Document e3p6a8gvxz65J4NR0GpeX6rg

CHRONIC LYMPHOCYTIC LEUKEMIA IN HODGKIN'S DISEASE R e p o r t of a Case and Review of the Liteatul-e TINHAN, M D * We recently observed the occurrence of chronic lymphocytic leukemia in a patient with Hodgkin's disease of mixed cellularity type involving the right in- guinal region who had been treated with radiation therapy. T h e patient developed classical chronic lymphocytic leukemia with generalized lymphadenopathy, splednomegaly, and lymphocytosis after a 13-year remission of Hodgkin's disease. I n vitro lymphocyte response to phytohemagglutinin showed the depressed and delayed DNA synthesis, and immunoglobulin determination showed marked deficiency of IgG and slight deficiency of IgA, usually seen in chronic lymphocytic leukemia. T h e medical literature contains reports of Hodg- kin's disease complicating chronic lymphocytic leukemia in 17 instances and reports of chronic lymphocytic leukemia complicating Hodgkin's disease in only two instances. This association of Hodgkin's disease and chronic lymphocytic leukemia probably represents the occurrence of two separate diseases. HODGKIN'S DISEASE AND CHRONIC LYMPHOCY- formed, and he was referred to the Roswell tic leukemia are usually regarded as two Park Memorial Institute in February 1955. distinct neoplastic diseases, with no known Histologic sections of the biopsied lymph common etiologic relationship. T h e occur- node were typical of Hodgkin's disease. T h e rence of Hodgkin's disease in patients with chronic lymphocytic leukemia has been rarely patient did not have systemic manifestations. Physical examination revealed no signifi- cant peripheral lymphadenopathy or hepatos- noted; 17 such cases were reporte~I.l-3.l~~~~--pl7le.nomegaly. 19,20.23,24,27 T h e occurrence of chronic lympho- Pertinent hematologic data are shown in cytic leukemia complicating Hodgkin's disease Table 1. An initial complete blood count was is extremely rare, and only two rep0rts2~J7 a5 follows: the hemoglobin was 13.2 g/lOO ml, were found in the medical literature. T h e pres- the white blood cell count was 5,75O/mm3, ent report describes a patient with Hodgkin's disease who was in complete remission for 13 years, then developed classical chronic lymphocytic leukemia. with 50% polymorphonuclear cells and 39% lymphocytes, and the platelet count was 237,500/mm3. Chest roentgenogram showed no hilar or mediastinal lymphadenopathy. T h e patient was given irradiation (2780 rads tumor dose) to the right inguinal and fe- CASEREPORTS moral areas from March 3 through March 18, 1955. He was seen in the clinic periodically H.G. (83083), a 35-year-old Caucasian man, and remained in remission. Several chest first noted a painful swelling in the right groin in December 1954. He was found to have right inguinal lymphadenopathy. An excisional biopsy of the lymph node was per- roentgenograms were normal. In 1965, following more than a 10-year re- mission, the original histologic sections were reviewed and the diagnosis of Hodgkin's dis- From the Division of Medicine, Roswell Park Memo- ease was confirmed. Blood count on each rial Institute, New York State Department of Health, clinic visit was within normal limits. T h e he- Buffalo, N. Y. P- r.e.s.e-n.ted- a t the Tenth International Cancer Con- gress, Houston, Tex., May 1970. + Cancer Research Internist, Roswell Park Memorial Institute; Assistant Research Professor of Medicine, matocrit was 43%, the hemoglobin was 12.4 g/lOO ml, the white blood cell count was 5,456/mm3, with 85% polymorphonuclear cells and 14% lymphocytes, and the platelet State University of New York at Buffalo. Address for reprints: Tin Han, MD, Medicine B, Roswell Park Memorial Institute, 666 Elm St., Buffalo, N.Y. 14203. Received for publication January 22, 1971. count was 121,975/mm3 in March 1967. On March 22, 1968, physical examination re- vealed bilateral cervical and axillary lymphadenopathy. Hemoglobin was 12 g/100 ml, the 300 lo. 2 ___- Date ---- 2/ 8/55 6/30/58 4/ 4/61 I / 7/65 3/23/67 3/22/68 4/30/68 !>/24/68 2/14/69 10/17/69 2/13/70 __._c_ -CLL IN HODGKIND'ISEASE Hail ___ TABLE1. Summary of Clinical Data Lymphadenopathy h1oder;ite bilat. cerv. & axillary Parn-aortic & iliac Minimal cerv. & axillary Hemoglobin g/100 ml 13.2 12.3 13.5 14.3 12.4 13.0 12.0 11.0 14.0 9.8 12.7 Platelets 103/mm3 192.5 200.0 200.0 122.0 97.4 131.1 118.3 79.0 98.7 60.0 301 White Blood Cells lO3/mma 5.8 4.4 8.2 6.9 5.5 Lymphocytes (Per cent) 39 29 27 20 14 20.3 40.8 6.3 29.5 78.7 126.4 89 92 76 59 93 98 white blood cell count was 20,300/mm3, with 89(% lymphocytes. A bone marrow aspiration on April 12, 1968, showed normal cellularity wilh nearly 80% mature lymphocytes. Some immature forms were also seen. A lymphogram showed enlarged and foamy inguinal, iliac, and para-aortic lymph nodes. On April 30, 1968, the spleen was palpable 4 cm and the liver was palpable 2 cm helow the respective coctal margins. A cervical lymph node biopsy was performed on April 23, 1968. T h e histoloqic findings were typical of chronic lymphocyt ic leukemia or lymphosarcoma, without evidence of Hodgkin's diyease. The white blood cell count qadually incrmsed further to 40,S00/mm3, with 92% lymphocytes on April 30, 1968. He was given chlorambucil 6 mg and prednisone 45 mg orally daily from April 30, 1968 to July 11, 1968, with an excellent response, characterized by disappearance of hepatosplenomegaly, peripheral lymphadenopath), and marked shrinkage of (lye-filled para-aortic, iliac, and inguinal lymph nodes. T h e dose of prednisone was reduted to 15 mg daily on July 12, 1968. T h e hemoglobin was 12.3 g/'100 ml, the white bl'oodcell count was 8,50O/mm3 and the platelei count was 72.000/mm3 on September 10, 1968. T h e dose of chlorambucil was reduced to 2 mg daily. A punch biopsy, in December 1968,of a small skin lesion on the left post-auricular fold revealed basal cell carcinoma. T h e lesion was electrocauterized, with an excellent result. When last seen in February 1970, the patient was asymptomatic., without lymphadenopa thy or hepatosplenomegaly. HISTOLOGFIICNDINGS T h e lymph node section which was biopsied i n 1955 showed diffuse reticulum cell hyper- plasia entirely obscuring the normal lymphoid structure. Most of the reticulum cells were irregular, and some of them were anaplastic. A few lobulated, binucleated, or even multinucleated reticulum cells were found; some of them resembled Stermberg-Reed cells. T h e eosinophils were occasionally seen. Fibrosis was not found (Fig. 1). These findings are typical of Hodgkin's disease, mixed cellularity tYPe. Sections of lymph node biopsied in 1968 showed a severe distortion of normal architecture of lymph node by a pronounced lymphoproliferative process. Both the sinuses and a considerable portion of the cortex were infiltrated with small lymphocytes which had taken over some of the follicles; in some areas, residual follicles were encountered. A pronounced lymphoid infiltration of the node capsule and lymphoid spillage into the surrounding fatty tissue were noted. A large number of lymphocytes was found in the small vessels of the lymph node (Fig. 2). There was no evidence of Hodgkin's disease. IMMUNOLOSGTUIDCIFS T h e lymphocyte response to phytohemagglutinin (PHA) was performed according to the method previously reported.8 DNA synthesis was maximal on third day of lymphocyte culture in normal individuals. DNA synthesis was markedly depressed on the third day, and it was maximal on seventh day of lymphocyte culture in this patient. This depressed and delayed PHA response is usually seen in typical chronic Iymphocytic leukemia. 302 Vol. 28 FIG. 1. Lymph node biopsy showing Hodgkin's disease, mixed cellularity type with multinucleated Sternberg-Reed cell (H and E, X2700). Purified protein derivative (PPD), intermediate strength, and mumps skin tests were positive during the period 1964 through 1968, when Hodgkin's disease was in remission. This delayed skin test reactivity remained present when the patient developed chronic lymphocytic leukemia: however, both skin tests became negative 6 months after prednisone and chlorambucil administration was initiated. T h e serum electrophoretic pattern was normal with 1.1 g/100 ml gamma globulin prior to the onset of chronic lymphocytic leukemia. Hypogammaglobulinemia (700 mg/100 ml) was observed after the diagnosis of chronic lymphocytic leukemia was established. Immunoglobulin determination was performed according to the method of Fahey and Lawrence.6 IgG was 445 mg/100 ml, which is significantly lower than the normal value (1200 2 300 mg/100 ml). IgA was 125 mg/100 ml, which is slightly lower than the normal value (288 2 121 mg/100 ml). IgM was 54 mg/100 ml, which is within normal limits (80 -C 29 mg/100 ml). This patient with Hodgkin's disease of mixed cellularity type was in remission for 13 years, then developed classical chronic lymphocytic leukemia with generalized lymphadenopathy, splenomegaly, and lymphocytosis; a cervical lymph node biopsy was typical of chronic lymphocytic leukemia or lymphosarcoma. T h e delayed and depressed DNA synthesis of in vitro lymphocyte response to PHA, and liypogarnmaglobulinemia in this patient strengthen the diagnosis of chronic lymphocytic leukemia. Review of the literature indicates that Hodgkin's disease complicating chronic lymphocytic leukemia outnumbered chronic lymphocytic leukemia complicating Hodgkin's disease. T h e true incidence of Hodgkin's disease developing in patients during the course of chronic lymphocytic leukemia is unknown. I t seems to be very low; in this Institute, we have observed no Hodgkin's disease in approximately 400 patients with chronic lymphocytic leukemia. Moertel and Hagedornls reported a study of so.2 CLL IN HODGKIND'ISEASE* Hun 303 FIG2. . Lymph node biopsy showing chronic lymphocytic leukemia (H and E, ~ 2 7 0 0 ) . incidence of second malignant disease in 120 There are only a few reports in the litera- patients with lymphocytic leukemia and lym- ture regarding the incidence of second malig- phoma. They observed no incidence of Hodg- nancy in patients with Hodgkin's disease. kin's disease in patients with chronic lym- Razis et a1.21reported the incidence of malig- photytic leukemia. Gunz and Angus7 also did nant and non-malignant diseases in 1,102 pa- not observe any cases of chronic lymphocytic tients with Hodgkin's disease; there were no leukemia complicated by Hodgkin's disease in cases of chronic lymphocytic leukemia compli- their national survey in England. Hymanl2 cating Hodgkin's disease. We found only one recently reported an increased incidence of case of chronic lymphocytic leukemia among neoplasm in association with chronic lym- 976 patients with Hodgkin's disease during photytic leukemia. T h e author found four in- 1928 through 1968 at our Institute. There are stances of Hodgkin's disease complicating only 2 reports25~~o7f Hodgkin's disease compli- chi onic lymphocytic leukemia or lymphosar- cated by chronic lymphocytic leukemia (Table coma among 209 patients with these diag- 3). Warthin25 described a 45-year-old woman noses; n o case histories were given. We have with Stage I11 Hodgkin's disease of 4 years' found 17 well-documented cases of chronic duration who developed a blood picture of lymphocytic leukemia complicated by Hodg- chronic lymphocytic leukemia just prior to kin's disease during a 40-year period (1928- her death. Autopsy of this case showed no 1967) in the medical literat~re'~,1'.1~-~~,19,l2y~m,phocytic infiltration in the lymph nodes, 2 3 ~ 4 ~ 2(T7 able 2). spleen, liver, or bone marrow, with the excep `There were 12 male and 5 female patients. tion of lymphocytes in the blood vessels of T h e diagnosis of Hodgkin's disease was made these organs; Hodgkin's disease was found in at autopsy in the majority of these cases. T h e each organ. It is possible that the lymphocyto- granuloma type, found i n 10 patients, was the sis was a preterminal leukemoid reaction. most common among the different histologic Watson27 reported a 65-year-old man with cell types. Stage 111 Hodgkin's disease complicated by 304 CANCERAugust 1971 Vol. 28 TABL2E. Summary of Reported Cases of Hodgkin's Disease (HD) Complicating Chronic Lymphocytic Leukemia (CLL) .I Case no. Authors Time of Primary Secondary secondary Year Sex Age diagnosis diagnosis diagnosis 1 McCartney' 7 1928 2 MacMahon & P a r k e P 1930 3 Holler" 1931 4 Craver' 1936 5 Watsonn 1938 6 Seife et al." 1951 7 Krim et al.14 1952 8 Epstein3 1956 9 Keiser e t al.13 1961 10 Reiser et al.13 1961 11 Lortholary et a1.*6 1964 12 Lortholary et al.ls 1964 13 Lortholary e t a1.16 1964 14 Oberfieldlo 1966 15 New Eng. J. Med.2 1966 16 Tornyos e t aLZ4 1967 17 Orts & ManezZ0 1967 F M M M M M M F M M M M F F F M M 52 CLL H D Postmortem 61 CLL HD Postmortem 41 CLL H D Postmortem 35 CLL H D Postmortem 67 CLL H D Postmortem 76 CLL HD Postmortem 67 CLL H D -4ntemortem 30 CLL H D Postmortem 59 CLL H D -4ntemortem 64 CLL H D Postmortem 51 CLL H D Postmortom 58 CLL H D iintemortem 60 CLL H D Postmortem 55 CLL HD Postmortem 39 CLL H D Antemortern 67 CLL H D Postmortem 50 CLL HD An temortem lymphocytic leukemia. This patient died 2 years after the time of diagnosis. At autopsy, the diagnosis of Hodgkin's disease was confirmed; lymphocytic infiltration suggestive of lymphocytic leukemia was found in the lymph nodes, spleen, liver, and bone marrow. This case does not meet generally accepted criteria for chronic lymphocytic leukemia. O u r case seems to be unique, with classical chronic lymphocytic leukemia developing during a prolonged remission of Hodgkin's disease. An occurrence of myeloid leukemia in 3 patients with Hodgkin's disease was recently reported by Ezdinli et al.* from our Institute. T h e only common factor in these 3 patients and 4 of 5 cases with coexistent Hodgkin's disease and myeloid leukemia reported by others was radiation therapy. These authors concluded that these cases probably represent radiation-induced leukemia. This conclusion was strengthened by the incidence of leukemia in Hiroshima atomic bomb survivors.10 Chronic myelocytic leukemia was commonly observed among those of middle age, in both the heavily and lightly exposed group. However, acute leukemia predominated among those who were under 9 years of age or over 60 in the heavily exposed group. It is of interest that no case of chronic lymphocytic leukemia was encountered among atomic bomb survivors. Although our patient received irradiation 13 years prior to the diagnosis of chronic lymphocytic leukemia, we feel that the radiation was not an inducer of this leukemia and that these two diseases were merely coincidental in the same patient. T h e etiologic interrelationship among Hodgkin's disease, lymphosarcoma, reticulum cell sarcoma, and chronic lymphocytic leukemia is not well defined. It is generally agreed that lymphosarcoma may at times transform into either chronic lymphocytic leukemia or TABLE3. Case no. 1 2 3 Summary of Our Case and Reported Cases with Hodgkin's Disease ( H D ) Complicated by Chronic Lymphocytic Leukemia (CLL) ~~ Authors Time of Primary Secondary secondary Year Sex Age diagnosis diagnosis diagnosis Warthin25 Watsonz1 Present case 1906 1938 1970 F M M 45 HD CLL Antemortern 65 HD CLL Postmortem 35 HD CLL Antemortern so. L` -CLL IN HODGKIND'ISEASE H u n 305 reticulum cell sarcoma, and Hodgkin's disease may transform into re1iculum cell sarcoma in the coiirse of the discme. Richtel-22 first reported a case of chronic lymphocytic leukemia complicated bv reticulum cell sarcoma. Since then, mole cases of such association of these t w o diseases have been reported6 Conversion of reticulum cell sarcoma from chronic lympliocytic leukemia seems to be a usual progression of the disease. Tlw relationship between I Iodgkin's disease a n d lympliosarcoma or chronic lymphocytic leukemia is uncertain. Hodgkin's disease and other malignant lymphoproliferative disease are usually regarded as distinct neoplastic entities. I n addition to unusual cases of association of Hodgkin's disease and chronic lymphocytic leukemia already mentioned, there were a few reportsg.2" describing an association of Hoclgkin's disease and lymphosarcoma in the same individual. This association of Hodgkin's disease and chronic lymphocytic Ieitkeniia in our case probably represents the occurrence of two separate diseases, although the possibility that Hodgkin's disease can transform into chronic lymphocytic leukemia is not entirely ruled out. REFERENCE5 I . Craver. 1. F.: C1inic;il manifestations and treatment of lukcineia. Amer. /. Cancer 26:124-136, 1936. 9 . Case records of the Massachusetts General Hospital: weekly clinicopatholopical exercises, Case 28-1966, Y e w Eng. J. M e d . 274:1433--1440,1966. 3. Epstein, R . D.: An apparent case of chronic lympliocytic leukemia terminating as Hodgkin's disease (samima). N e w York /. M e d . 56:3518-3520, 1956. .i.Ezdinli, E. %., Sokal, J. E., Aungst, C. W., Kim, U., and Sandberg, A . A.: Myeloid leukemia in Hodgkin's disease: chromosomal abnormalities. A n n . Intern. Med. 71:1097-1104, 1969. 3 . Fahey, J. L., and Lawrence, J. E.: Quantitative determination of 6.6 S gammaglohulins, B2*globulin5 and garnrna,-mncioglobulins in human serum. /. Imniunol. 91:597-603, 1963. 6. Givler. R. I>.: Lymphocytic leukemia with coexis- tent localizetl reticulum cell sarcoma. Cancer 21:1184- llG2, 1968. ?. Gunz. I'. W.,and Angus, H. n.: Leukemia and cancer in t h e same patient. Cancer 18:145-152, 1965. 8. Han, T.: Lymphocytic response to phytohemagglutinin in "benign" chxonic lyrnphocytlc leukemia. ClIm Res. 17:604, 1969. !). Herliut. P. A,, Miller, F. R., and Erf, L. A.: T h e relation ticulum of IIodgkin's cell sarcoma. Adimseears.e],. lymphosarcoma an Path. 21:233-2.53, d re19-15. 10. Heysscl. R.. Brill, A. B., Woodbury, I.. A., Nisliimuiia, E. T., Gliose, T.. Hoshino, T., and Yamasaki, M,:Ixukemia in Hiroshima atomic bomb survivors. B l ~ o d15:313-331, 1960. I I . Holler, G.: Beobachtung Uber Die Wcchselwir- kung Zwischen Ixukamic: und Tuberkulose im Mensclilichen Organismus. K l i u . Wschr. 101663-1666, 1931. I?. Hynian, G. A,: Increased incidence of iieoplasia in association with chronic lymphocytic leukemia. Sciznd. J. Haenint. 6:99-104, 1969. 13. Keiser, V. G., Uelrlingcr, E., and Virieux, C.: Zwei Falle von chronischlymphatischer leukamie iind Morbus Hodgkin. Acla Haemat. 2G:2943, 19Gl. 14. Krim, M., Meyer, L. M., Rosenthal, J., and Ritz, N . D.: Conversion of lymphocytic leukemia to Hodgkin`s disease. Arch. Intern. Med. 89:297-302, 1952. 15. Lortholary. P., Boiron, M., Ripault, P.. Levy, J. P., .Manus, A., and Bernard, J.: Leucimie lymphoide chronique secondairment associee a une reticulopathie maligne, syndrome de Richter. Nouv. Rev. Franc. Hetnat.4:621-644, 1964. 16. MacMahon, 11. E.. and Parker, F. Ir.: A case of lymphoblastoma, Hodgkin's disease and tuberculosis. Amer. J . Path. 6:367-380, 1930. 17. McCartney, J. S. Jr.: Malignant Iymphoblastonia: a report of two cases. J . Cancer Res. 12:195-207, 1928. 18. Moertel, C. G., and Hagedorn, A. B.: Leukemia or lymphoma and coexistent primary malignant lesions: a review of the literature and a study of 120 cases. Blood 12788-802, 1957. 19. Oberlicld, R . A.: Coexistence of chronic lymphocytic leukemia and Hodgkin`s disease. J A M A 195:865867, 1966. 20. Orts, F. M., and Manez, J. E.: Leucemia linfocitica cronica y enfermedad de Hodgkin en un mismo enfermo. Rev. Clin. ESP. 106:394-397, 1967. 21. R a ~ i sD, . V.,Diamond, H. D., and Craver, I,. F.: Hodgkin's disease associated with other malignant tumors and certain non-neoplastic diseases. Amer. J . Med. Sci. 238527-335, 1959. 22. Richter, bf. N.: Generali7ed reticulum cell sarcoma of lymph nodes associated with lyniphatic leukemia. Artier. /. P d z . 43285-292. 1928. 23. Seife, M., Reich, C., and Lisa, J. R.: Chronic lymphatic leukemia associated with Hodgkin's dibease. Actn Iiaenicit 5:65-74, 1951. 24. Tornyos K., Macossay, C. R., and Gyorkey, F.: Chronic lympliocytic leukemia and Hodgkin's disease in the same patient: Report of a case, giving imrnunological and diagnostic considerations. Cancer 20:552-557, 1967. 25. Warthin, A. S.: A case of lymphatic leukemia with histological picture resembling that of Hodgkin's disease. Trans. Ass. Amer. Physicians 21:465-474, 1906. 26. Warthin, A. S.: T h e genetic neoplastic relationships of Hodgkin's disease, aleukemic and leukemic lymphoblastoma, and mycosis fungoides. Ann. Surg. 153:153-161, 1961. 27. Watson, C. J.: Lymphosarcoma and leukosarcoma. In Handbook of Hematology, vol. 4. New York, Hoeher Co., 1938; p. 3049.