2003.  [PUBMED Abstract]
   
   
8. Bangerter M, Moog F, Buchmann I, et al.: Whole-body 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for accurate staging of Hodgkin's disease. Ann Oncol 9 (10): 1117-22, 1998.  [PUBMED Abstract]
   
   
9. Hudson MM, Krasin MJ, Kaste SC: PET imaging in pediatric Hodgkin's lymphoma. Pediatr Radiol 34 (3): 190-8, 2004.  [PUBMED Abstract]
   
   
10. 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]
    
    
11. Friedberg JW, Fischman A, Neuberg D, et al.: FDG-PET is superior to gallium scintigraphy in staging and more sensitive in the follow-up of patients with de novo Hodgkin lymphoma: a blinded comparison. Leuk Lymphoma 45 (1): 85-92, 2004.  [PUBMED Abstract]
    
    
12. Rhodes MM, Delbeke D, Whitlock JA, et al.: Utility of FDG-PET/CT in follow-up of children treated for Hodgkin and non-Hodgkin lymphoma. J Pediatr Hematol Oncol 28 (5): 300-6, 2006.  [PUBMED Abstract]
    
    
13. Levine JM, Weiner M, Kelly KM: Routine use of PET scans after completion of therapy in pediatric Hodgkin disease results in a high false positive rate. J Pediatr Hematol Oncol 28 (11): 711-4, 2006.  [PUBMED Abstract]
    
    
14. Meany HJ, Gidvani VK, Minniti CP: Utility of PET scans to predict disease relapse in pediatric patients with Hodgkin lymphoma. Pediatr Blood Cancer 48 (4): 399-402, 2007.  [PUBMED Abstract]
    
    
15. Azizkhan RG, Dudgeon DL, Buck JR, et al.: Life-threatening airway obstruction as a complication to the management of mediastinal masses in children. J Pediatr Surg 20 (6): 816-22, 1985.  [PUBMED Abstract]
    
    
16. King DR, Patrick LE, Ginn-Pease ME, et al.: Pulmonary function is compromised in children with mediastinal lymphoma. J Pediatr Surg 32 (2): 294-9; discussion 299-300, 1997.  [PUBMED Abstract]
    
    
17. Shamberger RC, Holzman RS, Griscom NT, et al.: Prospective evaluation by computed tomography and pulmonary function tests of children with mediastinal masses. Surgery 118 (3): 468-71, 1995.  [PUBMED Abstract]
    
    
18. Prakash UB, Abel MD, Hubmayr RD: Mediastinal mass and tracheal obstruction during general anesthesia. Mayo Clin Proc 63 (10): 1004-11, 1988.  [PUBMED Abstract]
    
    
19. 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]
    
    
20. 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]
    
    
21. Brisse H, Pacquement H, Burdairon E, et al.: Outcome of residual mediastinal masses of thoracic lymphomas in children: impact on management and radiological follow-up strategy. Pediatr Radiol 28 (6): 444-50, 1998.  [PUBMED Abstract]
    
    
22. Weihrauch MR, Re D, Scheidhauer K, et al.: Thoracic positron emission tomography using 18F-fluorodeoxyglucose for the evaluation of residual mediastinal Hodgkin disease. Blood 98 (10): 2930-4, 2001.  [PUBMED Abstract]
    
    
23. Juweid ME, Stroobants S, Hoekstra OS, et al.: Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25 (5): 571-8, 2007.  [PUBMED Abstract]
    
    
24. Nasr A, Stulberg J, Weitzman S, et al.: Assessment of residual posttreatment masses in Hodgkin's disease and the need for biopsy in children. J Pediatr Surg 41 (5): 972-4, 2006.  [PUBMED Abstract]
    
    

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