- Email: [email protected]
Hodgkin's disease associated with systemic lupus erythematosus
Volume 22, No. 4 (April 1991)
HUMAN PATHOLOGY
however, received anabolic steroids, and this for only a brief period.‘” It is possible, therefore, that two types of liver tumors occur in Fanconi patients: hepatocellular carcinomas arising as a result of Fanconi anemia, and hepatocellular adenomas caused by anabolic steroids. It is also possible that such tumors represent different stages along an “adenoma-carcinoma” sequence resulting from the combined effects of disease and drug. Both agents may contribute to tumor initiation and promotion, as in certain experimental models of hepatic carcinogenesis.‘g REFERENCES 1. Erslev AJ: Aplastic anemia, I” Williams WJ, Beutler E. Erslev AJ. et al: (eds): Hematology (ed 3). New York. NY, McGraw-Hill. 1983, pp 151-170 2. Kennedy AW, Hart WR: Multiple squamous-cell carcinomas in Fanconi’s anemia. Cancer 50:81 l-814, 1982 3. Craig JR, Peters RL, Edmondson HA. et al: Fibrolamrllar carcinoma of the liver: A turnour of adolescents and young adults with distinctive clinico-pathologic features. Cancer 46:372-379. 1980 4. Recant L, Lacy P: Clinicopathologic conference. Fanconi‘s anemia and hepatir cirrhosis. Am J Med 39:464-475. 1965 5. Bernstein MS. Hunter RL, Yachnin S: Hepatorna and peliosis hepatir developing in a patient with Fanconi’s anemia. iX Engl J Met1 2X4: 1135- 1 136. 1971 6. Johnson FL, Fedgler JR, Lerner KG. et al: Association of androgentcanaboltc steroid therapy with development ot hepatocellular carcinoma. Lancet 2:1273-1276. 197’L
7. Guy JT, Auslander MO: A”drogentc steroids and hepatocellular carrmoma. Lancet 1: 148, 1973 (letter) 8. Cattan D, Kalifat K, Wautier J-L. et al: Maladte de Fanconi et cancer du foie. Arch Fr Mal App Dig 63:41-48, 1974 9. Sarna G, Tomasulo P, Lotz JM. et al: Multiple neoplasms in two slb1ing.s with d variant form of Fanconi’s anemia. Cancer 36: 1029-1033. 1975 10. Holder LE. Gnarra DJ, Lampkin BC. et ai. Hepdroma associarrd wtth anaboiic steroid therapy. Ann J Roentgenol 1?4:638-642, 1975 I I. Kew MC. Van Caller B. Prowse CM. et al: Occurrence of primary hepatocellular cancer and peliosis hepatis after treatment with androgenic steroids. S Afr Med J 50:1233-1237, 1976 12. Shapiro P. Ikeda RM. Ruebner BH. et al: Multiple hepatic tumors and peliosis hepatis in Fanconi‘s anemia treated wth androgens. Am J Dis Child 131: 1104.1106, 1977 13. Mokrahisky ST, Ambruso DR, Hathaway WE: Fulminant hepatic neoplasia after androgen therapy. N Engl J Med 269.141 l-1412, 1977 14. .4bbondanzo SL, Manz HJ, Klappenbach RS. et al: Hepatocellular carcinoma in an 11 -year-old girl with Fanconi’s anemia. Report of a case and review of the literature. 4m J Pediatr Hematol Oncol 8:334-337. 1986 15. Vecchio FM, Fabiano A, Ghirlanda G. et al: Fibrolamellar car& “oma of the liver: The malignant counterpart of focal nodular hyperplasia with oncocytic change. .4m J Clin Pathol 81:521-326. 1984 16. Christopherso” WM, Mays ET, Barrows G: A clinicopathologic study of.steroid-related liver tumors. Am J Surg Pathol 1:31-41. 1977 17. Westabv D, Portmann B. Williams R: Androgen related primary hepatic tumors in non-Fanconi patients. Cancer 5 I: 1947.1952. 1983 IX. Obeid DA, Hill KH. Harnden D, et al: Fanconi anemia: Oxymethalone hepatic tumors, and chromosome aberrationc associated with leukemc transition. Cancer 46: 1401-1404. 1980 19. Farber E, Sarma DSR: Hepatocartint)genesr.s: .A dynamic cellular perspective Lab Invest 56:4-22. 1987
HODGKIN’S DISEASE ASSOCIATED WITH SYSTEMIC LUPUS ERYTHEMATOSUS DYMPHNA
NETTO,
MD,
AND
IFAT
A. SHAH, MD
We F-eport on the rare association of Hodgkin’., diceuse with sytemit lupus erythematosus. Two years after the diagnosis ofsytemic h~pus erythematosw, the patient developed upper abdominal pain, jaundice, splenomega(v, andfeuer of unknown origin. He had a rapidl? fatal clinical course, despite being treated for systemic /upus eqthematosus, cholecystitis, and possible sepsis: Autojq resealed Hodgkin’s diseaie, lymphocyte-depletion type, i.nvokGng !ym@ nodes, li7jer, spleerl, and bone murrow. The uwarenes5 c~fthe association of Hodgkin’s disease with systemic lupus eqthematosus and its modes of presentationwill help zn the early diagnosis and marlagement of such. patienh. HUM PATHOL 22.398-401. Copyright 0 1991 by W.B. Saunder.) Compay
ease (Stage IIIb, mixed cellularity) 12 years after the diagnosis of SLE. Striking clinical and serologic remission of his previously steroid-dependent SLE followed radiotherapy and combination chemotherapy for the lymphoreticular malignancy.’ Systemic lupus erythematosus may precede, coexist, or follow the development of lymphoproliferative disorders. In most of the reported cases, SLE preceded the onset of’ Hodgkin’s disease.‘-’ The case presented here is one with a similar association. Reports on such associations will increase awareness of the possible link between a deranged immune status and lymphoproliferative neoplasms. REPORT
The association of autoimmune diseases and lymphoproliferative disorders is well known. Among the autoimmune diseases, considerable attention has been focused on the association of hematologic or other malignancies with systemic lupus erythematosus (SLE). This tendency is thought to be enhanced by the administration of immunosuppressive agents.’ Interestingly, case reports document resolution of SLE following treatment of an associated neoplasm. One patient developed Hodgkin’s dis-
OF A CASE
.4 45-y,ear-old white man presented in January 1987 with a psorlasiform eruption of predominantly photodistribution. He was diagnosed by skin biopsy as having subacute cutaneous lupus erythematosus (Fig 1). He had intermittent episodes of fever, arthralgia, and vasculitis, and was treated for SLE. Antinuclear (ANA) antibody titer progressively increased, reaching a level of 1: 1,280, prior to his last hospitalization. Serum C, and C, levels were 87% and 16%., respectively. Serum total protein was 6.5 g/dL (65 g/L), and serum protein electrophoresis showed polyclonal gammopathy. The erythrocyte sedimentation rate (ESR) was 116 mm per hour. The last hospitalization was because of fever, rectal bleeding, weakness, and frequent episodes of’ chest pain. He had splenomegaly, right upper quadrant abdominal tenderness, and increasing jaundice with a total bilirubin of 12.1 mg/dL, (206 kmol/L), and a direct bilirubin of 6.3 mg/dL, (105 FmoliL). Other levels were: blood urea nitrogen, 66 mg/dL, (23.5 mmol/L); creatinine, 4.5 mgidt. (397.7 FmoliL); aspartate aminotransferase, 138 U/L; alanine aminotransferase, 2 11 U/L; gamma-glutamyl transferase, 28.3 U/L; alkaline phosphatase, 3 1 1 U/L; and white
Received May 14, 1990 from the Laboratory Service, Veterans Affairs Medical Center and Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX. Accepted for publication July 31. 1990. Supported in part by the Institutional Research Grant. Southwestern Medical Center, Dallas, TX. Key wo& systemic lupus erythematosus. Hodgkin’s disease. Address correspondence and reprint requests to Ifat ‘4. Shah, MD, Laboratory Service, Veterans Affairs Medical Center, 650 E Indian School Rd, Phoenix, AZ 8.5012. Copyright 0 I991 by W.B. Saunders Company 0046-8 I77/91/2204-(101 f$5.00/0
398
CASE STUDIES
FIGURE 1. Systemic lupus erythemotosus. Skin showing hyperkeratosis, acanthosis, flattening of rete ridges, liquefaction degeneration, subepidermal edema, telangiectas/a, and perivascular chronic inflammation. (Hematoxylineosin stain; magnification x 400.)
blood cell count was 33OOimm~‘. (3.3 X 1O!‘/L). Sonogram of the abdomen revealed splenomegaly and cholecystitis. A C tube was placed for drainage of bile. Splenomegaly and abdominal adenopathv were noted on computed tomographic scan of the abdomen. Although he received antihiotics, the fever persisted. No infectious cause for the fever could be identified. Subsequently, he developed gastrointestinal bleeding, hypotension, and acute tubular necrosis, requiring hemodialysis. He was successfully resuscitated from a cardiac arrest, but was comatose, requiring ventilator support. Terminallv, he had a cardiac arrest and could not be resuscitated. At aut’opsy there was generalized Iymphadenopathy. ‘l‘he retroperitoneal and inguinal lymph nodes were markedly enlarged, the largest measuring 6 by 1.5 by 3 cm. They had a rubbtery consistency, and the cut surfaces were hemorrhagic, with irregular, yellow areas. The spleen was markedly enlarged and weighed 1,420 ,g. Multiple, paleyellow, firm. nodular areas were noted m the subcapsulal region. as well as scattered throughout the parenchyma. The markedly enlarged liver weighed 3,280 g. The cut surfaces showed multiple punctate hemorrhages scattered throughout the parenchyma. The gallbladder was distended and contained clotted blood, its wall was thickened or obstructive and edematous. There were no gallstones lesions in the cystic or common bile ducts. Parts of the hepatic ducts, proximal to the obstruction caused by the enlarged lymph nodes in the porta hepatis, were moderately dilated. Microscopic examination of the organs revealed features consistent with Hodgkin’s disease, lymphocytedepletion t) pe involving the lymph nodes, spleen, liver, and bone marrow. ‘I‘hr architecture of the lymph nodes was totally effaced. ‘l‘here was an overall paucity of lymphocytes, with fine, interstitial fibrosis, scattered plasma cells, many large lymphoid cells, and histiocytes. Diagnostic Reed-Sternberg cells (Fig 2) and “sarcomatous” variants were present in abundance. Multifocal areas of necrosis were presenr. Similar histologic features were noted in the
liver, spleen, and bone marrow. consistent with adult respiratory
The lungs showed changes distress syndrome.
DI!X:USSIOK
‘I‘here is much controversy regarding the role of immunodeficiency. chronic inflammation, and immunosuppressive treatment in the development of lymphoproliferative disorders in individuals with collagen-vascular diseases. Systemic lupus erythernatosus is a classic autoimmune disease. Although in some of the large series there does not appear to be an increased incidence of Hodgkin’s disease, isolated cases have been described in the literature,“-” including one of a patient who developed cutaneous Hodgkin’s disease at the site of healed discoid lupus erythematosus.” A diagnosis of SLE is made when four or more of the 1 1 revised diagnostic criteria of the American Rheumatism Association are present, serially or simultaneously.7 Thus, two clinical and two serologic, or three clinical and one serologic, criteria now allow for the classification of. an immune disorder as SLE. In this patient the diagnosis of SLE was based on the presence of biopsy-proven cutaneous lupus erythematosus. vasculitis, arthritis, serositis, Irukopenia, and a rising titer of ANA. Ly,mph node enlargement occurs in approximately 45% of the patients with SLE, and represents “nonspecific” lymphadenitis, usually with follicular hyperplasia. sometimes with vasculitis. 1 he lymph nodes are usually not tender and often small (0.5 to I.0 cm), but massive lymphadenopathy (up to 5 cm) can be observed in some patients. It responds to treatment of SLE, but may recur early in the course of flares.’ Sometimes the morphologic features mav be indistinguishable from Kikuchi’s Iymphadenitis.” The following are, however, more likely: to be associated with ( 1) the presence of SLE than with Kikuchi’s lymphademtis: hematoxyphilic bodies aggregated towards the edges of the necrotizing areas, in addition to the deposition of DNA on
399
HUMAN PATHOLOGY
Volume 22. No. 4 (April 1991)
FIGURE 2. Hodgkin’s disease, lymphocyte-depletion type, lymph node. (Hematoxylineosin stain; magnification x 400.) (Inset) A diagnostic Reed-Sternberg cell. (Magnification x 1,000.)
vessel walls; and (2) the type of necrosis which, in SLE, tends to be more widespread, acellular coagulative type with focal aggregates of nuclear dust due to karyorrhexis. These features, when associated with numerous plasma cells, favor a diagnosis of SLE rather than Kikuchi’s lymphadenitis. Many of the previously reported cases of SLE with Hodgkin’s disease had prominent palpable lymphadenopathy at the time of diagnosis of Hodgkin’s disease. The patient presented here had generalized lymphadenopathy with markedly enlarged abdominal and inguinal lymph nodes. Early biopsy of suspicious lymph nodes has been recommended in SLE, in order to distinguish the lymphadenopathy of SLE from a developing lymphoid malignancy.” The enlarged lymph nodes in the region of the porta hepatis explain the obstructive jaundice. About one third of patients with Hodgkin’s disease initially present with general systemic symptoms of fever and weight loss. These symptoms may also occur in SLE patients at onset and during flares of the disease.’ The possibility of Hodgkin’s disease should, therefore, be considered, when an infectious etiology has been ruled out and fever persists despite treatment with antibiotics. An elevated ESR is commonly found in patients with advanced Hodgkin’s disease and has been shown to confer a relatively poor prognosis. An ESR of more than 30 mmihr is found in 30% to 50% of cases, and the case presented here did have a very high ESR (118 mmihr). Clinical assessment of the involvement of the spleen by Hodgkin’s disease is difficult, and, when splenomegaly is present, this may not be due to infiltration by Hodgkin’s disease. In one quarter of patients with normal-sized spleens on physical examination, Hodgkin’s disease will be found in the spleen removed at surgery. Conversely, approximately 50% of patients with clinical or radiologic enlargement of the spleen do not have histologic involvementic In SLE only mild splenomegaly is occasionally seen. The diagnosis of hepatic Hodgkin’s disease may present several problems. There is little correlation be-
400
tween liver size, assessed clmrcally or by imaging methods, and the presence of Hodgkin’s disease histologically. Liver function tests may be deranged in Hodgkin’s disease in the absence of histologic involvement of the livser. Jaundice is usually found only in very advanced cases. Furthermore, liver biopsy specimens from patients with Hodgkin’s disease frequently show a variety of nonspecific inflammatory changes, Dich et al” studied 125 patients with Hodgkin’s disease. They found that patients with hepatic involvement by Hodgkin’s disease are much more likely to have histologic evidence of portal infiltrates larger than 1 mm in diameter, acute cholangitis, portal edema, and portal infiltrates with a predominance of atypical lymphocytes. They recommend a more diligent search for Reed-Sternberg cells when the above histopathologic changes are noticed. Bone marrow involvement is found in 5% to 14% of cases of Hodgkin’s disease, and this mav present as myelofibrosis, especially with delayed diagnosis.” Bone marrow aspiration and biopsy performed early may be potentially diagnostic, facilitating staging without laparotomy. The awareness of the association of Hodgkin’s disease with SLE and the modes of presentation will help in the early diagnosis and clinical management of such patients. Acknowlrdgr,lent. The authors thank B. Berg for valuable help in preparing the manuscript.
and F. Fleming
REFERENCES I. Peun I. PKIC .5:943-947.
Star21 TE: 197.1
Immune
Suppression
and Cancer.
Transplant
2. Goodwin JS: Kcnlission in systems lupus crythematosus after tombin&m chemotherapy for Hodgkin‘s disease. JAMA 244: 1962, 1980 3. Case records of the Massachusetts Engl J Med 319:768-781. 1988
General
Hospital.
Case 3% 1988. N
4. Liang K: Acute pancreatitis due to Hodgkin‘s disease in a patient systemic lupus erythematosus. Aust NZ J Med 18:X12-81:3. 1989
nith
CORRESPONDENCE 5. Efretmdis A, Elwr AR, (&man E. et al: Hodgkin’s Iymphoma in an .Idolescrnt with systemic lupus ervthematosus. Cancer 53: 112-116. 1984 6. Millel- DC;: The association of immune disease and malignant lymphoma. Ann Intern Med 66:.507-517. 1967 7. ‘1-a” Ehf. (Zohcn AS. Fries JF. ct al: The 19X2 revised criteria for the cldssdicatirm eat \\\itemil lupus rrythematosus. AI-thritis Rheum 25: 1?711?7i. I%? H. Smolcm JS. (Iinic al and serologr features: Incidence and diagnostlr npproxh. in Sm&n JS. Zielinski (I: (cds): Systemic Lupus Er-vthematows. (:linical and E.sprr-lmenral Aspects. NW York, NY. Springer i’rrlag. 19X7. p,, I XL I vi
Guidelines for Letters Letters to the Editor will be published at the discretion of the editor as space permits and are subject to editing and abridgement. They should be typewritten. double-spaced, and submitted in triplicate. They should be limited to 500 words or less and to no more than five pertinent references.
The Bethesda Classification System: A Counterintldtive Approach to Data Presentation TO t/z?.Editor:--Several years ago, we became aware of a problem concerning the interpretation of binarv test results: that is, results that are reported either “positive” or “negative” (eg, pregnancy tests and mononucleosis tests). in contrast to those in which a continuous range of answers is incremented according to the precision of the method (eg, blood glucoses and prothrombin times). The problem arose when we repeated a urine pregnancy test that had been reported as negative and found that the result was positive. Several different technologists re-performed the test on the same sample and found that it was reported positive approximately half of the time. There was nothing wrong with their techniques. It was simply that the WC<; concentration of the sample was borderline with reference to the sensitivity of the method. It became apparent that regardless of the analyte or method, all binary reporting systems are flawed when the concentration of analyte hovers at the threshold between positivity and negativity. Both subjective endpoint tests (such as RPRs and Papaniolaou smears) and objectiue (quantitative) endpoint tests (such as anti-HBc) are equally at risk. The solution was evident. Since decision making is enhanced when there is unambiguous communication between the laboratory and the clinician, it was necessary to define “borderline” categories for all such tests so that clinicians receiving results would more fully appreciate our message to them. It should be emphasized that a borderline It is an result is not a “hedge” that indicates indecision. important statement of fact. A borderline result may indicate that repeat testing at a later date is required, that some other testing modality would be more instructive, or simply that it is no\: possible to categorize the patient relative to the condition for which the test was applied. Papanicolaou smears were not part of these “binary dilemma” considerations because our reporting system had
9. D&man RF, Berry GJ: Kikuclu’s histiocytic nrcrotlzing lymphadenitis: .4n analysis ot 108 cases with emphasis on differrntial diagnosis. Semin Diagn Pathol 5:329-345. I988 10. Glirk .JH: Hodgkm’s disease, in Wyngaarden JB, Smith (Xl Textbook 01 Medicine (ed 18). Philadelphia. PA, Saunders. 1014.IO’L:!
I I. Dich NH. (;oodman ZD, Klein MA: Hodgkin’s disease. Cancer tX:2121-2126. 1989
Hepat]<
LH (eds): 1988, pp
inwlvement
12. Meadows LM. Kosse WR. Moore JO. et al: Hodgkms wnting as mvrlofihnxis. Cancer 64: 1720.l7?6. 19X9
disease
in pre-
(and still has) a negative category, “class I-no dysplastic cells present,” as well as multiple gradations of abnormality. We define nondysplastic atypia as “class II--benign atypia, injury and repair.” followed by three gradations of dysplasia and then “class III-severe dysplasia or carcinoma in situ,” etc. We have recently become concerned that wellmeaning, but possibly iil-conceived. attempts to revise and standardize the Papanicolaou smear classification system may introduce a binary reporting problem of the type described above. The Bethesda classification recognizes just two grades of dysplasia: low-grade and high-grade UN. Proponents of the Bethesda classification system assume that pathologists will have no difficulty in distinguishing low- from high-grade CIN and, in general, this is correct. However, the Bethesda classification system is a step backward because of its lack of provision for an intermediategrade GIN. Should it be adopted as the national standard, we believe the likely consequences will be as follows: 1, Clinicians receiving Papanicolaou smear reports on patients with dyspiasias will get less information from laboratories using the Bethesda system. 2. Pathologists using the Bethesda system will be obliged to either “bump up” or “ratchet down” intermediate-grade dysplasia to fit the two permissible categories, 3. This binary reporting system, which denies the reality of a continuum of dysplasia, will place greater reliance on the subjective abilities of pathologists than is medically ,justified, 4. Ultimately. most truly intermediate-grade CXNs will be upgraded to high grade because this constitutes a “safer harbor” for the responsible pathologist, possibly resulting in overly aggressive management. 5. Pathologists who genuinely try to adhere to this binary classification of dysplasia will find that their occasional errors will be very clear in hindsight-to referring physicians and to plaintiffs’ attorneys. Morphology is a subjective discipline and its practitioners, while generally good, are far from perfect. A keratinizing squamous cell carcinoma is usually- a straightforward cytologic or histopathologic diagnosis because squamous carcinomas are at the far end of the continuum. Yet, when an expert panel of hematopathologists examines problem lymph nodes, they disagree significantly. Furthermore, when individual panel members examine the very same cases at a later date, the rate of concordance with their original diagnoses is far from consistent. The reason, of course, is that the cases selected are difficult, the diagnostic criteria are subtle and defy rigorous standardization, and different diagnostic categories tend to converge and overlap.
401
HUMAN PATHOLOGY
however, received anabolic steroids, and this for only a brief period.‘” It is possible, therefore, that two types of liver tumors occur in Fanconi patients: hepatocellular carcinomas arising as a result of Fanconi anemia, and hepatocellular adenomas caused by anabolic steroids. It is also possible that such tumors represent different stages along an “adenoma-carcinoma” sequence resulting from the combined effects of disease and drug. Both agents may contribute to tumor initiation and promotion, as in certain experimental models of hepatic carcinogenesis.‘g REFERENCES 1. Erslev AJ: Aplastic anemia, I” Williams WJ, Beutler E. Erslev AJ. et al: (eds): Hematology (ed 3). New York. NY, McGraw-Hill. 1983, pp 151-170 2. Kennedy AW, Hart WR: Multiple squamous-cell carcinomas in Fanconi’s anemia. Cancer 50:81 l-814, 1982 3. Craig JR, Peters RL, Edmondson HA. et al: Fibrolamrllar carcinoma of the liver: A turnour of adolescents and young adults with distinctive clinico-pathologic features. Cancer 46:372-379. 1980 4. Recant L, Lacy P: Clinicopathologic conference. Fanconi‘s anemia and hepatir cirrhosis. Am J Med 39:464-475. 1965 5. Bernstein MS. Hunter RL, Yachnin S: Hepatorna and peliosis hepatir developing in a patient with Fanconi’s anemia. iX Engl J Met1 2X4: 1135- 1 136. 1971 6. Johnson FL, Fedgler JR, Lerner KG. et al: Association of androgentcanaboltc steroid therapy with development ot hepatocellular carcinoma. Lancet 2:1273-1276. 197’L
7. Guy JT, Auslander MO: A”drogentc steroids and hepatocellular carrmoma. Lancet 1: 148, 1973 (letter) 8. Cattan D, Kalifat K, Wautier J-L. et al: Maladte de Fanconi et cancer du foie. Arch Fr Mal App Dig 63:41-48, 1974 9. Sarna G, Tomasulo P, Lotz JM. et al: Multiple neoplasms in two slb1ing.s with d variant form of Fanconi’s anemia. Cancer 36: 1029-1033. 1975 10. Holder LE. Gnarra DJ, Lampkin BC. et ai. Hepdroma associarrd wtth anaboiic steroid therapy. Ann J Roentgenol 1?4:638-642, 1975 I I. Kew MC. Van Caller B. Prowse CM. et al: Occurrence of primary hepatocellular cancer and peliosis hepatis after treatment with androgenic steroids. S Afr Med J 50:1233-1237, 1976 12. Shapiro P. Ikeda RM. Ruebner BH. et al: Multiple hepatic tumors and peliosis hepatis in Fanconi‘s anemia treated wth androgens. Am J Dis Child 131: 1104.1106, 1977 13. Mokrahisky ST, Ambruso DR, Hathaway WE: Fulminant hepatic neoplasia after androgen therapy. N Engl J Med 269.141 l-1412, 1977 14. .4bbondanzo SL, Manz HJ, Klappenbach RS. et al: Hepatocellular carcinoma in an 11 -year-old girl with Fanconi’s anemia. Report of a case and review of the literature. 4m J Pediatr Hematol Oncol 8:334-337. 1986 15. Vecchio FM, Fabiano A, Ghirlanda G. et al: Fibrolamellar car& “oma of the liver: The malignant counterpart of focal nodular hyperplasia with oncocytic change. .4m J Clin Pathol 81:521-326. 1984 16. Christopherso” WM, Mays ET, Barrows G: A clinicopathologic study of.steroid-related liver tumors. Am J Surg Pathol 1:31-41. 1977 17. Westabv D, Portmann B. Williams R: Androgen related primary hepatic tumors in non-Fanconi patients. Cancer 5 I: 1947.1952. 1983 IX. Obeid DA, Hill KH. Harnden D, et al: Fanconi anemia: Oxymethalone hepatic tumors, and chromosome aberrationc associated with leukemc transition. Cancer 46: 1401-1404. 1980 19. Farber E, Sarma DSR: Hepatocartint)genesr.s: .A dynamic cellular perspective Lab Invest 56:4-22. 1987
HODGKIN’S DISEASE ASSOCIATED WITH SYSTEMIC LUPUS ERYTHEMATOSUS DYMPHNA
NETTO,
MD,
AND
IFAT
A. SHAH, MD
We F-eport on the rare association of Hodgkin’., diceuse with sytemit lupus erythematosus. Two years after the diagnosis ofsytemic h~pus erythematosw, the patient developed upper abdominal pain, jaundice, splenomega(v, andfeuer of unknown origin. He had a rapidl? fatal clinical course, despite being treated for systemic /upus eqthematosus, cholecystitis, and possible sepsis: Autojq resealed Hodgkin’s diseaie, lymphocyte-depletion type, i.nvokGng !ym@ nodes, li7jer, spleerl, and bone murrow. The uwarenes5 c~fthe association of Hodgkin’s disease with systemic lupus eqthematosus and its modes of presentationwill help zn the early diagnosis and marlagement of such. patienh. HUM PATHOL 22.398-401. Copyright 0 1991 by W.B. Saunder.) Compay
ease (Stage IIIb, mixed cellularity) 12 years after the diagnosis of SLE. Striking clinical and serologic remission of his previously steroid-dependent SLE followed radiotherapy and combination chemotherapy for the lymphoreticular malignancy.’ Systemic lupus erythematosus may precede, coexist, or follow the development of lymphoproliferative disorders. In most of the reported cases, SLE preceded the onset of’ Hodgkin’s disease.‘-’ The case presented here is one with a similar association. Reports on such associations will increase awareness of the possible link between a deranged immune status and lymphoproliferative neoplasms. REPORT
The association of autoimmune diseases and lymphoproliferative disorders is well known. Among the autoimmune diseases, considerable attention has been focused on the association of hematologic or other malignancies with systemic lupus erythematosus (SLE). This tendency is thought to be enhanced by the administration of immunosuppressive agents.’ Interestingly, case reports document resolution of SLE following treatment of an associated neoplasm. One patient developed Hodgkin’s dis-
OF A CASE
.4 45-y,ear-old white man presented in January 1987 with a psorlasiform eruption of predominantly photodistribution. He was diagnosed by skin biopsy as having subacute cutaneous lupus erythematosus (Fig 1). He had intermittent episodes of fever, arthralgia, and vasculitis, and was treated for SLE. Antinuclear (ANA) antibody titer progressively increased, reaching a level of 1: 1,280, prior to his last hospitalization. Serum C, and C, levels were 87% and 16%., respectively. Serum total protein was 6.5 g/dL (65 g/L), and serum protein electrophoresis showed polyclonal gammopathy. The erythrocyte sedimentation rate (ESR) was 116 mm per hour. The last hospitalization was because of fever, rectal bleeding, weakness, and frequent episodes of’ chest pain. He had splenomegaly, right upper quadrant abdominal tenderness, and increasing jaundice with a total bilirubin of 12.1 mg/dL, (206 kmol/L), and a direct bilirubin of 6.3 mg/dL, (105 FmoliL). Other levels were: blood urea nitrogen, 66 mg/dL, (23.5 mmol/L); creatinine, 4.5 mgidt. (397.7 FmoliL); aspartate aminotransferase, 138 U/L; alanine aminotransferase, 2 11 U/L; gamma-glutamyl transferase, 28.3 U/L; alkaline phosphatase, 3 1 1 U/L; and white
Received May 14, 1990 from the Laboratory Service, Veterans Affairs Medical Center and Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX. Accepted for publication July 31. 1990. Supported in part by the Institutional Research Grant. Southwestern Medical Center, Dallas, TX. Key wo& systemic lupus erythematosus. Hodgkin’s disease. Address correspondence and reprint requests to Ifat ‘4. Shah, MD, Laboratory Service, Veterans Affairs Medical Center, 650 E Indian School Rd, Phoenix, AZ 8.5012. Copyright 0 I991 by W.B. Saunders Company 0046-8 I77/91/2204-(101 f$5.00/0
398
CASE STUDIES
FIGURE 1. Systemic lupus erythemotosus. Skin showing hyperkeratosis, acanthosis, flattening of rete ridges, liquefaction degeneration, subepidermal edema, telangiectas/a, and perivascular chronic inflammation. (Hematoxylineosin stain; magnification x 400.)
blood cell count was 33OOimm~‘. (3.3 X 1O!‘/L). Sonogram of the abdomen revealed splenomegaly and cholecystitis. A C tube was placed for drainage of bile. Splenomegaly and abdominal adenopathv were noted on computed tomographic scan of the abdomen. Although he received antihiotics, the fever persisted. No infectious cause for the fever could be identified. Subsequently, he developed gastrointestinal bleeding, hypotension, and acute tubular necrosis, requiring hemodialysis. He was successfully resuscitated from a cardiac arrest, but was comatose, requiring ventilator support. Terminallv, he had a cardiac arrest and could not be resuscitated. At aut’opsy there was generalized Iymphadenopathy. ‘l‘he retroperitoneal and inguinal lymph nodes were markedly enlarged, the largest measuring 6 by 1.5 by 3 cm. They had a rubbtery consistency, and the cut surfaces were hemorrhagic, with irregular, yellow areas. The spleen was markedly enlarged and weighed 1,420 ,g. Multiple, paleyellow, firm. nodular areas were noted m the subcapsulal region. as well as scattered throughout the parenchyma. The markedly enlarged liver weighed 3,280 g. The cut surfaces showed multiple punctate hemorrhages scattered throughout the parenchyma. The gallbladder was distended and contained clotted blood, its wall was thickened or obstructive and edematous. There were no gallstones lesions in the cystic or common bile ducts. Parts of the hepatic ducts, proximal to the obstruction caused by the enlarged lymph nodes in the porta hepatis, were moderately dilated. Microscopic examination of the organs revealed features consistent with Hodgkin’s disease, lymphocytedepletion t) pe involving the lymph nodes, spleen, liver, and bone marrow. ‘I‘hr architecture of the lymph nodes was totally effaced. ‘l‘here was an overall paucity of lymphocytes, with fine, interstitial fibrosis, scattered plasma cells, many large lymphoid cells, and histiocytes. Diagnostic Reed-Sternberg cells (Fig 2) and “sarcomatous” variants were present in abundance. Multifocal areas of necrosis were presenr. Similar histologic features were noted in the
liver, spleen, and bone marrow. consistent with adult respiratory
The lungs showed changes distress syndrome.
DI!X:USSIOK
‘I‘here is much controversy regarding the role of immunodeficiency. chronic inflammation, and immunosuppressive treatment in the development of lymphoproliferative disorders in individuals with collagen-vascular diseases. Systemic lupus erythernatosus is a classic autoimmune disease. Although in some of the large series there does not appear to be an increased incidence of Hodgkin’s disease, isolated cases have been described in the literature,“-” including one of a patient who developed cutaneous Hodgkin’s disease at the site of healed discoid lupus erythematosus.” A diagnosis of SLE is made when four or more of the 1 1 revised diagnostic criteria of the American Rheumatism Association are present, serially or simultaneously.7 Thus, two clinical and two serologic, or three clinical and one serologic, criteria now allow for the classification of. an immune disorder as SLE. In this patient the diagnosis of SLE was based on the presence of biopsy-proven cutaneous lupus erythematosus. vasculitis, arthritis, serositis, Irukopenia, and a rising titer of ANA. Ly,mph node enlargement occurs in approximately 45% of the patients with SLE, and represents “nonspecific” lymphadenitis, usually with follicular hyperplasia. sometimes with vasculitis. 1 he lymph nodes are usually not tender and often small (0.5 to I.0 cm), but massive lymphadenopathy (up to 5 cm) can be observed in some patients. It responds to treatment of SLE, but may recur early in the course of flares.’ Sometimes the morphologic features mav be indistinguishable from Kikuchi’s Iymphadenitis.” The following are, however, more likely: to be associated with ( 1) the presence of SLE than with Kikuchi’s lymphademtis: hematoxyphilic bodies aggregated towards the edges of the necrotizing areas, in addition to the deposition of DNA on
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HUMAN PATHOLOGY
Volume 22. No. 4 (April 1991)
FIGURE 2. Hodgkin’s disease, lymphocyte-depletion type, lymph node. (Hematoxylineosin stain; magnification x 400.) (Inset) A diagnostic Reed-Sternberg cell. (Magnification x 1,000.)
vessel walls; and (2) the type of necrosis which, in SLE, tends to be more widespread, acellular coagulative type with focal aggregates of nuclear dust due to karyorrhexis. These features, when associated with numerous plasma cells, favor a diagnosis of SLE rather than Kikuchi’s lymphadenitis. Many of the previously reported cases of SLE with Hodgkin’s disease had prominent palpable lymphadenopathy at the time of diagnosis of Hodgkin’s disease. The patient presented here had generalized lymphadenopathy with markedly enlarged abdominal and inguinal lymph nodes. Early biopsy of suspicious lymph nodes has been recommended in SLE, in order to distinguish the lymphadenopathy of SLE from a developing lymphoid malignancy.” The enlarged lymph nodes in the region of the porta hepatis explain the obstructive jaundice. About one third of patients with Hodgkin’s disease initially present with general systemic symptoms of fever and weight loss. These symptoms may also occur in SLE patients at onset and during flares of the disease.’ The possibility of Hodgkin’s disease should, therefore, be considered, when an infectious etiology has been ruled out and fever persists despite treatment with antibiotics. An elevated ESR is commonly found in patients with advanced Hodgkin’s disease and has been shown to confer a relatively poor prognosis. An ESR of more than 30 mmihr is found in 30% to 50% of cases, and the case presented here did have a very high ESR (118 mmihr). Clinical assessment of the involvement of the spleen by Hodgkin’s disease is difficult, and, when splenomegaly is present, this may not be due to infiltration by Hodgkin’s disease. In one quarter of patients with normal-sized spleens on physical examination, Hodgkin’s disease will be found in the spleen removed at surgery. Conversely, approximately 50% of patients with clinical or radiologic enlargement of the spleen do not have histologic involvementic In SLE only mild splenomegaly is occasionally seen. The diagnosis of hepatic Hodgkin’s disease may present several problems. There is little correlation be-
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tween liver size, assessed clmrcally or by imaging methods, and the presence of Hodgkin’s disease histologically. Liver function tests may be deranged in Hodgkin’s disease in the absence of histologic involvement of the livser. Jaundice is usually found only in very advanced cases. Furthermore, liver biopsy specimens from patients with Hodgkin’s disease frequently show a variety of nonspecific inflammatory changes, Dich et al” studied 125 patients with Hodgkin’s disease. They found that patients with hepatic involvement by Hodgkin’s disease are much more likely to have histologic evidence of portal infiltrates larger than 1 mm in diameter, acute cholangitis, portal edema, and portal infiltrates with a predominance of atypical lymphocytes. They recommend a more diligent search for Reed-Sternberg cells when the above histopathologic changes are noticed. Bone marrow involvement is found in 5% to 14% of cases of Hodgkin’s disease, and this mav present as myelofibrosis, especially with delayed diagnosis.” Bone marrow aspiration and biopsy performed early may be potentially diagnostic, facilitating staging without laparotomy. The awareness of the association of Hodgkin’s disease with SLE and the modes of presentation will help in the early diagnosis and clinical management of such patients. Acknowlrdgr,lent. The authors thank B. Berg for valuable help in preparing the manuscript.
and F. Fleming
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4. Liang K: Acute pancreatitis due to Hodgkin‘s disease in a patient systemic lupus erythematosus. Aust NZ J Med 18:X12-81:3. 1989
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CORRESPONDENCE 5. Efretmdis A, Elwr AR, (&man E. et al: Hodgkin’s Iymphoma in an .Idolescrnt with systemic lupus ervthematosus. Cancer 53: 112-116. 1984 6. Millel- DC;: The association of immune disease and malignant lymphoma. Ann Intern Med 66:.507-517. 1967 7. ‘1-a” Ehf. (Zohcn AS. Fries JF. ct al: The 19X2 revised criteria for the cldssdicatirm eat \\\itemil lupus rrythematosus. AI-thritis Rheum 25: 1?711?7i. I%? H. Smolcm JS. (Iinic al and serologr features: Incidence and diagnostlr npproxh. in Sm&n JS. Zielinski (I: (cds): Systemic Lupus Er-vthematows. (:linical and E.sprr-lmenral Aspects. NW York, NY. Springer i’rrlag. 19X7. p,, I XL I vi
Guidelines for Letters Letters to the Editor will be published at the discretion of the editor as space permits and are subject to editing and abridgement. They should be typewritten. double-spaced, and submitted in triplicate. They should be limited to 500 words or less and to no more than five pertinent references.
The Bethesda Classification System: A Counterintldtive Approach to Data Presentation TO t/z?.Editor:--Several years ago, we became aware of a problem concerning the interpretation of binarv test results: that is, results that are reported either “positive” or “negative” (eg, pregnancy tests and mononucleosis tests). in contrast to those in which a continuous range of answers is incremented according to the precision of the method (eg, blood glucoses and prothrombin times). The problem arose when we repeated a urine pregnancy test that had been reported as negative and found that the result was positive. Several different technologists re-performed the test on the same sample and found that it was reported positive approximately half of the time. There was nothing wrong with their techniques. It was simply that the WC<; concentration of the sample was borderline with reference to the sensitivity of the method. It became apparent that regardless of the analyte or method, all binary reporting systems are flawed when the concentration of analyte hovers at the threshold between positivity and negativity. Both subjective endpoint tests (such as RPRs and Papaniolaou smears) and objectiue (quantitative) endpoint tests (such as anti-HBc) are equally at risk. The solution was evident. Since decision making is enhanced when there is unambiguous communication between the laboratory and the clinician, it was necessary to define “borderline” categories for all such tests so that clinicians receiving results would more fully appreciate our message to them. It should be emphasized that a borderline It is an result is not a “hedge” that indicates indecision. important statement of fact. A borderline result may indicate that repeat testing at a later date is required, that some other testing modality would be more instructive, or simply that it is no\: possible to categorize the patient relative to the condition for which the test was applied. Papanicolaou smears were not part of these “binary dilemma” considerations because our reporting system had
9. D&man RF, Berry GJ: Kikuclu’s histiocytic nrcrotlzing lymphadenitis: .4n analysis ot 108 cases with emphasis on differrntial diagnosis. Semin Diagn Pathol 5:329-345. I988 10. Glirk .JH: Hodgkm’s disease, in Wyngaarden JB, Smith (Xl Textbook 01 Medicine (ed 18). Philadelphia. PA, Saunders. 1014.IO’L:!
I I. Dich NH. (;oodman ZD, Klein MA: Hodgkin’s disease. Cancer tX:2121-2126. 1989
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LH (eds): 1988, pp
inwlvement
12. Meadows LM. Kosse WR. Moore JO. et al: Hodgkms wnting as mvrlofihnxis. Cancer 64: 1720.l7?6. 19X9
disease
in pre-
(and still has) a negative category, “class I-no dysplastic cells present,” as well as multiple gradations of abnormality. We define nondysplastic atypia as “class II--benign atypia, injury and repair.” followed by three gradations of dysplasia and then “class III-severe dysplasia or carcinoma in situ,” etc. We have recently become concerned that wellmeaning, but possibly iil-conceived. attempts to revise and standardize the Papanicolaou smear classification system may introduce a binary reporting problem of the type described above. The Bethesda classification recognizes just two grades of dysplasia: low-grade and high-grade UN. Proponents of the Bethesda classification system assume that pathologists will have no difficulty in distinguishing low- from high-grade CIN and, in general, this is correct. However, the Bethesda classification system is a step backward because of its lack of provision for an intermediategrade GIN. Should it be adopted as the national standard, we believe the likely consequences will be as follows: 1, Clinicians receiving Papanicolaou smear reports on patients with dyspiasias will get less information from laboratories using the Bethesda system. 2. Pathologists using the Bethesda system will be obliged to either “bump up” or “ratchet down” intermediate-grade dysplasia to fit the two permissible categories, 3. This binary reporting system, which denies the reality of a continuum of dysplasia, will place greater reliance on the subjective abilities of pathologists than is medically ,justified, 4. Ultimately. most truly intermediate-grade CXNs will be upgraded to high grade because this constitutes a “safer harbor” for the responsible pathologist, possibly resulting in overly aggressive management. 5. Pathologists who genuinely try to adhere to this binary classification of dysplasia will find that their occasional errors will be very clear in hindsight-to referring physicians and to plaintiffs’ attorneys. Morphology is a subjective discipline and its practitioners, while generally good, are far from perfect. A keratinizing squamous cell carcinoma is usually- a straightforward cytologic or histopathologic diagnosis because squamous carcinomas are at the far end of the continuum. Yet, when an expert panel of hematopathologists examines problem lymph nodes, they disagree significantly. Furthermore, when individual panel members examine the very same cases at a later date, the rate of concordance with their original diagnoses is far from consistent. The reason, of course, is that the cases selected are difficult, the diagnostic criteria are subtle and defy rigorous standardization, and different diagnostic categories tend to converge and overlap.
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