The Clinical Picture of Hodgkin's Disease1

[CANCER RESEARCH 26 Part I, 1047-1060, June 1966] The Clinical Picture of Hodgkin's Disease1

JOHN E. ULTMANN,2 JAMES K. CUNNINGHAM,3 AND ALFRED GELLHORN

Department of Medicine, Columbia University College of Physicians and Surgeons, and the Francis Delafield Hospital, New York, New York

Summary and it might be asked: "What have we learned since then? Has our clinical knowledge increased since microscopy, bacteriology, The clinical manifestations and laboratory findings in patients with Hodgkin's disease have been reviewed. Variability of the virology, immunologi', and other medical disciplines have begun to flourish? How have the developments of radiotherapy, chemo course makes prognostication for any 1 patient difficult. Extent therapy, antibiotics, and blood transfusion affected the natural of disease; histologie appearance; age and sex; involvement of history and prognosis of the disease?" specific organs, such as liver or bone; and response to initial The present conference affords us the opportunity to examine therapy all affect prognosis. The cause of death of patients with those features of the clinical picture of Hodgkin's disease which Hodgkin's disease may be due to tumor involvement or due to might present obstacles to its control. A review of the recent complications, in particular, infections and bleeding. During the literature (1, 27, 34, 94, 102, 131, 147, 154, 238) and of the 135 past 50 years, improvement in survival of patients has been due cases seen at Francis Delafield Hospital during the past 14 years largely to identification of patients with local or regional disease confirms a number of previous observations and raises some and their treatment with aggressive radiotherapy. Current modes additional questions. of chemotherapy combined with improvements in supportive care have had only modest effects on survival rates. The major obstacle to a rational approach to the problem of Hodgkin's dis Clinical Findings ease is the identification of the etiology of this disorder. Characteristically, the patient gives a history of excellent health until the onset of his disease which usually is manifested Introduction by adenopathy with or without systemic manifestations. Occa In a recent review of 19th century foundations of cancer re sionally a brief antecedent history of upper respiratory infection, search, TriÃ³lo(229, 230) reported that the 1st cooperative ven or of infections about the head and neck is given. The duration ture in oncology was promoted by a group of English clinicians of symptoms and of physical findings before biopsy is variable. who in 1802 organized themselves into a professional society. In Delay by the patient or by his physician prior to the recognition 1806, they circulated a questionnaire among practitioners in of the disease may be considerable. which they inquired regarding current opinions on etiology, The presenting symptoms most commonly are those of pain heredity, diagnosis, and treatment of cancer. This English cancer less, progressive enlargement of a superficial lymph node or a society thrived under the aegis of Hunter, and his tradition was group of lymph nodes, especially in the neck, and various sys continued by the work of Home and others (230). Among this temic manifestations, including malaise, anorexia, weight loss, group of investigators was a pathologist named Thomas Hodgkin, nausea, vomiting, fever, or pruritus. The order of frequency of who, in 1832, reported 7 cases of generalized lymphadenopathy involvement of the superficial lymph nodes is the cervical (60- and splenomegaly and noted that "as far as could be ascertained 80%), the axillary (6-20%), and the inguinal (6-12%) (34, 81). . . . this enlargement of the glands appears to be a primitive af The mediastinal lymph nodes are involved initially in 6 to 11 per fection of those bodies" (58, 87). In 1865, Wilks clarified the cent of cases (34, 81). The retroperitoneal lymph nodes, the liver, clinical entity by describing 15 cases, 13 of which "resembled in and the spleen are less commonly clinically involved in the early all particulars the first four which Dr. Hodgkin first brought unto phases of the disorder. the notice of the profession," and he suggested the name Fever occurs eventually in 30-5090 of cases, is cyclic, continu "Hodgkin's disease" (245, 246). ous, intermittent, or more rarely the Murehison-Pel-Ebstein Now, l| centuries have passed since the original description type (34, 48, 87, 94, 135, 158, 167, 168). During fever, the pulse is rapid and drenching sweats are common. Occasionally patients complain of diaphoresis even in the absence of fever. Weakness, 1This work was supported by USPHS Research Grant No. fatigue, anorexia, weight loss, and cachexia eventually occur in RIO CA-02332-11 from the National Cancer Institute, The Health all patients. In 10-15% of cases, pruritus is an early symptom Research Council of the City of New York (1-109), and the Anne but up to 85% of the cases have pruritus some time during their Winton Memorial Fund. Requests for reprints should be addressed to: John E. Ultmann, Columbia University College of Physicians illness (94). and Surgeons, 630 West 168th Street, New York, New York. Intrathoracic involvement is frequent (146) and mediastinal 2 Career Scientist, The Health Research Council of the City of nodes are involved in over 60% of the patients in the course of New York. the disease (34). Symptoms of involvement of thoracic structures 3 Clinical Fellow, American Cancer Society. â€¢â€”suchasdyspnea due to mediastinal node pressure, a brassy

JUNE 1966 1047

cough, and dysphagiaâ€”all may mimic other tumors and infec tions of the chest. Obstruction of the superior vena cava may 100 Q occur. Clinical involvement of the lungs is seen eventually in up B to 40% of cases (34, 116, 155, 156, 186, 217) and may simulate other tumors and pulmonary infections. Pulmonary fibrosis with I severe restriction of ventilatory capacity may appear in the 80 course of the disease or as a result of radiotherapy to the lungs (50, 217, 218). Cavitation has been reported (44, 214). Endo- bronchial lesions may occur (72). Cytologie study of sputum and of bronchial washings may show tumor cells, which, with experi ence, are recognizable as Hodgkin's cells (221). One-third of the NORMAL BLOOD i 60 patients show pleural effusion (217) ; however, at autopsy up to 8! 60% of cases have this finding (248). Although positive identifi BLOOD cation of the lymphomas can be made in over \ the cases of pleural effusion, malignant cells are seldom found in Hodgkin's 20 disease (149). Other thoracic structures, including thymus (141), HEMATOCRIT (%) heart (24, 103, 185) or pericardium (77, 103), may be affected. Abdominal and retroperitoneal disease is extremely frequent in the course of Hodgkin's disease (34). Symptoms of abdominal Å’ SPLEEN disease may be those of bleeding; obstruction; or nausea, vomit I ing, and diarrhea secondary to infiltration of the mucosa of the CE LIVER O gastrointestinal tract (28, 34, 109, 115, 174, 216). Bleeding from NORMAL SPLEEN esophageal varices as a result of portal hypertension from exten NORMAL LIVER sive involvement of the liver has been reported (126). Pressure symptoms from a large mass in the retroperitoneum or from the 10 15 20 enlargement of spleen and liver are common. DAYS The spleen is involved initially in up to 30% of patients; CHART1. Results of 6lCr HBC life-span study in a patient with eventually, in 80% of cases (34, 81, 102). Primary splenic Hodgkin's disease. There was a severe anemia, the direct Coombs Hodgkin's, however, is rare (34, 194). In the presence of enlarge test was negative, and the spleen was enlarged 5 cm below the left ment of the spleen, hypersplenism may occur with anemia, leuko- costal margin. The study indicates a 50% RBC survival of ap penia, thrombocytopenia, or a combination of these. Hepa proximately 12 days with major uptake of the radioactive label tomegaly is an early finding in \ of cases; liver involvement, over the spleen. determined microscopically, occurs in over \ of patients (34, 128) ; however, in 2 large series the incidence of clinical jaundice other portions of the urinary tract. Reed-Sternberg cells may be was only 10-15% (16, 127, 128). recognized by cytologie examination of urine sediment (193). Bone involvement is found in 60% of autopsied cases; how Involvement of the tonsil or Waldeyer ring may occur as an ever, during the course of illness, the number of patients with initial manifestation (163); other portions of the nasopharynx bone pain or X-ray evidence of destruction of osseous structures and the larynx may also be affected. is less than 30% of total (34, 53, 94, 102, 220). Most studies appear to indicate that pregnancy can be well Abnormalities of the central nervous system are noted in over tolerated, particularly in patients who have the "chronic form" 10% of the patients (43, 80, 94, 102, 227). The brain or spinal of the disease. It has been suggested that pregnancy be avoided cord may be invaded directly (43). However, more commonly, until 2 symptom-free years have passed (10, 34, 59, 83, 84, 97, symptoms are due to compression from tumor outside the spinal 112,210,211). cord (43). Toxic encephalitis without manifest lesions of Hodgkin's disease in the brain, particularly in the cerebellum Laboratory Findings (cerebellar leukoencephalopathy), has been reported (34, 39, 45, 180). Alcohol intolerance has been described in 17-20% of cases Anemia is a frequent complication. A few patients (10%) have but does not appear to be specific for Hodgkin's disease (13, 17, a hypochromic microcytic anemia, usually secondary to blood 29, 104, 105). Peripheral neuropathies and cranial nerve palsies loss. Hemolytic anemia (101, 233) may occur with localized dis may occur (43). Involvement of the eye with invasion of lacrimal ease, but is present in 80% of cases with late Hodgkin's disease. gland, uveal tract, optic nerve, or retroorbital region has been This anemia is characterized by normochromic, normocytic recorded (172). erythrocytes; anisoeytosis; spherocytosis with increased osmotic Skin involvement may be due to direct invasion, an "id reac fragility of red cells; reticulocytosis; and minimal icterus. The tion" or excoriations produced in response to pruritus (34, 51, 94, direct Coombs test is usually negative. In instances where 102, 139, 184, 222). Ichthyosis and severe anhidrosis are seen Coombs-positive hemolytic anemia is present, quantitative occasionally (51). studies of the effect of red blood cell sensitization on red cell sur Almost any organ may be involved initially or in late stages vival have been performed implicating the protein coating in the by Hodgkin's disease, including: thyroid (182, 190), breast (118, erythroclasia (31). Hoff brand has reported 2 patients with 145, 152), ovary (9), cervix (161), vulva, bladder (138), and Hodgkin's disease and severe hypo--y-globulinemia who had

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Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1966 American Association for Cancer Research. Clinical Picture anemia, reticulocytosis, shortened red cell life-spans, and marked crease in the a2-globulins is largely due to an increase of hapta- hyperplasia of reticuloendothelial cells (88). The anemia appears globin and ceruloplasmin (136). An increase in hexose bound to to be related to the proliferation of histiocytcs in the spleen and aa-globulin has been noted (243). Although some authors feel other reticuloondothelial sites capable of phagocytosing red cells that hypo-7-globulinemia is seen only rarely in patients with (18). Chart 1 summarizes the results of a red blood cell (RBC) Hodgkin's disease (89), we have found that significant hypo-7- life-span study in a patient with severe anemia and splenic en globulinemia (<0.6 gm) occurs in almost ^ the cases, particu largement. A marked decrease in T J 51Cr RBC life-span and larly in advanced disease (90). Elevation of â€¢y-globulinswasseen significant sequestration of red blood cells in the spleen are seen. in over 40% of our patients. Fibrinogen values may be markedly Cline and Berlin (26) and others (40, 60, 64, 95, 124, 176, 244) elevated, but there appears to be no clear-cut relationship to have reported similar findings. In addition, hypoferremia and extent of disease or to results of therapy (181). C-Reactive abnormalities in iron (59Fe) metabolism consisting of excessive proteins are also frequently elevated (249). uptake of iron by liver and spleen and impaired incorporation of Increased excretion of tryptophan metabolites and an abnor iron into erythrocytes have been noted (26). It has also been mal response to tryptophan loading have been noted (36). Ele demonstrated that labeled hemoglobin-iron (Hb-5SFe) is re- vation of serum hydroxyproline has been reported (123). Serum utilized poorly (79). A relative decrease in erythropoiesis may, enzyme abnormalities have been recorded (239). A low plasma in part, be due to a deficiency of folie acid [(175) (Klipstein and zinc content (7, 223) and an elevated serum copper content ritmami, unpublished observations, 1965)]. The anemia becomes (107)â€”particularly marked in Hodgkin's disease as compared to progressively worse as the disease advances and correlation with the other lymphomas and leukemiasâ€”have been observed. There disease activity is often possible (176). have been reported no differences in the incidence of major blood The changes in the white blood cells are not constant and not types in patients with Hodgkin's disease as compared to various diagnostic (34, 56, 94, 102, 234). Leukocytosis with neutrophilia control groups (129). is present in over 50% of patients. Monocytosis and lympho- cytosis have been noted in a few. Leukopenia as well as lympho- Rocntgeiiologic and Isotope-scanning Studies penia often occur in advanced disease. Eosinophilia, occasionally marked, may be seen. The leukocyte alkaline phosphatase (LAP) The evaluation of the extent of initial involvement is of im value is often elevated during the active phase of disease and measurable help in prognosis and in planning of therapy for each falls during remissions. When leukopenia occurs, increased LAP patient. The correlation of the clinical findings with radiologie activity can be used as an index of active disease (57, 120, 142, studies is extremely important and useful. Tomography, intra 150). The platelets are normal or increased (9% of cases) in the venous pyelography, gastrointestinal studies, and splenopor- beginning of the illness; in the course of the disease, they usually tography have been employed for many years. More recently diminish in number because of the cumulative toxic effects of employment of radiopaque iodized oil (Ethiodol) for lymphangi- radiation and chemotherapy and, more rarely, because of bone ography (11, 117, 196, 197), radioactive gold (198Au)for liver marrow replacement by Hodgkin's disease. About 5% of cases scanning and for bone marrow scanning (49), heat-damaged show myeloid metaplasia associated with hypoplastic bone 51Cr-labeled red cells for spleen scanning, and m I-aggrega ted marrow or tumor infiltration of bone marrow (125). Bone marrow albumin for lung scanning (225) have all addivi new dimensions aspiration is usually not helpful in ruling out bone marrow in to the meaning and limitations of "clinical local disease." A major volvement and formal biopsy may be necessary (94, 130, 234, by-product of these diagnostic studies is the possibility of de 251). When present, Reed-Stemberg cells are readily recogniza livering therapeutic agents to local areas. Therapy with radio ble (251). On rare occasion, these cells appear in the blood active colloidal or iodized oil substances by these routes is (137, 195). already under investigation. The erythrocyte sedimentation rate (ESR) is elevated in the presence of active disease and falls after effective therapy or Prognosis during spontaneous remission. Thus, in patients who have eleva tion of the ESR at an early stage of their disease, this test be Prognosis has always been difficult to evaluate, as the clinical comes a good index of the activity (34, 94). course of Hodgkin's disease is characterized by great variability. Hypercalcemia may occur (up to 30% of cases) and is usually Progression is by successive exacerbations which may occur at associated with hypophosphatemia and elevated serum alkaline intervals of weeks, months, or years. Shimkin (201) as well as phosphatase. Roentgenographic evidence of skeletal involvement Osgood (165) have stressed the difficulty of comparing results of by tumor may be absent, although autopsy usually reveals treatment in Hodgkin's disease between various centers. This osseous involvement (157). Hyperglycemia may be seen in asso occurs because of: (a) differing methods of reporting survival ciation with steroid therapy and during exacerbations of the (from onset, from accession to hospital, from biopsy, from disease (140). Gout as well as decreased renal function following therapy; some divide their series into living and dead patients, persistent hyperuricemia have been reported (173, 224). Uremia others consider all patients '"dead" at time of tabulation, whereas may occur as a terminal event. still others examine their data by life-table (actuarial) ap Serum abnormalities occur regularly. Albumin is often reduced, proaches, etc.); (6) variability of patient material (i.e., age, sex, mainly due to a decrease in synthesis (236); in patients with economic background, etc.); and (c) differences in approach to effusions, fractional degradation of 131I-labeled albumin is in patients over a long period of years, yet all patients being in creased (236). Serum at-, Â«2-(77% of cases), and /32-(35% of cluded in a single series. cases) globulins are often increased (5, 67, 162, 188). The in The actuarial method measuring probability of survival from

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Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1966 American Association for Cancer Research. John E. Ultmann, James K. Cunningham, and Alfred Gellhorn date of biopsy probably reflects results most accurately. A com cates that the prognosis of cases with disseminated disease parison (Table 1) of a selected number of recent reports shows a (Stage III) is poor in all reported series (34, 85, 164, 171, 198, range of 5-year survival for all patients with Hodgkin's disease 240). from 22 to 38% and of 10-year survival from 5 to 24% (32, 34, The data show an impressive difference in survival between 63, 85, 148, 164, 171, 208, 240). the patients presenting initially with local or regional disease and Chart 2 summarizes the age and sex distribution in our group those presenting initially with disseminated disease. Since, by of patients. Sixty % of our patients were males. Table 2 (34, 55, history, the patients with Stage III disease have not apparently 102, 124, 147, 232, 235) compares our series with others regarding all gone through Stages I or II, the possibility exists that we are age distribution. In our series, a larger proportion of patients dealing with variants of Hodgkin's disease rather than a single were over 40 years of age compared to other reported series. The disease entity. Our lack of understanding of this issue appears effect of age on survival is shown in Chart 3. A comparison of to be an obstacle to the effective control of Hodgkin's disease. survival data according to sex in our patients and in selected The effect on survival of histologie type has been clearly estab reports is shown in Table 3 (124, 202). It is readily apparent that lished since Jackson and Parker's studies (102). Patients with young patients or females will show longer survival than older paragranuloma show over-all survival results superior to the patients or men regardless of differences in other parameters or other groups (37, 208, 250). Recently, Lukes (131, 132) and in therapy. Hanson (78) have shown that nodular sclerosing Hodgkin's Chart 4 emphasizes the not unexpected finding that survival disease has a prognosis as favorable as paragranuloma. of patients with localized disease is better than that of the other Cohen et al. (27) have attempted to prognosticate regarding cases. In our patient material, the therapy of the Class I and II survival in the presence or absence of certain clinical and labora cases was often carried out in nonspecialty hospitals and the tory findings. They found that as the number of initial physical majority of these patients did not receive intensive radiotherapy. findings and laboratory abnormalities increased, the survival de- Table 4 stresses the further improvement which can be achieved by intensive radiation to localized disease. The table also indi- SEX NUMBER %. FEMALE '55 44 TABLE 1 MALE 80 59 COMPARISONOFSURVIVALDATAIN PATIENTSWITHHODGKIN'S TOTAL 135 DISEASE 12

AuthorsNice of Survival survival patients20838812122134741151410715013513550% CO (mo.)27242823255-yrsurvival(%)253326383532383132222510-yr(%)10178241910512Lu CO (164)Smetanaand Stenstrom 3 (208)Gellhornand Cohen (63)Peters OC (171)Cookand Middlemiss 111 et al.(32)Warwick m (240)Craverand Sellers (34)Hilton (85)Meighanand Sutton (140)Ultmannand Ramsey I (survivalmethod)Ultmannet al. upto 10 20 30 40 50 60 70 80 AGE IN YEARS tablemethod)Yr1954195619571958195919591964196219631965No.et al. (life CHAUT2. Age at onset and sex of 135patients with Hodgkin's disease seen at the Francis Delafield Hospital from 1951to 1964.

TABLE 2 DISTRIBUTIONBYAGE IN HODGKIN'SDISEASE

AUTHORSÃœddstrÃ¶mer OFPATIENTS53617232917591186490135YEARS0-96293312310-199101115199131120-29243316212729311630-39192415162917231340-49141215161112121850-5914121510810101560-691171413313817>70356917

(232)Videbaek (235)Jackson (102)Fayosand Parker (55)Levinsonel al. (124)Meighanet al. (148)Craver (34)Ultmann YorkCityNew et al.LOCATIONSwedenDenmarkBostonMichiganUtahSaskatchewanNewYork CityYEAR1915-19311930-19451902-19461940-19551945-19551946-19591949-19551951-1905No.

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Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1966 American Association for Cancer Research. Clinical Picture creased. Using an analogous approach, we have calculated sur tomatic or was discovered roentgenologically, it appeared to be vival from date of biopsy in symptomatic Stage III patients with a serious complication and ^ the patients succumbed within hepatomegaly (Chart 5). The poor prognosis of a finding of 6 months. hepatomegaly is striking. It has been stated by Stuhlbarg and Ellis (220) that "unlike Complications and Cause of Death other forms of malignant disease involving bone, that seen in Hodgkin's disease occurs in patients who have a longer survival It has been stated in the literature that the most common than patients without such clinical manifestations." In their causes of death of patients with Hodgkin's disease are a "toxic study, survival was measured from date of 1st biopsy and not state" associated with extensive visceral involvement or a termi from occurrence of the 1st bone lesion. Examination of our own nal state associated with secondary infection. The nature of the patient material (Chart 6) indicates that evidence of involve toxic state has never been defined (34, 94, 102). In our own group ment of bone by Hodgkin's disease is an ominous sign. Patients of 135 patients, 115 have died. The following clinical conditions who had this type of involvement at the time the diagnosis of were apparently responsible for the patient's death (often more Hodgkin's disease was proven had a short survival. Those pa than 1 condition was present): severe infection (21% of cases), tients who developed bone involvement at a later date in the failure of pulmonary function (20% of cases), central nervous course of their disease were indeed patients who had lived system involvement or malfunction (11% of cases), gastro longerâ€”an average of 35 months (range 1-140 months, median intestinal bleeding (10% of cases), and liver failure (7% of cases). 22 months) ; however, whenever bone involvement became symp In 30 patients, anemia, leukopenia, thrombocytopenia, or a com-

SURVIVAL 100 AGE PATIENTS 50% 5 YR SURVIVAL â€¢â€”10-29 37 35 MO. 35% CLASS FWIENTS 50% 5YR â€¢â€”30-49 42 32 MO. 29% 36 MO. 37% :\ 50-69 43 I9MO. 12% 22 MO 20% 135 25MO. 25% 24 MO. 25%

CHART 4. Survival from date of biopsy according to regional CHART 3. Survival from date of biopsy according to age in 135 classification in 135 patients with Hodgkin's disease. The calcula patients with Hodgkin's disease. The calculations of survival were tions of survival were performed according to the life table performed according to the life table method (63). method.

TABLE 3 COMPARISONOFSURVIVALDATAIN PATIENTSWITHHODGKIN'SDISEASEACCORDINGTOSEX

AUTHORSLevinson ofpatients62157 of survival survival(%)8patients29 survival survival(%)20 (%)27 (%)50

et al. (124) Shimkin(201)Ultmann 1964CHRONOLOGICPERIOD1940-4420 12 112 24 14 1945-491950-54MALENo.367609805-yr22251910-yr145FEKALENo.270419555-yr343727I0-yr215

el al.YR1957

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TABLE 4 COMPARISONOFSURVIVALDATAIN PATIENTSWITHHODGKIN'SDISEASEACCORDINGTOREGIONAL CLASSIFICATION

I5-yr IIsurvival90355638553810-yrIII5-yr

AUTHORSNice survival8710-yrsurvival7757716079665819STAGEsurvival35358STAGEsurvival101215153171810-yrsurvival2234

(164)Sellersand Stenstrom (198)Peters (171)Warwickand Middlemiss (240)Hiltonand Sellers (185)Graverand Sutton (34)Ultmann el al.YR195419571958195919621964STAGE

100 SURVIVAL BONE SURVIVAL SURVIVAL INVOLVEMENT 50% 5 YR. INVOLVEMENT FROM 50% 5YR.

LIVER ONLYj OR LIVER 7 MO. IST BIOPSY 18 MO 80 AND SPLEEN ISTBIOPSY 42 MO 34% ALL PATIENTS WITH; 27 MO. 18% ISTBONE 6 MO 0 SYSTEMIC LESION MANIFESTATIONS 60 PRURITUS FEVER cr BUT WITHOUT HEPATOMEGALY 40 S*

468 10 12 YEARS 468 YEARS CHART5. Survival from date of biopsy in 28 patients with hepatomegaly compared with all patients with systemic mani CHART6. Survival according to bone involvement in 44 patients festations but without hepatomegaly. with Hodgkin's disease. Eight patients had bone involvement at the time of the 1st biopsy (EARLY). In the other 36 patients bination of these, directly attributable to antecedent radio (LATER), the interval between the 1st biopsy and 1st bone lesion was 1-140 months (average 35, median 22 months). therapy or chemotherapy, contributed to the death of the patient. The frequency of infections merits further examination. Others in this conference will speak in greater detail on the character also were encountered. Pneumocystis carinii pneumonia (98) and istics of the immune defect (1-3, 46, 91). Anergy to tuberculin, listeriosis (189) have been reported. Serum 7-globulin abnormali Trichophyton, Candida, streptokinase, and diphtheria toxoid as ties were frequent; leukopenia, however, was not a constant well as delayed homograft rejection have been demonstrated feature. Active tuberculosis occurs in approximately 2% of cases (1, 203). Response to vaccination with typhoid, mumps, and (178). pneumococcal polysaccharides has been inconclusive (203). There were 16 patients with .severe monilial infection; 10 of Properdin levels are low (188) but serum complement is normal these had hypo-7-globulinemia. An additional patient had cen (187). Cellular defense mechanisms as measured by the skin- tral nervous system torulosis (Cryptococcus neofarmans) (15, 69, window technic appear to be normal (203, 241). Serum 7- 153). Other types of fungus infections, including aspergillosis globulin changes have been mentioned earlier. (23, 100), mucormycosis (52, 99), and nocardiosis (93) have been Various types of infections were encountered. Episodes of bac encountered. The occurrence of toxoplasmosis has been recorded terial septicemia as well as pulmonary, skin, and urinary tract (25, 30, 114). infections occurred in many patients. Common organisms were Seventeen patients had 19 episodes of herpes zoster. 7-Globu- Staphylococcus aureus, Escherichia coli, and Pneumococcus pneu- lins were reduced in 5 the cases. Six patients progressed to gen moniae. Salmonella typhimurium (82) and Klebsiella pneumoniae eralized herpes zoster; 4 of these were receiving prednisone.

1052 CANCER RESEARCH VOL 26

90 "'.""'cSÃ•o" -NICEAND

CLASSIC NICE AND STENSTROM â€” â€” CLASS Ht " ALL HILTON AND SUTTON

PETERS

PETERS '""" _ MEMORIAL C

, SELLERS HILTON AND SUTTON 5Q|_ LUMB AND NEWTON

Q; ULTMANN ^? LUMB AND NEWTON __ MEMORIAL C PETERS ^^~ HEALY $S KAPLAN SELLERS .;.;.;â€ž.;" ' " HOHL B-^â€”â€”^^â€” _^^^ ^ULTMANN pETERS *- HILTON AND SUTTON BODEN ^â€” HI TutMM NICE AND STENSTROM _^_^^_^ MERNER AND STENSTROM

"*"" MEMORIAL C

HQHL A-. SELLERS Â¡V> ^^^^?7?V-r-r-r_r.r.r.r.i-. PETERS "â€¢NICE AND STENSTROM GOLDMAN ...-.HILTON AND SUTTON 1910 1930 1950 1970 YEAR CHART7. Five-year survival from biopsy or therapy according to regional classification in patients with Hodgkin's disease reported in the literature from 1920 to 1965.

Similar experiences have been reported by many investigators from 10 to 25% of the cases (33, 41, 55, 102, 106, 124, 133, 207, (35, 38, 199, 242). 219, 232, 235). Unquestionably, infections contribute in a major way to The next era is that in which radiotherapy was retained as the morbidity and mortality in Hodgkin's disease. In many instances prime agent of treatment but in which sulfa drugs and peni the patients were already in the advanced phase of their disease cillin were available to combat infections (Chart 7) (12, 14, when they contracted the infection. It is difficult to assign re 32-34, 41, 55, 66, 81, 85, 92, 102, 106, 110, 124, 133, 151, 164, sponsibility to the various factors which may be involved in the 169, 198, 207, 219, 232, 235). During this time, further improve high rate of infection. They include: (a) deficit in antibody for ment in 5-year survival from biopsy is apparent. mation, hypo-7-globulinemia, and lymphopenia; (6) failure of Finally, one would like to look for alterations in the manage cell-bound antibody mechanisms; (c) leukopenia and neutro- ment of disseminated disease with our present chemotherapeutic penia secondary to replacement of bone marrow, hypersplenism, armamentarium together with the tremendous changes brought and drug or radiation toxicity; (d) glucocorticoid administration; about in the management of infectious diseases by broad spec (e) prior administration of antibiotics; (/) debility and poor nutri trum antibiotics and of anemia by modern transfusion technic. tional state; and (g) local predisposing factors, such as tumor In the last 15 years there appears to have been only slight im involvement or radiotherapy. provement in the over-all survival statistics and this is due mainly to recognition and intensive therapy of the localized Effects on Survival of Changes in Management: 1900-1965 disease (47, 110, 170). The survival of patients with disseminated disease (Class III) remains at between 5 and 20% (5-year sur One might conveniently examine the natural history of the disease in various time periods defined in terms of the therapeutic vival) (12,14, 32, 34, 66, 81, 85, 92, 110, 133,151, 164, 169, 198). Let us now turn to a consideration of the obstacles to effective modalities available. During the earliest period no therapy at all therapy. If the phenomenon of progression of Hodgkin's disease was given. The number of cases recognized was too small to come to any conclusions regarding the prognosis of untreated disease exists, that is, if there is a unicentric origin and a subsequent (68, 166, 179, 204, 215). spreading from that region, the medical profession does not seem Beginning in 1908 and to the end of the 1930's was the period to be in a position to identify it early. Examination of our proto of radiotherapy prior to the advent of antibiotics and of efficient cols indicates that patient delay, together with delay by physi blood-banking. Five-year survival from onset in most series was cians from onset of symptoms to 1st biopsy, averaged 7 months

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Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1966 American Association for Cancer Research. John E. Ultmann, James K. Cunningham, and Alfred Gellhorn in each 5-year period from 1940 to 1965. The effect of the edu TABLE 5 cational process of stressing the importance of early recognition CHARACTERISTICSorLONG-TERMANDSHOUT-TERMSURVIVORS and early biopsy seems to have been negligible. However, if further education could achieve a decrease in patient or doctor delay, would this necessarily improve the patient's prognosis? yr)3430476223520931006200Short-termÂ«6mo.)1750701002656547652500 Peters and Middlemiss (171) have [jointed out that the patients No. ofcasesMedian who have adenopathy of more than 6 months' duration prior to (yr)Malesage at onset seeking medical attention have a longer survival than those seek ing treatment under 6 months from the onset of disease. This (%)Class was particularly true for Stages I and II. Our own data regarding III(%)Sarcoma the Stage III cases suggest a similar relationship but lack sta (%)Presenting tistical significance. It is likely that Hodgkin's disease which is with:Systemic slowly progressive and comes to the attention of the patient and (%)Fever symptoms (%)Splenomegaly doctor only gradually has a better prognosis than the early symptomatic or early recognizable diseaseâ€”an intrinsic property (%)Hepatomegaly (%)Benefit of the tumor alluded to previously. If the patient were to seek from:Radiotherapy medical attention promptly, can we identify the individuals (%)Nitrogen subject to early progression or those who have already progressed (%)All mustard when we still think they have localized disease? Dr. Lee in dis other agents (%)Long-term(>5 cussing lymphangiography will indicate to us how we have extended our capability of identifying individuals who have already extended their disease. Do these individuals have a par CHEMOTHERAPY ticular histologie characteristic which would allow us to identify 100 IN them early in their disease? Dr. Lukes will speak on this subject. EFFECTIVE EFFECTIVE Comparison of cases who died early with those who lived over 5 years (Table 5) indicates that widespread disease, histology of MONTHS l" BIOPSY * sarcoma, and initial systemic manifestations and fever do not 80KOPATIENTSi\ \RX\ TO I51 CHEMO preclude a long survival. It is readily apparent, however, that MEDIAN530-1321862233370-829130 these features together with early hepatomegaly or splenomegaly (MO.)â€¢50% SURVIVAL predispose to an unfavorable course in many cases. Most striking, 2 YR. SURVIVAL (%)RANGEAVERAGE however, is the difference in response to the modalities of therapy available at present. The "long" survivors have uniformly re sponsive disease; the "short" survivors generally fail to respond I cc to anything available at present. Other investigators have made CO 40 similar observations (56). Comparison (Chart 8) of the Stage III patients, who never responded to any chemotherapeutic agent, with those who had at least 1 significant response to chemotherapy indicates that the 20 responders had their disease process significantly longer prior to 1st administration of chemotherapy and eventually lived con siderably longer than the nonresponders. Reference to previous or later experience with radiotherapy in these patients indicates 6 8 10 good but not complete correlation of chemotherapy and radio YEARS therapy response. CHART8. Survival from date of 1st chemotherapy as related to The appearance of new classes of chemotherapeutic agents may response in patients with Stage III Hodgkin's disease. change the survival statistics for Class III patients. The results obtained with vinblastine (Velban) by others (6, 61, 119) and ourselves suggest that this alkaloid may suppress disease in pa ministered after intensive chemotherapy or radiotherapy has tients who have failed to respond to radiation and the alkylating been advocated but has not been proved to be of real value (143). agents from the start or have become resistant to these modali If the rationale of intensive radiotherapy and intensive chemo ties of therapy. The experience with the methylhydrazine de therapy is based upon the hypothesis of Skipper (206), which rivatives (Natulan) (19, 54, 144, 228) also indicates that previ suggests that one must eliminate the last neoplastic cell, we have ously resistant disease may be amenable to chemotherapeutic not been successful in patients with disseminated disease. After control. Some of the patients resistant to the alkylating agents 1, 2, or many significant responses to radiotherapy or to chemo and vinblastine have shown significant remissions following ad therapeutic agents, the disease becomes refractory. It has re ministration of methylhydrazine. The attempt to treat Class III cently been pointed out by Gross et al. (76) that the virus of cases with extensive high voltage radiotherapy as advocated by murine leukemia persists even after all neoplastic cells are wiped Kaplan and by others may further improve the prognosis for out by 7-irradiation because it is particularly resistant to radia these patients. Storage of autologous bone marrow to be ad- tion. Thus, if a virus is found to be the causal agent of Hodgkin's

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Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1966 American Association for Cancer Research. Clinical Picture disease, even if we were able to eradicate the last Hodgkin cell, whether all patients start with unicentric disease or whether the virus might reinfect new cells and the disease would con some have variants of Hodgkin's disease which are multicentric tinue. The characterization of the etiologic agent responsible for from the start. The rate of progression of the disease and its re Hodgkin's disease and identification of modes of anti-viral sponse to radiotherapy or chemotherapy are unpredictable and therapy must be a prime goal of research in this area. the mechanisms responsible for these differences remain un known. Certain histologie features, tissue culture experiments, and biochemical observations suggest differences from rather Etiologic Considerations than similarities to cancer in general. The etiology of Hodgkin's Kassel (113), Aisenberg (1), and others have reviewed recent disease remains unknown and this presents the major obstacle reports regarding the etiology of Hodgkin's disease. Any current to a rational approach to the problem. hypothesis must take the following into consideration: (a) the The studies of the clinical and laboratory features, investiga developments in tumor virology (73, 75); (o) the findings tions of laboratory models which might shed light on patho- gathered in connection with the African lymphoma; (c) the epi genetic mechanisms, development of new chemotherapeutic and demiologie data collected by MacMahon (134) and others; (d) roentgenologic technics, and the broad investigations into viral the increased incidence of Hodgkin's disease in individuals who carcinogenesis and antiviral therapy will be required to unravel have a close relative with the disease (42, 108, 177) ; (e) the find the mysteries which still surround Hodgkin's disease. ing of the Atomic Bomb Casualty Commission that the incidence of Hodgkin's disease is 4 times greater in exposed than non- Acknowledgment exposed individuals (4); (/) the possible interrelationship be tween Hodgkin's disease and other lymphomata, Kaposi's We wish to thank Miss R. Arthur, Mrs. P. Bertun, Mrs. B. disease, and leukemia (20, 121); (g) the finding of Hodgkin's-like Hatherley, Mrs. F. Lefcourt; Miss C. Kenton of the National lymphomata in other species, particularly the rat (74) and the Library of Medicine; and the staff of the record room of the Francis dog (205, 209, 213); and (h) the finding of Hodgkin's-like lesions Delafield Hospital for their assistance. in the adenopathy induced by anticonvulsants, in which the lesions regress when the offending drug is removed (191, 192). References We have already alluded to the fact that some histologie 1. Aisenberg, A. C. Hodgkin's Diseaseâ€”Prognosis, Treatment features point to a neoplastic nature in this disorder, others re and Etiologic and Immunologie Considerations. New Engl. semble more those of a granuloma. Murray and Stout (159, 160), J. Med., 270: 508-14; 565-70; 017-22, 1964. employing tissue culture technics, found that "the behavior of 2. . Immunologie Aspects of Hodgkin's Disease. Medicine, the Hodgkin's node in vitro distinguishes it sharply from neo 43: 189-93, 1964. plastic tissues in general and tends to align it with granulomatous 3. Aisenberg, A. C., and Leskowitz, S. Antibody Formation in lesions." The resemblance to tissue cultures of lymph nodes from Hodgkin's Disease. New Engl. J. Med., 282: 1269-72, 1963. Boeck's sarcoid or infectious lymphadenitis may be great, 4. Anderson, R. E., and Ishida, K. Malignant Lymphoma in whereas no Hodgkin's disease cells behave autonomously as Survivors of the Atomic Bomb in Hiroshima. Ann. Internal Med., 61: 853-62, 1964. would be expected of a cancer. Rottine has made similar observa 5. Arends, T., Coonrad, E. V., and Bundles, R. W. Serum Pro tions (183). In contrast, chromosome analyses of Reed-Sternberg teins in Hodgkin's Disease and Malignant Lymphoma. Am. J. cells show hyperdiploid forms compatible with a neoplastic Med., 16: 833-41, 1954. disorder (8, 62, 212). 6. Armstrong, J. G., Dyke, K. W., Fonts, P. J., and Gahimer, In connection with this question, the previously mentioned J. E. Hodgkin's Disease, Carcinoma of Breast, and Other report of LeRoy (123) regarding the levels of hydroxyproline- Tumors Treated with Vinblastine Sulfate. Cancer Chemo containing protein in human plasma is of interest. They suggest therapy Kept., 18: 49-71, 1962. 7. Auerbach, S. Zinc Content of Plasma, Blood, and Erythro- that hydroxyproline peptides reflect collagen degradation. In a cytes in Normal Subjects and in Patients with Hodgkin's survey study, elevated values were found in connective tissue dis orders, inflammatory and febrile diseases, and afebrile Hodgkin's Disease and Varions HÃ©matologie Disorders. J. Lab. Clin. Med., 65: 628-37, 1965. disease but not in the other lymphomas or other tumors. 8. Baker, M. C. and Atkin, N. B. Chromosomes in Short-term In addition to the abnormalities in immune response, altered Cultures of Lymphoid Tissue from Patients with Reticulosis. hypersensitivity, delayed homograft rejection, autoimmune Brit. Med. J., /: 770-71, 1965. hemolytic anemia, and lack of response of lymphocytes in in vitro 9. Bare, W. W., McCloskey, J. F. Primary Hodgkin's Disease cultures to various stimuli (86), the occasional finding of amyloi- of the Ovary. Obstet. Gynecol., 17: 477-80, 1961. dosis (65, 200, 226, 237, 247), and the appearance of rheumatic 10. Barry, R. M., Diamond, H. D., and Graver, L. F. Influence diseases (22, 122), SjÃ¶gren'ssyndrome (21) and L. E. phenomena of Pregnancy on the Course of Hodgkin's Disease. Am. J. (96) should be considered not only as complications of Hodgkin's Obstet. Gynecol., 84: 445-54, 1962. 11. Baum, S., Bron, K. M., Wexler, L., and Abrams, H. L. Lym- disease but also as possible clues to the pathogenesis of the phangiography, Cavography, and Urography: Comparative disease (70, 71, 111, 231). Accuracy in the Diagnosis of Pelvic and Abdominal MÃ©tas tases. Radiology, 81: 207-18, 1963. Conclusion 12. Bethell, F. H., Andrews, G. A., Neligh, R. B., and Meyers, M. C. Treatment of Hodgkin's Disease with Roentgen Ir The influence on the course of age and sex, of localization of radiation and Nitrogen Mustards. Am. J. Roentgenol., 64: disease, and of histologie type was noted. The question was raised 61-74, 1950.

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13. Bichel, J. The Alcohol-Intolerance Syndrome in Hodgkin's Practice of Medicine, Vol. 6, pp. 1017-64. Hagerstown, Md.: Disease. ActaMed. Scand., 164: 105-12, 1959. W. F. Prior Company, Inc., 1964. 14. Bodcn, (!. Results of X-ray Treatment of Reticuloses. Brit. 35. Graver, L. F., and Haagensen, C. D. A Note on the Occur J. Radiol., $4: 494-98, 1951. rence of Herpes Zoster in Hodgkin's Disease, Lymphosar- 15. Bonnard, J., Guihard, 11., Guihard, D., and Leroux, M. J. A coma, and the Leukemias. Am. J. Cancer, 16: 502-14, 1932. propos d'un cas de toriilose mÃ©ningÃ©e,phaseterminale d'une 36. Crepaldi, G., and Parpajola, A. Excretion of Tryptophan maladie de Hodgkin. J. Radiol. Klectrol. Med. NucÃ.,45: 591- Metabolites in Different Forms of Haemoblastosis. Clin. 94, 1964. Chim. Acta, 9: 106-17, 1964. 16. Bouroncle, B. A., Old, J. W., Jr., Vazques, A. G. PathogÃ¨ne- 37. Dawson, P. J., and Harrison, C. V. A Clinicopathological sis of Jaundice in Hodgkin's Disease. Arch. Internal Med., Study of Benign Hodgkin's Disease. J. Clin. Pathol., 14: 219- 110: 872-83, 1962. 31, 1961. 17. Braun, W. E., and Shnider, B. I. Alcohol-induced Pain in 38. Dayan, A. D., Morgan, H. G., Hope-Stone, H. F., and Hodgkin's Disease. J. Am. Med. Assoc., 168: 1882-85, 1958. Boucher, B. J. Disseminated Herpes Zoster in the Retic 18. Brown, R. J. K., and Meynell, M. J. Haemolytic Anaemia uloses. Am. J. Roentgenol., 92: 116-23, 1964. Associated with Hodgkin's Disease. Lancet, 2: 835-38, 1949. 39. Deep, W. D., Fraumeni, J. F., Tashima, C. K., and McDivitt, 19. Brunner, K. W., and Young, C. W. A Methylhydrazine R. Leukoencephalopathy and Dermatomyositis in Hodgkin's Derivative in Hodgkin's Disease and other Malignant Neo Disease. Arch. Internal Med., 113: 635-40, 1964. plasms. Ann. Internal Med., 63: 69-86, 1965. 40. Desforges, J. F., Ross, J. D., and Moloney, W. C. Mechanism 20. Brunning, R. D., Foley, J. F., and Fortuny, I. E. Hodgkin's of Anemia in Leukemia and Malignant Lymphoma. Am. J. Disease and Kaposi's Sarcoma, Report of a Case. Arch. In Med., 28: 69-76, 1960. ternal Med., 11Ã•:363-9, 1963. 41. Desjardins, A. U., and Ford, F. A. Hodgkin's Disease and 21. Bunim, J. J., Buchanan, W. W., Wertlake, P. T., Sokoloff, Lymphosarcoma; Clinical and Statistical Study. J. Am. L., Bloch, K. J., Beck, J. S., and Alepa, F. P. Clinical, Patho Med. Assoc., 81: 925-27, 1923. logic, and Serologie Studies in SjÃ¶gren's Syndrome, Com 42. DeVore, J. W., and Doan, C. A. Studies in Hodgkin's Syn bined Clinical Staff Conference at the National Institutes of drome. XII. Hereditary and Epidemiologie Aspects. Ann. Health. Ann. Internal Med., 61: 509-30, 1964. Internal Med., 47: 300-16, 1957. 22. Cammarata, R. J., Rodnan, G. P., Jensen, W. N. Systemic 43. Diamond, H. D. Hodgkin's Disease. Neurologic Sequelae. Rheumatic Disease and Malignant Lymphoma. Arch. In Missouri Med., 945-56, 1957. ternal Med., Ill: 330-7, 1963. 44. Dickson, R. J., and Smitham, J. H. Cavitation of Lung Lesions in Hodgkin's Disease; Report of Two Cases. Brit. J. 23. Carbone, P. P., Sabesin, S. M., Sidransky, H., and Frei, E., Ill Secondary Aspergillosis. Ann. Internal Med., 60: 556-67, Radiol., 25: 48-52, 1952. 1964. 45. Dolman, C. L., and Cairns, A. R. M. Leukoencephalopathy 24. Carney, E. K., Oppelt, W. W., Gleason, W. L., and Brindley, Associated with Hodgkin's Disease. Neurology, //: 349-53, C. O. Cardiac Hodgkin's Disease. A Clinical, Heinodynamic, 1961. and Angiocardiographic Evaluation of a Case. Am. Heart 46. Dubin, I. N. The Poverty of the Immunological Mechanism J., 64: 106-10, 1962. in Patients with Hodgkin's Disease. Ann. Internal Med., 27: 25. Cheever, A. W., Valsarais, M. P., and Rabson, A. S. Necrotiz- 898-913, 1947. ing Toxoplasmic Encephalitis and Herpetic Pneumonia 47. Easson, E. C., and Russell, M. H. The Cure of Hodgkin's Complicating Treated Hodgkin's Disease. New Engl. J. Disease. Brit. Med. J., i: 1704-07, 1963. Med. 27%: 26-29, 1965. 48. Ebstein, W. von. Das chronische RÃ¼cksfallsfieber, eine neu 26. Cline, M. J. and Berlin, N. I. Anemia in Hodgkin's Disease. Infectionekrankheit. Berlin. Klin. Wochschr., 24: 565-68, Cancer, 16: 526-32, 1963. 1887. 27. Cohen, B. M., Smetana, H. F., and Miller, R. W. Hodgkin's 49. Edwards, C. L., Andrews, G. A., Sitterson, B. W., and Disease: Long Survival in a Study of 388 World War II Army Kniseley, R. M. Clinical Bone Marrow Scanning with Radio- Cases. Ibid., 17: 856-66, 1964. isotopes. Blood, 23: 741-56, 1964. 28. Cohen, N., and Canter, J. W. Hodgkin's Disease of the Small 50. Emirgil, C., and Heinemann, H. O. Effects of Irradiation of Intestine. Am. J. Digest. Diseases, 4: 361-77, 1959. Chest on Pulmonary Function in Man. J. Appi. Physiol., 16: 331-338, 1961. 29. Conn, H. (). Alcohol-induced Pain as a Manifestation of Hodgkin's Disease. A. M. A. Arch. Internal Med., 100: 241- 51. English, R. S., Hurley, H. J., Witkowski, J. A., and Sanders, J. Generalized Anhidrosis Associated with Hodgkin's Disease 47, 1957. 30. Connolly, C. S. Hodgkin's Disease Associated with Toxo- and Acquired Ichthyosis. Ann. Internal Med., 08: 676-81, plasma Gondii. Arch. Internal Med., lie: 393-96, 1963. 1963. 52. Eriksen, K. R., and H0jgaard, K. Disseminerei Mucormy- 31. Constantoulakis, M., Costea, N., Schwartz, R. S., and Dame- kose. Ugeskrift Laeger, 125: 1849-53, 1963. shek, W. Quantitative Studies of the Effect of Red-Blood- 53. Falconer, E. H., and Leonard, M. E. Skeletal Lesions in Cell Sensitization on In Vivo Hemolysis. J. Clin. Invest., Hodgkin's Disease. Ann. Internal Med., 29: 1115-31, 1948. 42: 1790-801, 1963. 54. Falkson, G., de Villiers, P. C., and Falkson, H. C. iV-Iso- 32. Cook, J. C., Krabbenhoft, K. L., and Leucutia, T. Combined propyl - a(2 - methylhydrazino) - p - toluamide hydrochloride Radiation and Nitrogen Mustard Therapy in Hodgkin's (NSC-77213) for Treatment of Cancer Patients. Cancer Disease as Compared with Radiation Therapy Alone. Am. J. Chemotherapy Rept., 46: 7-16, 1965. Roentgenol., Radium Therapy NucÃ.Med., 82: 651-57, 1959. 55. Fayos, J., Hendrix, R., MacDonald, V., and Lampe, I. 33. Graver, L. F. Value of Early Diagnosis of Malignant Hodgkin's Disease: A Review of Radiotherapeutic Experi Lymphomas and Leukemiasâ€”A Monograph for the Physician, ence. Am. J. Roentgenol., Radium Therapy NucÃ.Med., 93: No. 7. New York: American Cancer Society, 1952. 557-67, 1965. 34. . Hodgkin's Disease. In: F. Tice (ed.), Tice-Harvey 56. Finkbeiner, J. A., Graver, L. F., and Diamond, H. D. Prog-

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iiostic Signs in Hodgkin's Disease. J. Am. Med. Assoc., 156: tion of Iron in Anemia Complicating Malignant Neoplasms. 472-77, 1954. Blood, 22: 73-81, 1963. 57. Flury, R. von, and Wegmann, T. (The Behavior of Leukocytic 80. Haynal, V. A., and Regli, F. Neurologische Symptome bei Alkaline Phosphat Ã¤se in Hodgkin's Disease.) (German.) Morbus Hodgkin. Schweiz. Med. Wochschr., 94: 1515-18, Schweiz. Med. Wochschr., 94: 958-61, 1964. 1964. 58. Fox, II. Remarks on the Presentation of Microscopic Prep 81. Healy, R. J., Amory, H. I., and Friedman, M. Hodgkin's arations Made from Some of the Original Tissue Described Disease. A Review of Two Hundred and Sixteen Cases. by T. Hodgkin, 1832. Ann. Med. Hist., 8: 370-74, 1926. Radiology, 64: 51-55, 1955. 59. Frank, H. G. The Effect of Hodgkin's Disease on Pregnancy 82. Heineman, H. S., Jensen, W. N., Cooper, W. M., and Brande, and Fertility. J. Obstet. Gynecol. Brit. Empire, 62: 266-68, A. I. Hodgkin's Disease and Salmonella lyphimurium infec 1955. tion. J. Am. Med. Assoc., 118: 632-34, 1964. 00. Freymann, J. G., Burrell, S. B., and Marier, E. Role of 83. Hennessy, J. P., and Rottino, A. Hodgkin's Disease in Preg Hemolysis in Anemia Secondary to Chronic Lymphocytic nancy with a Report of 12 Cases. Am. J. Obstet. Gynecol., Leukemia and Certain Malignant Lymphomas. N. Engl. J. 63: 756-64, 1952. Med., 259: 847-55, 1958. 84. â€” â€”. Hodgkin's Disease in Pregnancy. Ibid., 87: 851-53, 61. Frost, J. W., Goldwein, M. I., and Bryan, J. A. Clinical Ex 1963. perience with Vincaleukoblastine in Far-advanced Hodgkin's 85. Hilton, G., and Sutton, P. M. Malignant Lymphoma: Classi Disease and Various Malignant States. Ann. Internal Med., fication, Prognosis, and Treatment. Lancet, /: 283-87, 1962. 56: 854-59, 1962. 86. Hirschhorn, K., Schreibman, R. R., Bach, F. H., and Siltz- 62. GalÃ¡n, H. M., Lida, E. J., and Kleisner, E. H. Chromosomes bach, L. E. In Vitro Studies of Lymphocytes from Patients of Sternberg-Heed Cells. Lancet, 1: 335, 1963. with Sarcoidosis and Lymphoproliferative Diseases. Ibid., 2: 63. (iellhorn, A. End-results in Lymphosarcoma and Hodgkin's 842-43, 1964. Disease. Proc. Nati. Cancer Conf., 3rd (1956), pp. 862-69, 87. Hodgkin, T. On Some Morbid Appearances of the Absorbent 1957. Glands and Spleen. Medico-Chir. Trans., 17: 68-114, 1832. 64. Giannopoulos, P. P., and Bergsagel, 1). E. Mechanism of 88. Hoffbrand, B. I. Haemolytic Anaemia in Hodgkin's Disease Anemia Associated with Hodgkin's Disease. Blood, Â¡4:856- Associated with Immunoglobiilin Deficiencies. Brit. J. 69, 1959. Cancer, 18: 98-101, 1964. 65. Gledhill, R. C., and Shillitoe, A. J. Purpura and Amyloidosis 89. . Hodgkin's Disease and Hypogammaglobulinaemia: in Hodgkin's Disease. Brit. Med. J., 1: 1336-37, 1952. A Rare Association. Brit. Med. J., 1: 1156-58, 1964. 66. Goldman, L. B. Hodgkin's Disease: An Analysis of 212 Cases. 90. . Hodgkin's Disease, Autoimmunity, and the Thymus. J. Am. Med. Assoc., 114: 1611-16, 1940. lbid.,1: 1592-94, 1965. 67. Goulian, M., and Fahey, J. L. Abnormalities in Serum Pro 91. Hoffman, (!. T., and Rottino, A. Studies of Immunologie teins and Protein-bound Hexose in Hodgkin's Disease. J. Reactions of Patients with Hodgkin's Disease: Antibody Lab. Clin. Med., 67: 408-19, 1961. Reaction to Typhoid Immunization. Arch. Internal Med., 68. Gowers, Sir W. R. Hodgkin's Disease. Reynold's System of 86: 872-76, 1950. Medicine, Vol. 5, pp. 306-52. London: MacMillan & Co., 1878. 92. Hohl, K., Sarasin, P., and Bessler, W. Therapie und Prognose 69. Gowing, N. F. C. Observations on a Case of Torulosis Asso der Lymphogranulomatose: ZÃ¼richerErfahrungen von 1922- ciated with Hodgkin's Disease. Proc. Roy. Soc. Med., 61: 1950. Oncologia, 4: l, 1951. 494-96, 1958. 93. HÃ¶rn, W. S. Miliary Nocardiosis, Fatal Complication in 70. Green, H. N. Immunological Aspects of Cancer. Ciba Found. Hodgkin's Disease. Texas State J. Med., 61: 328-29, 1965. Symp. Carcinogenesis: Mechanisms Action, pp. 131-64, 1959. 94. Hoster, H. A., and Dratman, M. B. In: L. F. Graver and II. 71. Green, I., Inkelas, M., and Allen, L. B. Hodgkin's Disease: A. Roinick (eds.), Hodgkin's Disease. Part 1. 1832-1947. A Maternal-to-Foetal Lymphocyte Chimaera? Lancet, 1: Cancer Res., 8: 1-78, 1948. 30-32, 1960. 95. Hotchkiss, D. J. The Anemia of Lymphomas and LeukemiaÂ». 72. Gregory, J. J., Ribaudo, C. A., and Grace, W. J. Endo- Med. Clin. N. Am., 48: 1479-92, 1964. bronchial Hodgkin's Disease. Ann. Internal Med., 62: 579- 96. Howqua, J., and Mackay, I. R. L. E. Cells in Lymphoma. 86, 1965. Blood, 22: 191-98, 1963. 73. Gross, L. Oncogenic Viruses, p. 393. Oxford and New York: 97. Hultberg, S. Pregnancy Â¡nHodgkin's Disease. Acta Radiol., Pergamon Press, Inc., 1961. 41: 277-89, 1954. 74. â€” â€”. Serial Cell-free Passage in Rats of the Mouse Leu 98. Huneycutt, H. C., Anderson, W. R., and Hendry, W. S. kemia Virus. Effect of Thymectomy. Proc. Soc. Exptl. Biol. Pneumocystis Carinii Pneumonia. Case Studies with Elec Med., 112: 939-45, 1963. tron Microscopy. Am. J. Clin. Pathol., 41: 411-18, 1964. 75. â€” â€”. Viral Etiology of Leukemia and Lymphomas. (Edi torial.) Blood, 26: 377-81, 1965. 99. Hutter, R. V. P. Phycomycetous Infection (Mucormycosis) in Cancer Patients: A Complication of Therapy. Cancer, 76. Gross, L., Roswit, B., Malsky, S. J., Dreyfuss, Y., and Â¡2:330-50, 1959. Amato, C. G. Resistance of Mouse Leukemia Virus to In 100. Hutter, R. V. P., Lieberman, P. H., and Collins, H. S. Asper- Vitro Gamma Rays Irradiation. Proc. Am. Assoc. Cancer gillosis in a Cancer Hospital. Ibid., 17: 747-56, 1964. Res., 6: 94, 1965. 77. Hagans, J. A. Hodgkin's Granuloma with 1'ericardial Effu 101. Hyman, G. A. Anemia in Malignant Neoplastic Disease. J. sion. Am. Heart J., 40: 624-29, 1950. Chronic Diseases, 16: 645-66, 1963. 102. Jackson, H., Jr., and Parker, F., Jr. Hodgkin's Disease and 78. Hanson, T. A. S. Histological Classification and Survival in Hodgkin's Disease. A Study of 251 Cases with Special Refer Allied Disorders. New York: Oxford University Press, 1947. ence to Nodular Sclerosing Hodgkin's Disease. CÃ¡ncer, 17: 103. Jakob, H. G., and Zirkin, R. M. Hodgkin's Disease with 1595-KÃ•03,1964. Involvement of the Heart and Pericardium. J. Am. Med. 79. Haurani, F. I., Young, K., and Tocantins, L. M. Re-utiliza Assoc., 173: 338-42, 1960.

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104. James, A. H. Hodgkin's Disease With and Without Alcohol- 130. Limarzi, L. R. and Paul, J. T. Sternal Marrow Studies in induced Pain. Quart. J. Med., 29: 47-06, 1960. Hodgkiifs Disease. Am. J. Clin. Pathol., 19: 929-61, 1949. 105. James, A. H., Harley, H. R. S., Horton, E. H., and Storriug, 131. Lukes, R. J. Relationship of Histologie Features to Clinical F. K. Alcohol-induced Pain Due to Carcinoma. Lancet, 1: Stages in Hodgkin's Disease. Am. J. Roentgenol., Radium 299-301, 1957. Therapy NucÃ.Med., 90: 944-55, 1963. 106. Jelliffe, A. M., and Thomson, A. D. Prognosis in Hodgkin's 132. . Prognosis and Relationship of Histologie Features to Disease. Brit. J. Cancer, 9: 21-36, 1955. Clinical Stage. J. Am. Med. Assoc., 190: 914-15, 1964. 107. Jensen, K. B.. Thorling, E. B., and Andersen, C. J. Serum 133. Lumb, G., and Newton, K. A. Prognosis in Tumors of Lym- Copper in Hodgkin's Disease. Scand. J. Haematol., 1: 63-74, phoid Tissue; Analysis of 602 Cases. 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1<)<)<> CANCER RESEARCH VOL. 26

John E. Ultmann, James K. Cunningham and Alfred Gellhorn

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