Delayed hypersensitivity in Hodgkin's diseaseA study of 103 untreated patients

Delayed Hypersensitivity in Hodgkin’s Disease

A Study of 103 Untreated Patients

ROBERT C. YOUNG, M.D.

MICHAEL P. CORDER, M.D.”

HARLEY A. HAYNES, M.D.’

VINCENT T. DeVITA, M.D.

Bethesda, Maryland

From the Solid Tumor Service, Medicine

Branch and the Dermatology Branch, Na-

tional Cancer Institute, National Institutes

of Health, Bethesda, Maryland 20014. Re-

quests for reprints should be addressed to

Dr. Robert C. Young. Manuscript received

June 3,1971. *: Present address: Department of Hema-

tology-Oncology, Letterman General Hos- pital, Presidio of San Francisco, California

94129. f Present address: Department of Derm-

atology, Massachusetts General Hospital,

Boston, Massachusetts.

Delayed hypersensitivity in Hodgkin’s disease was examined in 103 untreated patients in all stages of disease and related to prognosis. No relationship was found between skin test reactivity at the time of diagnosis and survival, frequency of re- lapses or duration of remission. Skin test reactivity at the onset of Hodgkin’s disease is not a useful prognostic sign.

Cutaneous anergy was uncommon in these patients; only 11.7 per cent had no reaction to any of the six skin tests applied. No patient with stage I disease was anergic. The incidence of anergy increased with stage but only 26.6 per cent of the patients with stage IV disease were anergic. Mumps antigen and dinitrochlorobenzene (DNCB) were the most likely skin tests to rule out anergy. Skin test reactivity correlates with the absence of systemic symptoms as well as with histologic type. In patients with nodular sclerosis and lymphocyte predominant patterns the incidence of skin test reactivity is higher than in patients with mixed cellularity and lymphocyte-depleted Hodgkin’s disease.

Absolute peripheral lymphocyte counts were noted to reflect staging and skin test reactivity. The mean absolute lymphocyte counts fell in more advanced stages, and skin test reactivity generally increased as the peripheral lymphocyte count increased. Peripheral lymphocytopenia at the onset of the patient’s course, however, did seem to be a bad prognostic sign.

The immunologic reactivity of patients with Hodgkin’s disease has been an area of intensive study over the past twenty years. Several major studies have demonstrated impaired delayed hypersensitivity [l-6], delayed skin homograft rejection [7,8] and defective lymphocyte function [g-13]. However, primary [14] and secondary [2] antibody response appears to be unim- paired in patients with Hodgkin’s disease. Many of the earlier studies involved patients who had been previously treated either with radiotherapy or chemotherapy. In 1967, a study from this

Volume 52, January 1972 63

DELAYED HYPERSENSITIVITY IN HODGKIN’S DISEASE-YOUNG ET AL.

TABLE I Relationship of lymph Node Histologic Type to Clinical Stage*

Lymphocyte Lymphocyte Total Stage Predominate Mixed Depleted Patients

I 9 (1) 6 (4) l(1) 16 II 7 (3) 30 (21) 5 (2) 42

III 6 (3) U(3) 2 (1) 18 IV 5 (1) 10 (4) U(2) 26

Totals 27 57 19 103

* Numbers in parentheses represent the number of nodular sclerosis type included.

institution described the immunologic features of

fifty untreated patients with Hodgkin’s disease and related the findings to clinical stage and histo-

pathology [14]. At that time it was not possible to relate immunologic status in the untreated patient firmly to subgroups in the histopathologic classi. fication or to ultimate survival. The present study includes forty-nine of the initial fifty patients, in- corporates an additional fifty-four untreated patients, relaZes the entire group of 103 patients to clinical stage and histopathology, and relates initial skin test reactivity to prognosis and survival.

MATERIALS AND METHODS

Patient Selection. From November 1965 to November 1967, 103 patients with active, previously untreated Hodgkin’s disease were admitted to the Clinical Center of the National Institutes of Health and included in the present study. Sixty-seven were male and thirty-six female; their mean age was twenty-nine years (range six to fifty-eight years). In all but eleven patients skin tests were performed within three months of their diag- nostic node biopsy. In the eleven patients skin tests were performed from four to twenty-two months af’ter the initial biopsy, but all were untreated prior to skin

testing. Staging. Clinical staging was performed during the initial evaluation and skin testing, and patients were

TABLE II Skin Test Reactivity in Hodgkin’s Disease

Patients Controls

No. Reactive No. Reactive

Antigen Tested No. Tested % No. Tested %

DNCB 57190 67 41143 95 Mumps 50173 68.5 22125 88 Candida albicans 23199 23 13125 52 Histoplasmin ll/lOO 11 4110 40

Purified protein derivative lO/lOl 10 6125 24

Coccidiodin o/59 One or more intradermal 66/100 66 25125 100 Two or more intradermal 23/102 22.5 17125 68

64

classified according to the Rye staging class’ification 1151. History, physical examination, complete blood counts, liver function tests and chest roentgenograms, were routinely performed. In addition, whole chest tomography when mediastinal disease was present,

metastatic bone series, intravenous pyelography, in- ferior venocavography and lymphangiography were performed on all patients. Bone marrow biopsy specimens were obtained routinely with a modified Vim-Silverman marrow biopsy needle, Strontium-85 bone scans were

performed on patients who had systemic symptoms or evidence of bone involvement. Pretreatment lymphocyte counts were determined in all patients at the time of their skin testing. When possible, three separate lymphocyte counts were used to determine mean lymphocyte count for the individual patients.

Histology. In all 103 patients the presence of Hodg- kin’s disease was proved by biopsy and confirmed before their entry into the study. Without knowledge of the clinical or immunologic status of the patient, the biopsy specimens were classified according to the histologic criteria of Lukes and Butler [16]. This classification was modified to include subcategories of the nodular sclerosis group as lymphocyte-predominant, mixed cellularity or lymphocyte-depleted. Skin Testing. Prior to treatment, all patients had a battery of skin tests, although each patient did not receive every skin test. The following tests were used: dinitrochlorobenzene (DNCB), mumps, Candida, histoplasmin, coccidioidin and intermediate strength purified protein derivative. Sixty patients (57 per cent) had the

entire battery of six skin tests. It is this group of patients that is used to relate skin test reactivity to prognosis and survival. In 102 patients (99 per cent) four or more of the skin tests were performed. All patients included in the study were tested with either DNCB or mumps antigen, or both, and no patient was included who had fewer than three different skin tests.

Control patients were evaluated with intradermal skin tests at the beginning of the study; the technics used were identical to those used for testing the patients with Hodgkin’s disease. Seventeen healthy persons and twenty-six patients with mycosis fungoides served as controls for DNCB sensitization. Previous studies had shown DNCB reactivity in patients with mycosis fungoides to be equivalent to that in controls [17]. Sensitization to 2,4-Dinitrochlorobenzene (DNCB). A sensitizing dose of 2,000 pg DNCB (K & K Laboratories, Inc., Plainview, N. Y., Lot 40175L) in 0.1 ml acetone was applied to the skin of the medial aspect of the up- per part of the right arm within a 2 cm diameter poly ethylene ring, allowed to evaporate and covered by an adhesive bandage for one week. Prior hypersensitivity to DNCB was excluded by control testing with 50 and 100 I*g DNCB in 0.1 ml acetone applied simultaneously

to the proximal half of the volar surface of the ipsilateral forearm, covered by adhesive bandages and examined at forty-eight hours. These control tests were also ob- served for a spontaneous flare reaction during the sec-

The American Journal of Medicine


and week after exposure. Fourteen days after the sen-

sitizing dose, challenge tests of 50 and 100 pg DNCB were applied to the skin of the distal half of the volar surface of the same forearm and covered by adhesive bandages for forty-eight hours. The reactions were evaluated over the next three days and graded as fol- lows: 0 = no reaction, l+ = erythema alone, 2+ = erythema and induration, 3+ = vesiculation and 4+ = bullae or ulceration. A 2+ or greater reaction was re- garded as evidence of DNCB sensitization. Any patient who received treatment prior to challenge testing was excluded from the study unless the initial application of DNCB had produced a spontaneous flare or a positive

reaction. Skin Tests with lntradermal Antigens. Patients received intradermal injections of 0.1 ml Candida albicans extract 1:lOO (dermatophytin “O”-Hollister- Stier Laboratories, Spokane, Wash.), coccidioidin 1: 100 (Cutter Laboratories, Berkeley, ‘Calif), histoplasmin (Parke, Davis & Co., Detroit, Mich.) and intermediate strength purified protein derivative of tuberculin (0.0002 mg PPD, Parke-Davis & Co.) on the volar surface of the left forearm. Seventy-three of the 103 patients (70 per cent) received 0.1 cc mumps skin test antigen (Eli Lilly & Co., Indianapolis, Ind.). Skin reactions were evaluated at forty-eight to seventy-two hours and induration of 5 mm or more was considered a positive response. Treatment. After staging and skin testing, patients with stage I, II and IIIA disease were treated with intensive radiotherapy [18]. Patients with stage IIIB disease were randomized to radiotherapy or chemotherapy and the patients with stage IV disease were treated with combination chemotherapy [19].

RESULTS

Clinical Stage and Histology. The classification of

the 103 patients by clinical stage and histopathology is shown in Table I. Lymphocyte-predomi-

nant Hodgkin’s disease was the most common histologic pattern seen in patients with stage I dis-

ease. Mixed cellularity predominated in the intermediate stages, and mixed cellularity and lympho-

cyte-depleted Hodgkin’s disease were the predominant histologic types in patients with stage

IV disease. Forty-six of the patients (44 per cent) had histologic features of nodular sclerosis. Twenty-five of forty-two (60 per cent) with stage II disease had nodular sclerosis. Of the sixty-seven

male patients, twenty (29 per cent) had nodular sclerosis and of thirty-six female patients, twenty-

six (72 per cent) had nodular sclerosis, a highly significant sex difference (P ~0.01). There was, however, no significant difference between the male:female ratios according to the stage of the disease. As a group, patients with nodular sclerosis were younger than those without nodular sclerosis. Mean age of the patients with nodular sclero-

sis was 25.7 years compared to 31.0 years for the patients without nodular sclerosis. This difference is significant (P <O.OS).

Skin Test Reactivity. Anergy was uncommon in these 103 patients. Only fourteen of the 103 (13.5 per cent) patients had no reaction to any of the skin tests applied. A more accurate figure is obtained, however, on analysis of only those patients who had the full battery of skin tests. Of the sixty patients who received all six skin tests, only seven (11.7 per cent) had evidence of anergy.

The results of skin tests with DNCB and the intradermal antigens are shown in Table II. Fifty- seven of the ninety patients tested (67 per cent) were sensitized to DNCB. lntradermal testing with mumps antigen proved as sensitive as did DNCB

in determining intact delayed hypersensitivity in these patients. Fifty of the seventy-three patients

c DNCB 100 m Mumps

/ w L

5 80 c

m Other Intradermal

Figure 1. Skin test reactivity related to stage of disease by individual tests.

0 I III



SKIN TESTS:

One or More =T wo or More

m Three Major

lx

100

w z l- g 80 a.

Ir z 60 w

$

.g 40

20

0

(68.5 per cent) tested with mumps antigen had a positive response. Of interest, there was no correlation between reactivity to the mumps skin test and a past history of mumps in these patients. Sixty-six of the 100 patients tested (66 per cent) were reactive to at least one intradermal test, but this was chiefly due to the high contribution of positive mumps skin tests. Positive reactions were seen most commonly to DNCB and mumps antigen; in fact, only two of the 103 patients had other positive skin tests when the DNCB and mumps tests were negative.

The relation of skin test reactivity to clinical stage of disease is shown in Figure 1. In patients with stage I Hodgkin’s disease the incidence of

I or More Tests+ A Symptoms I or More Tests t B Symptoms

B ‘%$$ 2or More Tests + A Symptoms * * 2 or More Tests + B Symptoms

3 Tests + A Symptoms 3 Tests + B Symptoms

-._I

Figure 3. Skin test reactivity related to stage of disease and symptoms.

66 The American Journal of Medlelna

Figure 2. Skin test reactivity related to stage of disease. Major skin test groups defined as (a) DNCB, (b) mumps, (c) other intradermal skin test antigens.

skin reactivity to DNCB was normal but tended to decline as the stage of the disease advanced and differed significantly from our controls in stages II, III and IV (P ~0.01). A marked decrease in skin test reactivity, however, was apparent only in patients with stage IV disease. A similar general pattern was noted with the other intradermal antigens except for mumps reactivity. Mumps reactivity appears to be independent of the stage of the disease. Per cent reactivity was virtually the same in patients with stage IV disease as in patients with stage I disease. There was no significant difference in the frequency of mumps reactivity between any of the individual clinical stages. Collective reactivity by stage is listed jn Figure 2. Only the sixty patients who had the complete battery of six tests were included, and skin test antigens were divided into three major groups: (1) DNCB, (2) mumps and (3) any of the other intradermal skin tests (intermediate purified protein derivative, histoplasmin, Candida and coccidioidin). As seen in Figure 2, multiple positive skin tests decreased as the stage of the disease increased. For each clinical stage there is a signifi-

cant difference (P ~0.05) ‘between the frequency of positive reactions in the three major skin test groups.

Skin test reactivity correlated well with the absence of systemic symptoms according to the stage of the disease. Patients with stage I and II disease were combined to achieve adequate numbers for analysis as were the patients with stage III and IV disease. The results are given in Figure 3. In these combined groups, skin test reactivity was less in patients with “B” symptoms (fever, -night sweats, weight loss and/or pruritus) than in

DELAYED HYPERSENSITWTY IN HODGKIN’S DISEASE - YOUNG ET AL.

100

20

r- /

,- Figure

C 4. Skin test reactivity related to

histologic type.

DNCB

@@j M”,,,ps

m Other

asymptomatic patients. S,ignificance probabilities appear on Figure 3 next to the compared columns. All the anergic patients had systemic symptoms; in no symptomatic patient were reactions to all three of the major skin test groups positive.

The relation of skin test reactivity to the histologic classification of the lymph node biopsy speci- men is shown in Figure 4. The patients were histo- logically classified by the criteria of Lukes and Butler. In the present study the patients with nodular sclerosis were considered separately. It is apparent that there is a high order of skin test reactivity in patients with nodular sclerosis and

lymphocyte-predominant Hodgkin’s disease, but in patients with mixed cellularity and lymphocyte- depleted patterns skin test reactivity is generally less. DNCB reactivity in patients with nodular sclerosis and lymphocyte-predominant Hodgkin’s disease is significantly different (P <O.OS) from that in patients with lymphocyte-depleted Hodg- kin’s disease. Mumps reactivity in patients with

nodular sclerosis is significantly different (P ~0.01) from that in patients with mixed type Hodgkin’s disease. A comparison between patients with and without nodular sclerosis in all stages of the disease is made in Figure 5. Generally, patients with nodular sclerosis are more reactive than the other patients to DNCB and mumps antigen. This difference appears to be reversed with the other intradermal skin tests, but the difference between skin test reactivity in this group is not significant (P cO.1). Lymphocyte Counts and Skin Test Reactivity. Peripheral lymphocyte counts in the 103 patients ranged from 220 to 3,1OO/cu mm (normal ab-

NODULAR LYMPHOCYTE

SCLEROSIS PREDOMINANT

MIXED LYMPHOCYTE DEPLETED

solute lymphocyte count range in our hospital is

from 1,490 to 3,93O/cu mm). The relationship

between absolute peripheral lymphocyte count and clinical stage of the disease is shown in Figure 6. The mean lymphocyte count falls in more advanced stages of the disease. There are significant differ-

ences between peripheral lymphocyte counts in stages I and III, I and IV and II and IV, respectively (P ~0.05). Skin test reactivity generally increases

m Nodular Sclerosis

D Non-Nodular Sclerosis

Figure 5. Skin test reactivity of nodular sclerosis com-

pared to non-nodular sclerosis Hodgkin’s disease (a\! stages).

DNCB MUMPS OTHER



. ; . .

m i

a m

. . . 1 . t . .

J !+,I; . . ’ Tw . t . .

I . :

l ; . . i : b

i 8

0 I II m m

Figure 6. Absolute peripheral blood lymphocyte count prior to therapy related to the stage of Hodgkin’s disease.

as the peripheral lymphocyte count increases (Figure 7).

Anergic patients have significantly lower peripheral lymphocyte counts as compared with pa-

tients in whom multiple skin tests are positive

(P ~0.01). Patients with two or more positive skin tests had lymphocyte counts that were significantly lower than patients in whom the reaction to all major skin tests was positive (P ~0.05). Skin test reactivity for DNCB and mumps antigen was positively correlated with the peripheral lymphocyte count (Figure 8). The reaction to DNCB and mumps antigen is less frequently posi-

3500. t- z 2 2500- ”

F & 2000-

P

% ?I 1500- .

F 3 5: IOOO- 9 8

H . 500 - .

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9 ‘:‘ m

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8

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0’ ANERGIC I OR 2 OR 3 MAJOR

MORE TESTS MORE TESTS TESTS

POSITIVE POSITIVE POSITIVE

Figure 7. Skin test reactivity in patients with Hodgkin’s disease related to peripheral lymphocyte count prior to therapy (all stages).

68

tive in the presence of lymphocytopenia (P ~0.02). There was little correlation with other intradermal

skin tests (P ~0.1). Peripheral lymphocyte counts were related to histologic stage (Figure 9). In this study nodular sclerosis was considered separately from the other histologic types. Mean lymphocyte counts were significantly higher in patients with nodular sclerosis than in patients with lymphocyte

depleted Hodgkin’s disease (P <O-02), as were mean counts between lymphocyte-predominant and lymphocyte-depleted Hodgkin’s disease

(P <0.05). Patients with or without systemic symptoms

were compared in regard to absolute peripheral lymphocyte counts. Patients with stage I and II disease were combined to achieve adequate numbers for comparison as were patients with stages III and IV disease. For each category, patients with “B” symptoms had lower mean peripheral lymphocyte counts than those who were asymptomatic, but the difference was not statistically significant. Prognosis and Survival Related to Skin Test Reac- tivity. For purposes of cumulative life table analysis, only the group of sixty patients who had all three major groups of skin test antigens (DNCB, mumps and others) were included. This was considered to be the only way that true anergy could be defined with any accuracy. Only seven patients who had the entire battery of skin tests were anergic and in six of the seven the disease was in stage III or IV. Therefore, cumulative life table analysis was performed comparing survival in anergic patients with survival in nonanergic patients with stage III and IV disease. The ,results appear in Figure 10. Although there is a slight dif-

35001 3000

t 5 3 2500- ”

k 6 2000 -

:

% ?I 1500-

F 3 g IOOO-

8

500 - B *Positive oNegative 8 8 8

0; / DNCB MUMPS OTHER

INTRADERMAL SKIN TESTS

Figure 8. Absolute peripheral blood lymphocyte count prior to therapy related to individual skin test reactivity (all stages).

The American Journal of Medicine


ference in the rate of early deaths for the anergic

patients, up to approximately twenty-eight months,

there is no significant difference between the curves. Pretreatment anergy does not appear to indicate an unfavorable prognosis in patients who receive optimal therapy for their Hodgkin’s dis-

ease, at least for the first forty months of follow-up. Cumulative life table analysis was performed on patients with stage I and II disease, comparing the survival of patients with anergy or reactivity to individual skin tests and comparing the individual skin tests with each other. We found no significant differences between any particular skin test or

combination of skin tests which related to prognosis and survival in patients with stage I and II Hodgkin’s disease for the first forty months after initial treatment.

. 3000 t- .

. r .

ii .

2 2500~ . ” .

. . 500L

. : . i

0: I NODULAR LtWtUXYTE MIXED LYMPHOCYTE

SCLEROSIS PREGOMNANT DEPLETED

In those with stage III and IV disease, a cumulative life table analysis comparing the results of individual skin tests is shown in Figure 11. Al- though there are some early differences in the curves for DNCB and especially for mumps antigen, these differences are not significant. The presence or absence of particular skin test reactivity does not correlate with prognosis and sur-

vival in patients with stage III and IV disease. If one looks at the survival of those patients with stage III and IV disease who had a positive reaction to

one and two major groups of skin test antigens, again no difference in survival is seen.

Figure 9. Histology of Hodgkin’s disease related to ab-

solute peripheral blood lymphocyte count lprior to therapy

(all stages).

Peripheral Lymphocytopenia and Survival. Cumu- lative life table analysis was performed on patients presenting with marked peripheral lymphocytopenia (absolute lymphocyte count less than l,OOO/ cu mm), comparing their survival with that in patients without lymphopenia. Patients with stage I and II disease were compared separately from those with stage III and IV disease. The results of this analysis appear in Figure 12. At the top of the figure are the survival curves for patients with stage I and II disease. There is no difference between survival of the patients with stage I and II disease and peripheral lymphopenia and those without lymphopenia. The bottom portion of the figure compares patients with lymphopenia and stage III and IV disease with their nonlymphopenic counterparts. In this instance thereis a significant difference between survival (P co.05 at twelve months) of the patients with stage III and IV disease who present with peripheral lymphocytopenia and those who do not.

Frequency of Relapse Related to Skin Test Reac- tivity. The frequency of relapse and the duration of remissions were analyzed to be sure that there

was no prognostic significance to skin test reactivity which was not reflected in survival. The results appear in Tables III and IV. There is no significant difference between the number of patients in remission, the number in relapse, the

mean time to relapse or the mean time of remission for any of the skin tests. Likewise, there is no significant difference in the survival of similarly staged patients with individual skin tests positive

or negative. Results of Repeat Skin Tests. Twenty-two patients

had a repeat battery of skin tests at some time later in the course of their illness. Twelve of the twenty-two had repeat skin tests during complete remission. In nine of these twelve patients reactions were now positive for one or more skin tests

which had been negative prior to their therapy for Hodgkin’s disease. Three patients, however,

0 I I I I I I 0 IO 20 30 40 50 60

MONTHS

Figure 10. Cumulative life-table analysis: Anergic versus nonanergic patients with stage Ill and IV disease. Num- bers in parentheses indicate number of patients remaining in the study at that point in follow up.



60-

ONCE

Others

t’l i 60 (5) &!~~_________j7~

1

I i

60 I lit---T ’ -i

Ok*& + _-4$__ --iI

50 60

MONTHS

Figure 11. Cumulative life-table analysis: Survival com-

pared to individual skin test reactivity in stage III and IV

Hodgkin’s disease. Numlbers in parentheses indicate

number of patients remaining in the study at that point

in follow up.

showed no reaction to skin tests which had been positive previously.

Ten of the twenty-two patients were retested at the time of relapse. Nine of the ten patients now showed no reaction to one or more of the skin tests to which they had previously shown a positive reaction. A single patient, however, showed a reaction to mumps antigen and Candida at the time of nodal relapse although he was anergic at

the time of initial skin testing.

COMMENTS

Contrary to the impression given in much of

the published literature, cutaneous anergy is un-

TABLE III Duration of Remissions and Frequency of Relapse Related to Skin Test Reactivity in Patients with Stage I and II Disease

% Mean Time Mean

No. Remaining to First Time of

Relapsed/ in Relapse or Remission Skin Test Total Remission Death (mo) (mo)

Mumps antigen Positive 10/31 68 18.9 44+ Negative 3/10 75* 18.3 42+

DNCB Positive 15137 59 23.8 47+ Negative 4112 67* 11 51+

Others Positive 5112 77 26.8 48+ Negative 14/34 59* 19.2 46+

* Difference not significant (P >O.l).

STAGE I8 II

100 -

go-

5 5 STAGE III 8 I37

I --a Lymph - Non-Lymphopenic

70 - b$O)

’ (9) b __v_-_ __- _____ &?__g!_&?_____ 60 -

50 -

I I I I I I 0 IO 20 30 40 50 60

MONTHS

Figure 12. Cumulative life-table analysis: Survival related to absolute peripheral blood lymphocyte count prior to therapy. Patients with stages I and II disease, and III and

IV disease compared separately. Numbers in parentheses indicate number of patients remaining in the study at that point in follow up.

common in Hodgkin’s disease. Only 13.5 per cent of the 103 patients in the present series had no reaction to any of the skin tests applied. Since

the probability of anergy varies with the number and type of skin tests applied, studies which report only a few skin tests give a falsely high incidence of anergy. If one looks at the sixty patients in the present study who had the entire battery of six skin tests only seven (11.7 per cent) had evidence of anergy. Mumps antigen and DNCB were the most likely skin tests to rule out anergy. Previous studies of contact sensitization [3,20,21] or intradermal reactivity [1,5-81 reported anergy in 45 to 100 per cent of patients with active Hodg-

TABLE IV Duration of Remissions and Frequency of Relapse Related to Skin Test Reactivity in Patients with Stage III and IV Disease

_____

% Mean Time Mean

No. Remaining to First Time of

Relapsed/ in Relapse or Remission

Skin Test Total Remission Death (mo) (mo)

Mumps antigen Positive 7/16 56 16.0 47+ Negative 5/10 50* 20.2 54+

DNCB Positive 8117 53 14.7 52+ Negative 11/19 42* 17.9 45+

Others Positive 5112 58 15.0 42+ Negative 14128 50s 18.6 51+

__---

* Difference not significant (P >O.l).

70 The American Journal of Medicine

DELAYED HYPERSENSITI,JITY IN HODGKIN’S DISEASF - - YcIUNG ET AL

kin’s disease. Our patients were tested shortly after

diagnosis and before any treatment. In previous reports many of the patients had prolonged periods of active disease and had received therapy. Some had neither the mumps antigen nor DNCB skin

test. Contrary to previous suggestions, it seems

likely that anergy. when it exists, is a result of disease progression. not the cause of the disease.

Although anergy is uncommon, it varies with the stage of the disease. No patient with stage I disease in this series was anergic. One of the twenty-two patients with stage II disease who received all six of the skin tests was anergic (4.5 per cent). Eighteen per cent of the patients with

stage III disease were anergic and 26.6 per cent of the patients with stage IV disease had cutaneous

anergy. In patients with localized stage I Hodg- kin’s disease skin test reactivity is not significantly different from that in normal controls. Skin test reactivity generally declines as the stage of the disease advances and is most strikingly altered in patients with stage IV disease. Mumps antigen reactivity, however, appears independent of the stage of the disease, an observation which has not previously been made. The reason for this difference between mumps antigen reactivity in patients with Hodgkin’s disease is unclear. One might speculate that because mumps represents one of the early antigenic exposures, immunologic memory for this antigen persists whereas the ability to react to an antigen of more recent exposure or new sensitizing antigen is lost more easily. There is some suggestive evidence in sup- port of this postulate [2].

Skin test reactivity correlates with the presence or absence of systemic symptoms. Patients with B symptoms (fever, night sweats, pruritus and/or weight loss) had less skin test reactivity than asymptomatic patients. Previous reports cited a lower prevalence of reactivity in patients with systemic manifestations [6] or in “poor condi- tion” [5]. There is also a correlation with the histologic type of Hodgkin’s disease. Patients with nodular sclerosis and lymphocyte predominant patterns had a high order of skin test reactivity whereas patients with mixed and lymphocyte depleted patterns had less reactivity. In the previous study from this institution, patients with nodular sclerosis were not considered separately. In that study, patients with lymphocyte predominant patterns had significantly higher reactivity than those with lymphocyte depleted patterns but patients with mixed cellularity patterns were also highly

Volume 52, January 1972

reactive. This was chiefly due to the inclusion of

a large number of patients with nodular sclerosis

in the group with mixed cellularity patterns. When nodular sclerosis is considered separately, patients with mixed cellularity and lymphocyte-depleted Hodgkin’s disease have significantly lower reac-

tivity.

Absolute peripheral lymphocyte counts were noted to reflect staging and skin test reactivity. The mean absolute lymphocyte counts fall with more advanced stages of disease, and skin test reactivity generally increases as the peripheral lymphocyte count increases. In anergic patients ab-

solute peripheral lymphocyte counts are significantly lower than in patients with skin test reac-

tivity. Individual reactivity to mumps antigen and DNCB also correlated with peripheral lymphocyte count-the patients with positive reactions had significantly higher counts than the patients with negative reactions. Peripheral lymphocyte counts also reflected differences in histology-patients with nodular sclerosis and lymphocyte predominant Hodgkin’s disease had significantly higher peripheral lymphocyte counts than patients with the lymphocyte depleted type of Hodgkin’s disease. These differences were suggested in the original paper from this institution, but the number of patients was too small for significance at that time.

Previous studies [22,23] have suggested that cellular immune mechanisms might constitute the principal determinant of “host resistance” in Hodgkin’s disease. If such a mechanism were a major factor in ultimate prognosis and survival, the skin test reactivity at the time of diagnosis and before any treatment might provide valuable prognostic information. Although the numbers of anergic patients is small, cumulative life table analysis of survival of anergic and nonanergic patients in advanced stages of Hodgkin’s disease shows no significant difference in the survival of these groups up to the forty month period. Whether a significant difference in survival will appear later in the course of follow up is as yet unknown. Separate life table analysis comparing results of individual skin tests and of groups of skin tests also failed to demonstrate significant differences in survival for similarly staged patients with both localized and advanced disease. Current modes of therapy utilizing intensive radiotherapy for localized disease [18] and combination chemotherapy for advanced disease [19] have radically changed the survival of patients with Hodgkin’s disease. Such successful therapy may have ob- scured any effect contributed by cellular immune

71

DELAYED HYPERSENSITIVITY IN HODGKIN’S DISEASE- YOUNG ET AL.

mechanisms in these patients. Because of the pro- lympholytic. In all the patients included in our longed survival of most of the patients in the study, studies skin tests and lymphocyte counts were the frequency of relapse, time to relapse, fre- performed prior to the initiation of therapy. Cumu- quency of remission and length of remission in the lative life table analysis indicates that the sur- patients were examined to see if there was any dif- vival of patients with stage III and IV disease who ference in quality of therapeutic response which present with peripheral lymphocytopenia is sig- was not reflected in survival. Response to initial nificantly poor. This difference was not significant skin testing does not appear to reflect any differ- for patients who presented with localized Hodg- ence in these parameters. kin’s disease (stage I and II).

Lymphocytopenia in Hodgkin’s disease was noted by several early workers in the field [24,25] and its possible role more clearly elucidated in more recent studies [26]. It has been suggested

that the anergy of Hodgkin’s disease may be a peripheral defect, actually a manifestation of ab- normal lymphocyte function. The difficulty in in- terpreting much of the early work is that many of

the studies were performed after therapy with radiation, alkylating agents and/or adrenocorti- costeroid therapy, all of which are known to be

ACKNOWLEDGMENT

We would like to express our appreciation to Dr. Costan Berard and Dr. Louis Thomas who re- viewed all the pathologic material for this study; to Dr. Paul P. Carbone who initiated the original study; to Miss Eleanor Stashick who helped with the life table analysis, and to Mrs. Sandra Carter for clerical assistance in the preparation of this manuscript.

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72 The American Journal of Me’dicine

Delayed hypersensitivity in Hodgkin's diseaseA study of 103 untreated patients

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