Res. Exp. Med. 166, 35 - 42 (1975) ©by
Springer-Verlag 1975
Immunopathological Lymph Node Findings in Hodgkin's Disease Correlation to Survival Piero TOSI, M.D., Professor of Morbid Anatomy and Histology Marcella CINTORINO, M.D., Associate Professor of Morbid Anatomy and Histology Pietro LUZI, M.D., Associate Professor of Morbid Anatomy and Histology Institute of Morbid Anatomy and Histology, University of Siena (Italy) Received August 22, 1974
Summary: 217 diagnostic lymph nodes biopsies from cases of Hodgkin's disease were classified according to the criteria established by the Rye Conference, These were later subdivided into survival groups using immunopathological parameters solely. In the light of findings based upon 63 cases whose progress has been followed, it appears that the classification of Hodgkin's disease according to immunopathological parameters may serve to eliminate many of the inconsistencies encountered with the utilization of classical procedures, especially in the correlation between histopathological analysis and prognosis. The new classification consists of three groups: I.Long survivals (>5 years): extensive lymph node preservation of antibody mediated (average ~ 65%) and cell mediated (average ~ 37%) immunity, and/ or a nodular birefringent fibrosis-hyalinosis. - - - (15,9%) II.Medium survivals (j 5 > 2 years): partial lymph nodes preservation of antibody mediated (average ~ 42%) and/or cell mediated (average ~ 17%) immunity, and/or numerous epithelioid cell infiltrates in paracortical areas, (42,9%) III.Short survivals (j :2 years): minimal lymph node antibody mediated (average 7%) and cell mediated (average ~ I%) immunological activity, no epithelioid cell infiltrates and no birefringent fibrosis-hyalinosis. (41,2%)
Key words: Hodgkin's disease - Lymph nodes - Pathology - Immunopathology Diagnosis
The average survival rate does not seem to be a significant index for application to single cases of Hodgkin's disease, as there is too much variation in survival within the individual subtypes (SYMMERS, 1968; CROSS, 1969; GOUGH, 1970). We believe that it is necessary for a classification system to be able to predict the behaviour of the disease in each of the patients. The parameters to be used for this purpose might derive from study of the immunological status of the patient as based upon immunopathological data detected in a diseased lymph node at the time of the diagnosis of Hodgkin's disease. For this new subtyping of Hodgkin's disease we have used immunopathological findings classified by the system in use at our own Institute and also in accordance with the morphological criteria for the detection of the functional
36
P. Tosi e t
immunological
~ .
status of lymph nodes as proposed by COTTIER e t a l .
(1973), Lymph
nodes removed at autopsy from patients who had died suddenly and unexpectedly without any clinical signs of disease were used as control.
MATERIAL AND METHODS We have examined peripheral Hodgkin's disease lymph nodes which had just been examined for diagnostic purposes. We have followed the subsequent survival of 63 patients. Our cases were divided into groups, applying the classical criteria of LUKES and BUTLER (1966) and LUKES (1971), to the definition of histopathological subtypes (lymphocytic predominance, mixed cellularity, nodular sclerosis, lymphocytic depletion), and afterwards were analyzed applying immunopathological parameters solely. In each case, antibody mediated immunity was evaluated from 0 to 1OO% according to a multifactorial outline by three Pathologists. Each case was classified as demonstrating 0%, 25%, 50%, 75%, or ]00% of preserved immunity, In the series of cases under discussion no divergence of evaluation was encountered. The outline used although indipendently conceived and constructed at our Institute has proved absolutely compatible and, in fact, in many of its elements exactly identical to that proposed by COTTIER e t al. (1973) for global evaluation of lymph node immunological function. The nodal elements utilized for purposes of evaluation were the germinal centers and medullary cords. Regarding the germinal centers, their presence, size and number of mitoses were evaluated using Haematoxilin and Eosin preparations; immunoblasts (pyroninophilic blast cells) were counted using the Unna-Pappenheim method; macrophage activity was evaluated by considering acid phosphatase activity according to the Takeuchi and Tanoue procedure. The medullary cords were examined in Haematoxilin and Eosin preparations for extension and number of mitoses. Immunoblasts were evaluated as has already been considered. Cell mediated immunity was evaluated by examining the paracortical areas and by noting the presence and number of epithelioid cell granulomas!, using the same outline and examination procedure as has been described for antibody mediated immunity. For the paracortical areas, the number of mitoses was counted after staining with Haematoxilin and Eosin; immunoblasts were counted using the Unna-Pappenheim technique; the number of small lymphocytes was estimated after staining by the Feulgen procedure; epithelioid cell granulomas were examined after Haematoxilin and Eosin staining. i _ Minute aggregations of epithelioid cells are frequent in lesions of Hodgkin's disease. Sometimes infiltrates of epithelioid cells organize themselves into sarcoid-like granulomas. Focal accumulations of epithelioid cells and sarcoid-like epithelioid cells granulomas are interpreted as due to transformation of bone marrow monocytes having macrophagic activity into epithelioid cells (SPECTOR, 1970; PAPADIMITRIOU and SPECTOR, 1971). This is possibly due to the fact that they have no materials to eliminate, or, perhaps, because they have eliminated all the materials accumulated by the mechanism of inverted pinocytosis. The fact that numerous bone marrow monocytes have reached lymph nodes is probably correlated to a continuing sensitivization of lymphocytes (NELSON, 1969). This is an indication of the preservation of immunological activity of the lymph node.
Immunopathology of Hodgkin's Disease
37
Immunologically active collagen was evaluated as a parameter separate from cell or antibody mediated immunity and has empirically been observed to be an important determinant of overall immunological preservation 2. Birefringence in polarized light after Congo red staining is a property held in common by immunologically active collagen, hyalin and amyloid substance. Immunologically active collagen is normally found in nodular and trabecular distribution. It is always birefringent and it is to be differentiated from the non-birefringent so-called "immature collagen" which usually presents in a diffuse pattern and does not seem related to immunological activity. Dichroism in polarized light is a constant characteristic of amyloid substance and is sometimes also noted in deposits of immunologically active collagen. In our series, amyloidosis was not present in a sufficient number of cases to merit evaluation although we recognize that it may be a valid parameter of the immunological process. RESULTS Chart n o 1 shows the percentage of immunological activity retained at the time of histopathological diagnosis in a series of 217 cases of Hodgkin's disease, of which 63 were subsequently followed. These have been presented according to the classification system of LUKES and BUTLER and are subdivided according to the per cent of preserved immunological activity, both cell and antibody mediated, as evaluated in the histopathological specimens. 2 _ Today we know something about the antigenicity of collagen: two varieties of collagen possess different immunological properties probably related to their different chemical constituents (ROBB-SMITH, 1970; ROMHANYI, 1971; STEFFEN e~ a~., 1971; ADELMANN, 1973; ADEL~IANN and KIRRANE, 1973). No one has demonstrated the immunocompetence of collagen in Hodgkin's disease, but it is well known (LUKES, 1971) that in nodular sclerosing Hodgkin's disease long survival has to be correlated with its presence and characteristic distribution. Birefringence of collagen in polarized light has been demonstrated in nodular sclerosing Hodgkin's disease. On the contrary birefringence has never been demonstrated in other subtypes, not even in lymphocytic depletion characterized by diffuse fibrosis. Moreover, diffuse fibrosis does not influence the prognosis in lymphocytic depletion (LUKES and BUTLER, ]966). Hyaline fibrosis, birefringent or not, has also been frequently found in Hodgkin's disease lesions. Many Authors have pointed out the presence of amyloid substance in Hodgkin's diseased lymph nodes and since the advent of our recent knowledge on the histochemical and histophysical properties of amyloid, its presence in Hodgkin's disease has been observed and confirmed ever more frequently (BENDITT, 1972). Peri-collagen and trabecular amyloid deposits, both birefringent and dichroic, are not interpreted as due only to the use of immunosuppressive drugs because they may be seen in lymph nodes at the onset of the disease. An excess of antigenic stimulation might be responsible for a high level of production of gamma-globulins, particularly when it is coexistent with an immunological deficiency or an anomaly of the immunological system (FRANKLIN and ZUCKER FRANKLIN, 1972). The pre" sence of light chains of immunoglobulins, pyroninophilic blast cells, plasma cells and fibroblasts (MISSHMAL, 1970) may be recognized as preceding causative factors for the production of amyloid substance.
P. Tosi et al,
38
The distribution of immunological
preservation
in the "total cases" can be
seen to parallel that of those 63 cases whose survival we were able to follow. In all subtypes the per cent of preservation was superior to that of cell mediated
of antibody mediated
immunity.
None of the subtypes has uniformly demonstrated servation of lymph node immunological Totally preserved antibody mediated cases of the lymphocytic predominance Totally preserved cell mediated of the lymphocytic predominance
immunity
complete loss or total pre-
activity. immunity was present only in certain and mixed cellularity
subtypes.
immunity was present only in certain cases
subtype.
Total loss of both cell and antibody ~ediated immunity was seen m6st frequently in cases of lymphocytic depletion although certain instances were present in all subtypes. Per cent preservation
of both cell and antibody mediated immunity appeared
to be directly related in all subtypes to the expected prognosis resulting from traditional
classification procedures,
with the exception of nodular
sclerosis where its empirically favorable clinical prognosis must be viewed in contradistinction body mediated
to a relatively
low preservation of both cell and anti-
immunity.
Immunologically nodular sclerosing
active collagen has been found to be present only in the subtype. Although fibrosis and hyalinosis
in the other subtypes,
often were present
they were always of the non-birefringent,
non immunolo-
gically active form. Epithelioid granulomas were never present in the lymphocytic depletion subtype. These granulomas,
on the contrary, have been expressive of a reaction
to the disease in the paracortical larity,
lymphocytic predominance
disease,
areas of lymph nodes with the mixed cellu-
or nodular sclerosing type of Hodgkin's
even when there were no morphological
signs of cell mediated
immunity.
Chart n o 2, an elaboration of Chart n o I, shows per cent of preservation immunological according
of
activity in lymph nodes from patients who have been grouped
to their survival. Group one includes those cases surviving more
than 5 years; group two, cases surviving 5 years or less, but more than 2 years: group three includes those cases surviving 2 years or less. Lymph node humoral mediated
immunity was found to be conspicuous
whose survival was > 5 years
(average ~ 65%), and proportionally
groups with a lower survival
(~ 42% in survival
< 2 years).
in patients
decreased
in
< 5 > 2 years; ~ 7% in survivals
Immunopathology of Hodgkin's Disease
"
SES
.....
.. i •.
39
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Abb. I. Per cent immunological activity (antibody mediated and cell mediated) in lymph nodes of 2]7 patients (upper) and of 63 (.lower) whose survival was followed , subdivided by histiotype (.RYE) A complete preservation of cell mediated immunity has only been detected in lymph nodes from some of the patients surviving > 5 years, the average being 37%. A partial preservation of cell mediated immunity has been found in survivals < 5 > 2 years (average ~ ]7%). A minimal preservation (average ~ ]%) was found in survivals < 2 years. Epithelioid cell nests in paracortical areas represented the only manifestation of cell mediated immunity in patients of the third group. DISCUSSION In each of the subtypes, except nodular sclerosis, a direct relationship between the histological signs of cellular and/or humoral immunity in lymph nodes, and survival seems to exist. In nodular sclerosis, preservation of immunological activity in lymph nodes has not been found to be of significant importance in determining survival. Survival in this subtype appears mainly related to birefringent fibrosishyalinosis. In the other subtypes ot the disease neither hyaline fibrosis nor non-birefringent fibrosis were found to be significant. The extremely rate occurrence of amyloid substance in lymph nodes did not furnish significant data.
40
P. Tosi et al.
Abb. 2. Per cent immunological activity (antibody mediated and cell mediated) in lymph nodes of 63 patients, whose survival was known, subdivided by survival group
In the lymphocytic predominance type of Hodgkin's disease, both humoral and cell mediated immunity have demonstrated a similar influence on the survival rate. However, in mixed cellularity and in lymphocytic depletion it is humoral mediated immunity which has been shown to have strongly influenced the survival, In conclusion, the study of lymph node immunological activity led us to define in Hodgkin!s disease some groups of survlval not related to classic histopathological types, but to immunopathological parameters:
Long survivals (over 5 years): patients whose lymph node findings indicate a high preservation of antibody mediated (average approximately 65%) and cell mediated (average approximately 37%) immunity and/or a nodular birefringent fibrosis-hyalinosis
Medi~
(10 of our 63 patients, that is 15.8%).
survivals (less than or equal to 5 years and greater than 2 years):
patients whose lymph
node
findings indicate a partial preservation of anti-
body mediated (average approximately 47%) and/or cell mediated (average approximately 17%) immunity and/or numerous epithelioid cell infiltrates in paracortical areas (27 of our 63 patients, that is 42.8%).
Short survivals (less than or equal to 2 years): patients whose lymph node findings indicate a minimal antibody mediated (average approximately 7%) and cell mediated (average approximately I%) immunological activity, no epithelioid
Immunopathology
of Hodgkin's Disease
4]
Abb. 3, Hodgkin's disease, per cent of 63 cases of known survival subdivided by hystiotype (RYE) and survival group
cell granulomas
and no birefringent
fibrosis-hyalinosis
(26 of our 63 patients,
that is 41.4%). Of our total cases
(see Chart n o 3), 3.2% classified as mixed cellularity
and 1.6% classified as lymphocytic depletion, (survival over 5 years):
in other words,
whose classic histological Lymphocytic
predominance,
correspond
to our group I
this group seems to include cases
typing would have indicated a low survival rate. mixed cellularity and nodular sclerosis were some-
times the type found in survivals
less than or equal to 2 years. The survival
rate of these cases is thus in disagreement with the classic histological prognosis. We believe that the classification which we have proposed may result in a more uniform standard for histopathological
diagnosis
We hope it may serve to diminish inconsistencies histological
and clinical prognosis.
up to now encountered between
typing and survival.
We are presently
continuing our study classifying patients
Groups using histopathological sis as the sole determinant.
evaluations
in Survival
obtained at the time of the diagno-
These cases will be followed and will serve to
evaluate the precision and sensitivity of our technique as an instrument of practical
clinical prognosis.
42
P. Tosi et al.
REFERENCES ADELMANN, B.C.: Immunology 24, 871-877 (1973) ADELMANN, B.C., KIRRANE, J.: Immunology 25, 123-130 (1973) BENDITT, E.P., ERIKSEN, N.: Lab. Invest. 26, 615-625 (1972) COTTIER, H., TURK, J., SOBIN, L.: J. clin. Path. 26, 317-331 (1973) CROSS, R.M.: J. clin. Path. 22, 165-182 (1969) FRANKLIN, E.C., ZUCKER FRANKLIN, D.: Adv. Immunol. 75, 249-304 (1972) GOUGH, J.: Int. J. Cancer 5, 273-281 (1970) LUKE S, R.J.: Cancer Res. 31, 1755-1767 (1971) LUKES, R.J., BUTLER, J.J.: Cancer Res. 26~ I063ri081 (1966) MISSMAHL, H.P.: Amiloidosi. fn: MIESHER, P.A. and M~JLLER-EBERHARD, H.J. (Eds.): Trattato di Immunopatologia. Roma: II Pensiero Scientifico 1970 NELSON, D.S.: Macrophages and immunity. Amsterdam-London: North Holland Publishing Company 1969 PAPADIMITRIOU, J.M., SPECTOR, W.C.: J. Path. 105, 187-203 (1971) ROBB-SMITH, A.H.T.: The functional significance of connective tissue, f~: FLOREY, H.W. (Ed): General Pathology. 4 tn ed. London: Lloyd-Luke Ltd. 1970 ROMHANYI, F.: Virchows Arch. Path. Anat. 354, 209-222 (1971) SPECTOR, W.C.: Adv. Exp, Path. 8, 1-55 (1970) STEFFEN, C,, DICHTI, M., KNAPP, W,, BRUNNER, H,: Immunology 21, 649-657 (1971) SYMMERS, W. St.C. Jr.: J. clin. Path. 21, 650-653 (1968)
Prof. Piero TOSI Istituto di Anatomia e Istologia Patologica Via Laterino, 8 53100 S i e n a Italy
Springer-Verlag 1975
Immunopathological Lymph Node Findings in Hodgkin's Disease Correlation to Survival Piero TOSI, M.D., Professor of Morbid Anatomy and Histology Marcella CINTORINO, M.D., Associate Professor of Morbid Anatomy and Histology Pietro LUZI, M.D., Associate Professor of Morbid Anatomy and Histology Institute of Morbid Anatomy and Histology, University of Siena (Italy) Received August 22, 1974
Summary: 217 diagnostic lymph nodes biopsies from cases of Hodgkin's disease were classified according to the criteria established by the Rye Conference, These were later subdivided into survival groups using immunopathological parameters solely. In the light of findings based upon 63 cases whose progress has been followed, it appears that the classification of Hodgkin's disease according to immunopathological parameters may serve to eliminate many of the inconsistencies encountered with the utilization of classical procedures, especially in the correlation between histopathological analysis and prognosis. The new classification consists of three groups: I.Long survivals (>5 years): extensive lymph node preservation of antibody mediated (average ~ 65%) and cell mediated (average ~ 37%) immunity, and/ or a nodular birefringent fibrosis-hyalinosis. - - - (15,9%) II.Medium survivals (j 5 > 2 years): partial lymph nodes preservation of antibody mediated (average ~ 42%) and/or cell mediated (average ~ 17%) immunity, and/or numerous epithelioid cell infiltrates in paracortical areas, (42,9%) III.Short survivals (j :2 years): minimal lymph node antibody mediated (average 7%) and cell mediated (average ~ I%) immunological activity, no epithelioid cell infiltrates and no birefringent fibrosis-hyalinosis. (41,2%)
Key words: Hodgkin's disease - Lymph nodes - Pathology - Immunopathology Diagnosis
The average survival rate does not seem to be a significant index for application to single cases of Hodgkin's disease, as there is too much variation in survival within the individual subtypes (SYMMERS, 1968; CROSS, 1969; GOUGH, 1970). We believe that it is necessary for a classification system to be able to predict the behaviour of the disease in each of the patients. The parameters to be used for this purpose might derive from study of the immunological status of the patient as based upon immunopathological data detected in a diseased lymph node at the time of the diagnosis of Hodgkin's disease. For this new subtyping of Hodgkin's disease we have used immunopathological findings classified by the system in use at our own Institute and also in accordance with the morphological criteria for the detection of the functional
36
P. Tosi e t
immunological
~ .
status of lymph nodes as proposed by COTTIER e t a l .
(1973), Lymph
nodes removed at autopsy from patients who had died suddenly and unexpectedly without any clinical signs of disease were used as control.
MATERIAL AND METHODS We have examined peripheral Hodgkin's disease lymph nodes which had just been examined for diagnostic purposes. We have followed the subsequent survival of 63 patients. Our cases were divided into groups, applying the classical criteria of LUKES and BUTLER (1966) and LUKES (1971), to the definition of histopathological subtypes (lymphocytic predominance, mixed cellularity, nodular sclerosis, lymphocytic depletion), and afterwards were analyzed applying immunopathological parameters solely. In each case, antibody mediated immunity was evaluated from 0 to 1OO% according to a multifactorial outline by three Pathologists. Each case was classified as demonstrating 0%, 25%, 50%, 75%, or ]00% of preserved immunity, In the series of cases under discussion no divergence of evaluation was encountered. The outline used although indipendently conceived and constructed at our Institute has proved absolutely compatible and, in fact, in many of its elements exactly identical to that proposed by COTTIER e t al. (1973) for global evaluation of lymph node immunological function. The nodal elements utilized for purposes of evaluation were the germinal centers and medullary cords. Regarding the germinal centers, their presence, size and number of mitoses were evaluated using Haematoxilin and Eosin preparations; immunoblasts (pyroninophilic blast cells) were counted using the Unna-Pappenheim method; macrophage activity was evaluated by considering acid phosphatase activity according to the Takeuchi and Tanoue procedure. The medullary cords were examined in Haematoxilin and Eosin preparations for extension and number of mitoses. Immunoblasts were evaluated as has already been considered. Cell mediated immunity was evaluated by examining the paracortical areas and by noting the presence and number of epithelioid cell granulomas!, using the same outline and examination procedure as has been described for antibody mediated immunity. For the paracortical areas, the number of mitoses was counted after staining with Haematoxilin and Eosin; immunoblasts were counted using the Unna-Pappenheim technique; the number of small lymphocytes was estimated after staining by the Feulgen procedure; epithelioid cell granulomas were examined after Haematoxilin and Eosin staining. i _ Minute aggregations of epithelioid cells are frequent in lesions of Hodgkin's disease. Sometimes infiltrates of epithelioid cells organize themselves into sarcoid-like granulomas. Focal accumulations of epithelioid cells and sarcoid-like epithelioid cells granulomas are interpreted as due to transformation of bone marrow monocytes having macrophagic activity into epithelioid cells (SPECTOR, 1970; PAPADIMITRIOU and SPECTOR, 1971). This is possibly due to the fact that they have no materials to eliminate, or, perhaps, because they have eliminated all the materials accumulated by the mechanism of inverted pinocytosis. The fact that numerous bone marrow monocytes have reached lymph nodes is probably correlated to a continuing sensitivization of lymphocytes (NELSON, 1969). This is an indication of the preservation of immunological activity of the lymph node.
Immunopathology of Hodgkin's Disease
37
Immunologically active collagen was evaluated as a parameter separate from cell or antibody mediated immunity and has empirically been observed to be an important determinant of overall immunological preservation 2. Birefringence in polarized light after Congo red staining is a property held in common by immunologically active collagen, hyalin and amyloid substance. Immunologically active collagen is normally found in nodular and trabecular distribution. It is always birefringent and it is to be differentiated from the non-birefringent so-called "immature collagen" which usually presents in a diffuse pattern and does not seem related to immunological activity. Dichroism in polarized light is a constant characteristic of amyloid substance and is sometimes also noted in deposits of immunologically active collagen. In our series, amyloidosis was not present in a sufficient number of cases to merit evaluation although we recognize that it may be a valid parameter of the immunological process. RESULTS Chart n o 1 shows the percentage of immunological activity retained at the time of histopathological diagnosis in a series of 217 cases of Hodgkin's disease, of which 63 were subsequently followed. These have been presented according to the classification system of LUKES and BUTLER and are subdivided according to the per cent of preserved immunological activity, both cell and antibody mediated, as evaluated in the histopathological specimens. 2 _ Today we know something about the antigenicity of collagen: two varieties of collagen possess different immunological properties probably related to their different chemical constituents (ROBB-SMITH, 1970; ROMHANYI, 1971; STEFFEN e~ a~., 1971; ADELMANN, 1973; ADEL~IANN and KIRRANE, 1973). No one has demonstrated the immunocompetence of collagen in Hodgkin's disease, but it is well known (LUKES, 1971) that in nodular sclerosing Hodgkin's disease long survival has to be correlated with its presence and characteristic distribution. Birefringence of collagen in polarized light has been demonstrated in nodular sclerosing Hodgkin's disease. On the contrary birefringence has never been demonstrated in other subtypes, not even in lymphocytic depletion characterized by diffuse fibrosis. Moreover, diffuse fibrosis does not influence the prognosis in lymphocytic depletion (LUKES and BUTLER, ]966). Hyaline fibrosis, birefringent or not, has also been frequently found in Hodgkin's disease lesions. Many Authors have pointed out the presence of amyloid substance in Hodgkin's diseased lymph nodes and since the advent of our recent knowledge on the histochemical and histophysical properties of amyloid, its presence in Hodgkin's disease has been observed and confirmed ever more frequently (BENDITT, 1972). Peri-collagen and trabecular amyloid deposits, both birefringent and dichroic, are not interpreted as due only to the use of immunosuppressive drugs because they may be seen in lymph nodes at the onset of the disease. An excess of antigenic stimulation might be responsible for a high level of production of gamma-globulins, particularly when it is coexistent with an immunological deficiency or an anomaly of the immunological system (FRANKLIN and ZUCKER FRANKLIN, 1972). The pre" sence of light chains of immunoglobulins, pyroninophilic blast cells, plasma cells and fibroblasts (MISSHMAL, 1970) may be recognized as preceding causative factors for the production of amyloid substance.
P. Tosi et al,
38
The distribution of immunological
preservation
in the "total cases" can be
seen to parallel that of those 63 cases whose survival we were able to follow. In all subtypes the per cent of preservation was superior to that of cell mediated
of antibody mediated
immunity.
None of the subtypes has uniformly demonstrated servation of lymph node immunological Totally preserved antibody mediated cases of the lymphocytic predominance Totally preserved cell mediated of the lymphocytic predominance
immunity
complete loss or total pre-
activity. immunity was present only in certain and mixed cellularity
subtypes.
immunity was present only in certain cases
subtype.
Total loss of both cell and antibody ~ediated immunity was seen m6st frequently in cases of lymphocytic depletion although certain instances were present in all subtypes. Per cent preservation
of both cell and antibody mediated immunity appeared
to be directly related in all subtypes to the expected prognosis resulting from traditional
classification procedures,
with the exception of nodular
sclerosis where its empirically favorable clinical prognosis must be viewed in contradistinction body mediated
to a relatively
low preservation of both cell and anti-
immunity.
Immunologically nodular sclerosing
active collagen has been found to be present only in the subtype. Although fibrosis and hyalinosis
in the other subtypes,
often were present
they were always of the non-birefringent,
non immunolo-
gically active form. Epithelioid granulomas were never present in the lymphocytic depletion subtype. These granulomas,
on the contrary, have been expressive of a reaction
to the disease in the paracortical larity,
lymphocytic predominance
disease,
areas of lymph nodes with the mixed cellu-
or nodular sclerosing type of Hodgkin's
even when there were no morphological
signs of cell mediated
immunity.
Chart n o 2, an elaboration of Chart n o I, shows per cent of preservation immunological according
of
activity in lymph nodes from patients who have been grouped
to their survival. Group one includes those cases surviving more
than 5 years; group two, cases surviving 5 years or less, but more than 2 years: group three includes those cases surviving 2 years or less. Lymph node humoral mediated
immunity was found to be conspicuous
whose survival was > 5 years
(average ~ 65%), and proportionally
groups with a lower survival
(~ 42% in survival
< 2 years).
in patients
decreased
in
< 5 > 2 years; ~ 7% in survivals
Immunopathology of Hodgkin's Disease
"
SES
.....
.. i •.
39
?
I
•
"
"'IN
I I•"I : ; "
: :I: I-
~II
I#~
...
..~
OOOl
OIOlI
- - 'I .t Iii
...
III
":
I
.°
...'" --
..
I
~'; NS
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•
."
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~OWI~ $UF VIVAL • •
~o e•
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•
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• -
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m
-.-
Y-~ ":~: ~ ,
:.-0.
|
LP ~,.
:-
~ee
, N$
LO,
, LF'
I I
•"-'- I "'."
.
MC
I
•
i
~c
NS
LD
Abb. I. Per cent immunological activity (antibody mediated and cell mediated) in lymph nodes of 2]7 patients (upper) and of 63 (.lower) whose survival was followed , subdivided by histiotype (.RYE) A complete preservation of cell mediated immunity has only been detected in lymph nodes from some of the patients surviving > 5 years, the average being 37%. A partial preservation of cell mediated immunity has been found in survivals < 5 > 2 years (average ~ ]7%). A minimal preservation (average ~ ]%) was found in survivals < 2 years. Epithelioid cell nests in paracortical areas represented the only manifestation of cell mediated immunity in patients of the third group. DISCUSSION In each of the subtypes, except nodular sclerosis, a direct relationship between the histological signs of cellular and/or humoral immunity in lymph nodes, and survival seems to exist. In nodular sclerosis, preservation of immunological activity in lymph nodes has not been found to be of significant importance in determining survival. Survival in this subtype appears mainly related to birefringent fibrosishyalinosis. In the other subtypes ot the disease neither hyaline fibrosis nor non-birefringent fibrosis were found to be significant. The extremely rate occurrence of amyloid substance in lymph nodes did not furnish significant data.
40
P. Tosi et al.
Abb. 2. Per cent immunological activity (antibody mediated and cell mediated) in lymph nodes of 63 patients, whose survival was known, subdivided by survival group
In the lymphocytic predominance type of Hodgkin's disease, both humoral and cell mediated immunity have demonstrated a similar influence on the survival rate. However, in mixed cellularity and in lymphocytic depletion it is humoral mediated immunity which has been shown to have strongly influenced the survival, In conclusion, the study of lymph node immunological activity led us to define in Hodgkin!s disease some groups of survlval not related to classic histopathological types, but to immunopathological parameters:
Long survivals (over 5 years): patients whose lymph node findings indicate a high preservation of antibody mediated (average approximately 65%) and cell mediated (average approximately 37%) immunity and/or a nodular birefringent fibrosis-hyalinosis
Medi~
(10 of our 63 patients, that is 15.8%).
survivals (less than or equal to 5 years and greater than 2 years):
patients whose lymph
node
findings indicate a partial preservation of anti-
body mediated (average approximately 47%) and/or cell mediated (average approximately 17%) immunity and/or numerous epithelioid cell infiltrates in paracortical areas (27 of our 63 patients, that is 42.8%).
Short survivals (less than or equal to 2 years): patients whose lymph node findings indicate a minimal antibody mediated (average approximately 7%) and cell mediated (average approximately I%) immunological activity, no epithelioid
Immunopathology
of Hodgkin's Disease
4]
Abb. 3, Hodgkin's disease, per cent of 63 cases of known survival subdivided by hystiotype (RYE) and survival group
cell granulomas
and no birefringent
fibrosis-hyalinosis
(26 of our 63 patients,
that is 41.4%). Of our total cases
(see Chart n o 3), 3.2% classified as mixed cellularity
and 1.6% classified as lymphocytic depletion, (survival over 5 years):
in other words,
whose classic histological Lymphocytic
predominance,
correspond
to our group I
this group seems to include cases
typing would have indicated a low survival rate. mixed cellularity and nodular sclerosis were some-
times the type found in survivals
less than or equal to 2 years. The survival
rate of these cases is thus in disagreement with the classic histological prognosis. We believe that the classification which we have proposed may result in a more uniform standard for histopathological
diagnosis
We hope it may serve to diminish inconsistencies histological
and clinical prognosis.
up to now encountered between
typing and survival.
We are presently
continuing our study classifying patients
Groups using histopathological sis as the sole determinant.
evaluations
in Survival
obtained at the time of the diagno-
These cases will be followed and will serve to
evaluate the precision and sensitivity of our technique as an instrument of practical
clinical prognosis.
42
P. Tosi et al.
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Prof. Piero TOSI Istituto di Anatomia e Istologia Patologica Via Laterino, 8 53100 S i e n a Italy
