Pretreatment Staging
        Subclassification of stage
        Stage I
        Stage II
        Stage III
        Stage IV
Early Chemotherapy Response Assessment
End of Chemotherapy Re-evaluation

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.

Stage is a critical determinant in the selection of treatment. Initial evaluation of the child with Hodgkin lymphoma includes history, physical examination, anatomic imaging (including chest x-ray; computed tomographic [CT] scan of chest, abdomen, and pelvis; functional imaging including positron emission tomography [PET] scan),[1-3] 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).[4] PET scans are reliable in assessing bone involvement. Stage is determined by anatomic evidence of disease by CT scanning in conjunction with functional imaging. A suspected anatomic lesion which is PET-negative should not be considered involved unless biopsy-proven. Areas of PET positivity, which do not correspond to an anatomic lesion, (by clinical examination or CT scan) should be disregarded in staging. Functional imaging (Fluorodeoxyglucose [FDG]-PET scan) is sensitive in determining initial sites of involvement, particularly in the neck and mediastinum. PET scanning may be particularly useful in demonstrating unsuspected areas of involvement in the spleen and bone. 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] FDG-PET is now the recommended functional imaging procedure for initial staging.[5,6]

Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation.[7-10] 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. In cases where general anesthesia may pose a risk, a CT or ultrasound-guided core needle biopsy should be considered. This procedure can frequently be carried out using light sedation and local anesthesia. 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 [11] and revised in 1989.[12]

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.

Early response assessment can be based on volume reduction of disease, functional imaging status, or both. Significant reduction in disease volume and PET negativity at an early stage (after one or two cycles of chemotherapy) is associated with a favorable outcome. Use of early response assessment to alter therapy remains investigational. In the current Children's Oncology Group (COG) intermediate-risk Hodgkin lymphoma trial, only anatomic reduction in disease is used for stratification into rapid and slow responder groups. In the trial which will follow, functional imaging will be used to determine response.

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 greater than a 70% to 80% reduction of disease and a change from initial positivity to negativity on either gallium or PET scanning.[13] 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.

There is a growing consensus that PET scanning is more accurate than gallium scanning in detecting viable Hodgkin lymphoma in posttherapy residual masses.[1,14] 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.[15] 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.[3] Currently, PET 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.[16-19]

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. 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. 
   
   
3. 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]
   
   
4. 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]
   
   
5. Hudson MM, Krasin MJ, Kaste SC: PET imaging in pediatric Hodgkin's lymphoma. Pediatr Radiol 34 (3): 190-8, 2004.  [PUBMED Abstract]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. Prakash UB, Abel MD, Hubmayr RD: Mediastinal mass and tracheal obstruction during general anesthesia. Mayo Clin Proc 63 (10): 1004-11, 1988.  [PUBMED Abstract]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. 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]
    
    

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