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Protocol for the examination of specimens from patients with Hodgkin’s disease

Archives of Pathology & Laboratory Medicine January 1, 1999 | Compton, Carolyn C; Ferry, Judith A; Ross, Dennis W This protocol is intended to assist pathologists in providing clinically useful and relevant information as a result of the examination of surgical specimens. Use of this protocol is intended to be entirely voluntary. If equally valid protocols or similar documents are applicable, the pathologist is, of course, free to follow those authorities. Indeed, the ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of the individual circumstances presented by a specific patient or specimen.

It should be understood that adherence to this protocol will not guarantee a successful result. Nevertheless, pathologists are urged to familiarize themselves with this document. Should a physician choose to deviate from the protocol owing to the circumstances of a particular patient or specimen, the physician is advised to make a contemporaneous written notation of the reason for the procedure followed.

The College recognizes that this document may be used by hospitals, attorneys, managed care organizations, insurance carriers, and other payers. However, the document was developed solely as a tool to assist pathologists in the diagnostic process by providing information that reflects the state of relevant medical knowledge at the time the protocol was first published. It was not developed for credentialing, litigation, or reimbursement purposes. The College cautions that any uses of the protocol for these purposes involve considerations that are beyond the scope of this document.

Intra-abdominal lymph nodes Lymph nodes of axilla or arm Lymph nodes of inguinal region or leg Pelvic lymph nodes Involvement of a given region may include involvement of more than 1 lymph node or lymph node group.

D: Special Studies.-Cytogenetic studies, flow cytometry, and HLA typing are not uniformly useful as prognostic indicators in Hodgkin’s disease. ‘6 However, special studies may be useful diagnostically. The main differential diagnosis in most cases of Hodgkiis disease is non-Hodgkin’s lymphoma. If necessary, immunohistochemical studies (immunophenotyping) and genetic studies (ie, gene rearrangement) should be performed to confirm the diagnosis and exclude non-Hodgkin’s lymphoma.” The typical immunophenotypes and genetic alterations associated with the specific histologic types of Hodgkin’s disease are listed in note E.

E: Histologic Type.-Histologic classification of Hodgkin’s disease should be based on sections of paraffin-embedded tissue stained with hematoxylin-eosin. Primary diagnosis of Hodgkin’s disease is rarely made by cytologic analysis; however, cytologic examinations may be useful in diagnosing relapse in patients with a history of Hodgkin’s disease. Hodgkin’s disease is traditionally categorized histologically by the Rye Classification, which recognizes 4 major histologic types. The Revised EuropeanAmerican Lymphoma (REAL) Classification of the International Lymphoma Study Group recognizes the 4 traditional types but has included a provisional category that is histologically distinct, ie, lymphocyte-rich classic Hodgkin’s disease. Both classifications are as follows. go to website hodgkin s disease

Rye Classification Lymphocyte predominance Nodular sclerosis Mixed cellularity Lymphocyte depletion Revised European-American Lymphoma Classification Lymphocytic predominance, nodular Nodular sclerosis Mixed cellularity Lymphocyte depletion Lymphocyte-rich classic Hodgkin’s disease (provisional category) In the current era of improved treatment with high rates of cure, the prognostic value of the histologic type of Hodgkin’s disease is limited. Formerly, mixed cellularity and lymphocyte depletion Hodgkin’s disease were assodated with increased risk of death from disease compared with nodular sclerosis and lymphocyte predominance. Currently, histologic type is of independent prognostic value only in clinical stage I and II disease treated with radiation therapy alone.’ The immunophenotypic characteristics and the genetic alterations that typify each of the subtypes of Hodgkin’s disease of the REAL Classification are as follows.

Immunophenotypes and Genetics (REAL Classification)ls H: Staging.-In general, TNM classification has not been used for staging the malignant lymphomas because the site of origin of the tumor is often uncertain, and there is no way to differentiate among T, N, and M. Thus, a special staging system (Ann Arbor System) is used for both Hodgkin’s disease and non-Hodgkin’s lymphoma. The Ann Arbor classification for lymphomas has been applied to Hodgkin’s lymphoma by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC), as shown below. Staging is based on the well-established knowledge that Hodgkin’s disease tends to spread in a contiguous fashion from one nodal chain to the next. The prognosis worsens with progressive spread of disease.l Pathologic staging depends on biopsy or resection of 1 or more regional lymph nodes, splenectomy, wedge and needle liver biopsies, bone marrow biopsy (optional in stages I and II), and biopsy of multiple lymph nodes on both sides of the diaphragm to assess distribution of disease. Clinical staging generally involves a combination of clinical, radiologic, and surgical procedures and includes medical history, physical examination, laboratory tests (eg, urinalysis, complete blood examination, and blood chemistry studies), imaging studies (eg, computed tomographic scans, magnetic resonance imaging studies, and nuclear medicine studies), and biopsy to determine diagnosis and histologic type of tumor (initial diagnosis is almost always made on biopsy).

There is general agreement that staging of Hodgkin’s disease is prognostically significant.l20 AJCC/UICC Staging for Hodgkin’s Disease Stage I Involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE)* Stage II Involvement of 2 or more lymph node regions on the same side of the diaphragm (II), or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes with or without other lymph node regions on the same side of the diaphragm (IIE)t Stage III Involvement of lymph node regions on both sides of the diaphragm (III) that may be accompanied by localized involvement of an extralymphatic organ or site (IIIE), by involvement of the spleen (HIs), or both (IIIE+s) Stage IV Disseminated (multifocal) involvement of 1 or more extralymphatic organs with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvementt:

* Multifocal involvement of a single extralymphatic organ is classified as stage IE and not stage IV.

t The number of lymph node regions involved may be indicated by a subscript, eg, II3. For Stage I to IIIA disease, involvement of 4 or more nodal regions has been shown to adversely affect rates of disease-free survival and overall survival.’ + For stage IV disease involvement of more than 2 extranodal sites has been shown to adversely affect rates of complete response to therapy, disease-free survival, and overall survival.l I: Direct Spread into Adjacent Tissues or Organs.Direct spread of a lymphoma into adjacent tissues or organs does not influence classification of stage.

J: Staging Laparotomy.-Staging laparotomy is the gold standard for defining the extent of subclinical disease in the abdomen. It includes detailed exploration of the abdomen with sampling of the upper abdominal nodes (celiac, splenic hilar, and porta hepatic), the midabdominal nodes (para-aortic and porta caval), and the pelvic nodes (common, external and internal iliac). In addition, it includes splenectomy and wedge plus needle biopsies of the liver as well as biopsies of any suspicious lesions in the abdomen.2 In the past decade, the use of staging laparotomy for Hodgkin’s disease has decreased for several reasons: (1) the inherent morbidity of the procedure; (2) the increased accuracy of imaging techniques for predicting positive laparotomy findings; and (3) the use of treatment approaches that do not require knowledge of the extent of subclinical disease. Nevertheless, a role for staging laparotomy still exists, primarily in patients with favorable disease who may be candidates for management with supradiaphragmatic irradiation alone if the laparotomy reveals no subclinical tumor.22 In staging laparotomy, thorough examination of the spleen is essential since splenic involvement is common but is often inapparent on macroscopic examination. The outer surface is inspected for nodules, and the parenchyma is sliced thinly in transverse fashion to be examined for nodular or suspicious lesions. The pathology report should state the number of macroscopically identifiable nodules as well as the microscopic correlation as to the extent of disease.22 In stage III Hodgkin’s disease, the amount of tumor in the spleen, specifically 4 or more tumor nodules, has been shown to adversely affect diseasefree survival in patients treated with radiation therapy alone.23 Careful examination of each of the organs and tissues submitted at staging laparotomy and detailed reporting of the extent of involvement by tumor are important to establish the total tumor burden. Measures of tumor burden that combine total extent and volume of tumor in the body have been shown to be highly significant independent prognostic indicates in Hodgkin’s disease.l4,5,11-13,2325 The histologic criteria for involvement by tumor at staging laparotomy are as follows: go to website hodgkin s disease

Lymph nodes and spleen Same criteria as primary diagnosis Bone marrow and liver Mononuclear Reed-Stemberg variants in the appropriate cellular background In patients with an established diagnosis of Hodgkin’s disease, granulomas may be found on staging laparotomy in the absence of diagnostic Hodgkin’s cells or variants in lymph nodes, spleen, or bone marrow. The liver may also show nonspecific triaditis. Tissues with these findings are considered free of involvement by Hodgkin’s disease.

Contributors: the College of American Pathologists Cancer Committee; Annik van den Abbeele, MD; Claire Fung, MD; Nancy L. Harris, MD; Irene Kuter, MD; and Peter Mauch, MD.

[Reference] References [Reference] 1. Gospodarowicz MK, Specht L, Sutcliff SB. Hodgkin’s disease. In: Hermanek P, Gospodarowicz MK, Henson DE, Hutter RVP, Sobin LH, eds. Prognostic Factors in Cancer New York, NY: Springer-Verlag; 1995.

2. Haybittle IL, Haygoe FGJ, Easterling MJ, Et al. Review of British National Lymphoma Investigation studies of Hodgkin’s disease and development of prognostic index. Lancet.1985;1:967-972.

3. Specht L, Nissen NI. Hodgkin’s disease and age. Eur/ Hematol. 1989;43: 127-135.

4. Strauss DJ, Gaynor JJ, Myers J, et al. Prognostic factors among 135 adults with newly diagnosed advanced Hodgkin’s disease treated with alternating potentially noncross-resistant chemotherapy and intermediate-dose radiation therapy. J Clin Oncol. 1990;8:1173-1186.

5. Sutcliffe SB, Gospodarowicz MK, Bergsagel DE, et al. Prognostic groups for management for localized Hodgkin’s disease. Clin Oncol. 1985;3:393-401. 6. Mauch P, Goffman T, Rosenthal DS, et al. Stage III Hodgkin’s disease: improved survival with combined modality therapy as compared with radiation alone. J Clin Oncol. 1985;3:1166-1173.

7. Anderson H, Jenkins JPR, Brigg DJ, et al. The prognostic significance of mediastinal bulk in patients with stage IA-IVB Hodgkin’s disease: a report from the Manchester Lymphoma Group. Clin Radiol. 1985;36:449-454.

8. Bonadonna G, Valagussa P, Santoro A. Prognosis of bulky Hodgkin’s disease treated with chemotherapy alone or combined with radiotherapy. Cancer Res. 1985;31:1860-1861.

9. Pavlovsky S, Maschio M, Santarelli MT, et al. Randomized trial of che [Reference] motherapy versus chemotherapy plus radiotherapy for stage I-II Hodgkin’s disease. J Natl Cancer Inst. 1988;80:1466-1473.

10. Liew KH, Easton D, Horwich A, et al. Bulky mediastinal Hodgkin’s disease management and prognosis. Hematol Oncol. 1984;2:45-59. 11. Verger E, Easton D, Brada M, et al. Radiotherapy results in laparotomy stage Hodgkin’s disease. Clin Oncol.1988;39:428431.

12. Specht L, Nissen NI. Prognostic factors in Hodgkin’s disease with special reference to tumour burden. Eur] Hematol. 1988:41:80-87. 13. Specht L, Nordentoft AM, Soren S, et al. Tumor burden as the most important prognostic factor in early stage Hodgkin’s disease. Cancer. 1988:61:17191727.

[Reference] 14. Crnkovich M), Leopold K, Hoppe RT, Mauch PM. Stage I to IIB Hodgkin’s disease: the combined experience at Stanford University and the Joint Center for Radiation Therapy. J Clin Oncol. 1987:5:1041-1049.

15. Hermanak P, Henson DE, Hutter RVP, Sobin LH. TNM Supplement. New York, NY: Springer-Verlag NY Inc; 1993.

16. Specht L. Prognostic factors in Hodgkin’s disease. Cancer Treat Rev.1991: 1 8;21-53.

17. Ferry JA, Harris NL. The pathology of Hodgkin’s disease: what’s new? Semin Radiat Oncol. 1996;6:121-130.

18. Chan JKC, Banks PM, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms proposed by the International Lymphoma Study Group: a summary version. Am J Clin Pathol. 1995;103:543-560.

19. MacLennan KA, Bennett MH, Tu A, et al. Relationships of histopathologic features to survival in nodular sclerosing Hodgkin’s disease. Cancer. 1989;64: 1686-1693.

[Reference] 20. Specht L. Prognostic factors in Hodgkin’s disease. Semin Radiat Oncol. 1996;6:146-161.

21. Fleming ID, Cooper JS, Henson DE, et al, eds. AJCC Manual for Staging of Cancer. 5th ed. Philadelphia, Pa: Lippincott Raven; 1997. 22. Mendenhall NP. Diagnostic procedures and guidelines for the evaluation and follow-up of Hodgkin’s disease. Semin Radiat Oncol. 1996;6:131-145.

23. Hoppe RT, Cox RS, Rosenberg SA, et al. Prognostic factors in pathologic stage lil Hodgkin’s disease. Cancer Treat Rep.1982:66;743-749. 24. Specht L. Tumour burden as the main indicator of prognosis in Hodgkin’s disease. Eur J Cancer.1992:28A;1982-1985.

25. Specht L, Lauritzen AF, Nordentoft AM, et al. Tumour cell concentration and tumour burden in relation to histopathologic subtype and other factors in early stage Hodgkin’s disease. Cancer.1990:65;2594-2601. Bibliography [Reference] Collins RD. Lymph node examination: what is an adequate work-up. Arch Pathol Lab Med.1985;109:796-799.

Cousar )B. Surgical pathology examination of lymph nodes. Am J Clin Pathol 1995:104;126-132.

[Author Affiliation] Carolyn C. Compton, MD, PhD; Judith A. Ferry, MD; Dennis W Ross, MD, PhD; for the Members of the Cancer Committee, College of American Pathologists [Author Affiliation] Accepted for publication August 26, 1998. From the Department of Pathology, Massachusetts General Hospital, Boston (Drs Compton and Ferry) and the Department of Pathology, Forsyth Memorial Hospital, Winston-Salem, NC (Dr Ross).

This protocol was developed by the Cancer Committee of the College of American Pathologists and was submitted for editorial review and publication. It represents the views of the Cancer Committee and is not the official policy of the College of American Pathologists.

Reprints: Joe Schramm, College of American Pathologists, 325 Waukegan Rd, Northfield, IL 60093-2750.

Compton, Carolyn C; Ferry, Judith A; Ross, Dennis W