Histopathology 1992, 21,439-446
Lymph node findings in generalized mastocytosis H.-P-HORNY, E.KAISERLING, M.R.PARWARESCH* & K.LENNERT* Institutes of Pathology, Universityaf Tiibingen, Tiibingen and *University of Kiel, Kiel, Germany Date of submission 21 January 1992 Accepted for publication 10 June 1992
HORNY H.-P., KAISERLING E.. PARWARESCH M . R . & LENNERT K.
(1992) Histopathology 21, 439-446
Lymph node findings in generalized mastocytosis Lymph nodes from 2 1 cases of generalized mastocytosis were studied histologically to confirm or exclude mast cell infiltration, and to investigate their micro-architecture. Mast cell infiltrates were detected in 17 (80%)of the lymph nodes and were found mainly in the medullary cords and sinuses. Diffuse infiltration was seen in 14 cases and focal infiltration in three cases. The following pathological findings were frequently observed: germinal centre hyperplasia (n= 14), which is probably a nonspecific finding;and hyperplasia of small blood vessels, which sometimes resembled high endothelial venules (14),eosinophilia (8), plasmacytosis (7)and collagen fibrosis (6),all of which may well be related to the effectsof mediators released by mast cells. Infiltrates of acute or chronic myeloid leukaemia were seen in six lymph nodes. Division of the cases into two prognostically different groups, i.e. systemic mastocytosis, in which the skin lesions of urticaria pigmentosa are present and the prognosis is favourable,and malignant mastocytosis, in which there is no cutaneous involvement and the prognosis is poor, revealed that all six lymph nodes exhibiting leukaemic infiltrates came from the malignant mastocytosis group: eosinophilia, plasmacytosis and fibrosis were seen significantly more often in malignant than in systemicmastocytosis, but blood vessel hyperplasia and germinal centre hyperplasia were encountered with the same high frequency in both groups: and mast cell atypia tended to be more pronounced in malignant mastocytosis; this diagnosis could therefore easily be missed without naphthol AS-D chloroacetate esterase staining. In four lymph nodes no mast cell infiltrates could be detected, although two of these exhibited eosinophilia, plasmacytosis and fibrosis. As only one example of the lymphadenopathic variant of generalized mastocytosis was found amongst 18 1 archive and published cases reviewed, this would appear to be very rare. Keywords: lymph node, malignant mastocytosis, mast cell, systemic mast cell disease, systemic mastocytosis
Introduction Mastocytosis is defined as a disease in which there is an abnormal (reactive or neoplastic) increase in mast cell numbers in certain tissues’, although this definitionmay be considered etymologically not completelycorrect. The diagnosis depends on characteristic histopathological findings and should not be based solely on the signs and symptoms associated with mast cell degranulation. The organs commonly involved in generalized mastocytosis and showing typical histological changes are bone liverap9 and skinlo; lymph nodes have been reported to be involved less often and show a complex histological picture’-’l. Since no widely Dedicated to Pr0f.Dr.Dr.h.c.A.Ebhle. Tubingen, Germany. on the occasion of his 70th birthday. Address for correspondence: Dr H.-P. Horny. Institut fiir Pathologie der Universitat, Liebermeisterstr. 8, D-7400 Tiibingen. Germany.
accepted classificationof tumorous proliferation of mast cells exists, it is di8ticult to compare the histopathological and clinical findings of different investigators’. The distinction between pure cutaneous mastocytosis (in most cases urticaria pigmentosa) and generalized variants is well recognized. We have also identified two different subtypes of generalized mastocytosis: systemic mastocytosis, in which the cutaneous lesions of urticaria pigmentosa are present and the prognosis is generally favourable, and malignant mastocytosis, in which there is no cutaneous involvement and the disease is usually rapidly fatal’2*13.Further subgroups of mastocytosis have been identified by some authors, e.g. mastocytosis with chronic ne~tropenia’~ and lymphadenopathic mastocytosis with eosinophilia, which is regarded as an aggressive form of generalized mastocytosis characterized by the rapid development of lymphadenopathy”. We have analysed the clinical and histomorphological 439
440
H.-P.Horny et al.
lymph node findings in our cases of generalizedmastocytosis in order to c o n h or exclude mast cell infiltration, to describe the topographical distribution and the morphological spectrum of changes in the micro-architecture of enlarged lymph nodes in generalized mastocytosis, to establish histological criteria for differentiating between systemic and malignant mastocytosis and to confirmor exclude the existence of a lymphadenopathic variant of generalized mastocytosis.
Materials and methods Clinical and histopathological lymph node findings in generalized mastocytosis were assessed in 53 cases of our own and 128 cases reported in the literature. The case reports have been listed separately in ‘appendicesto the references’ in three previously published papers concerning liver, spleen and blood findings in generalized mastocyt~sis~*~*’~. Cases for which there was no information about lymph nodes were rejected. The diagnosis of generalized mastocytosis had been confirmed histologically (mostly in trephine biopsies taken from the iliac crest) in all of our 53 cases. As detailed el~ewhere~*’~, the cases were divided into two groups depending upon the presence or absence of skin involvement resembling urticaria pigmentma-systemic and malignant mastocytosis, respectively.Since the group of patients investigated was almost the same as that recently described in a study reporting liver findings in generalid mastocyto~is~, the general clinical features (age, sex, actuarial survival) will not be described further. The site from which the enlarged lymph nodes had been removed and the presence or absence of mast cell infiltrates in the lymph nodes were recorded for each case. Statistical analysis was performed using the x2 test. Twenty-one lymph nodes (from 2 1 patients) were available for histological evaluation: 19 were biopsy specimens and two were autopsy specimens. All tissue samples had been fixed in 5% buffered formalin and embedded in paraffln. Sections, 4 pm thick, were cut and subjected to the following stains and enzyme reactions: haematoxylin and eosin (H& E), Giemsa, the periodic
Table 1. Lymph node findings in 53 archive cases and 128 published cases of histologically/cytologicallyconfirmed generalized mastocytosis (GM).The cases are subdividedaccording to the presence (systemic mastocytosis: SM) or absence (malignant mastocytosis; MM) of skin involvement. Data for the archive cases are given in parentheses ~~
Number SM l 2 8 ( 2 9 ) MM 53 (24) GM 181 (53)
~
~~~~
1
2
3
4
5
66(18) lO(3) 76 (21)
2 (1) 2(0) 4 (1)
22(2) 5(1) 27(3)
l(1) 3(3) 4(4)
37(7) 33(17) 70(24)
1 =No lymphadenopathy,no information about mast cell (MC) intiltration;2 =no lymphadenopathy,MC infiltration excluded histologically; 3 =lymphadenopathy, no information about MC infiltration; 4 =lymphadenopathy, MC infiltration excluded histologically; 5 =lymphadenopathy,MC infiltration c o n h e d histologically.
acid-Schiff reaction, Gomori’s silver impregnation and the naphthol AS-D chloroacetate esterase reaction. The latter is strongly positive in mast cells: these cells can easily be distinguished from mature neutrophils, which are also stained, by their round or ovoid nuclei16. The following were recorded for each of these lymph nodes: site: density and localization of mast cell infiltration; number of eosinophils, plasma cells and neutrophils; degree of collagen fibrosis; presence or absence of germinal centre hyperplasia; and presence or absence of leukaemic infiltrates.
Results GENERAL ASPECTS
Amongst our own 53 archive cases, localized or generalized lymphadenopathy had been recorded as present in 31 and absent in 22 (Table 1).The actual site of the enlarged lymph node had been noted in only nine cases--retroperitonea1(2), generalized (2), axillary (2).
Figure 1. Systemic mastocytosis; inguinal lymph node (case. SM 19). There is idtration of the medullary cords by dense aggregates of strongly metachromatic mast cells. A dilated sinus with loosely scattered mast cells is seen at the centre. Giemsa. x 560. Figure 2. Systemlc mastocgtosfs: axillary lymph node (case SM 33). There is dltruse inliltration of the lymphoreticular t i m e by spindle-shaped. loosely scattered, moderately metachromatic mast cells. Note the marked proliferation of small blood vessels amongst the mast cells. Sometimes mast cells appear to form an endothellum-likelining (centre). Gienwa. x 560. Figure 3. Systemic mastocytosis: inguinal lymph node (case SM 32). a There is focal inliltration of the lymph node by dense clusters of mast cells. which exhibit b strong red cytoplasmic staining in the naphthol AS-D chloroacetate esterase reaction. Naphthol AS-D chloroacetate esterase reaction. a x 340, b x 560.
(Figures 1-3)
442
H.-P. Horny et aJ.
Total number of nodes LN with confirmed MC inliltration Predominant localization of MC infiltrates Medullary cords Sinuses LN with eosinophilia LN with plasmacytosis LN with fibrosis W with hyperplasia of small blood vessels LN with germinal centre hyperplasia LN with leukaemic infiltration
SM
MM
GM
8 7
13 10
21 17
7 0 2* 1** 2***
6 6
Of
6 4 6* 6** 5*** 8
13 4 8 7 7
8
14
6t
6
14
Table 2. Summary of histopathological findings in 21 lymph nodes (CN) removed from 21 patients with generalized mastocytosis (GM). The cases are subdivided according to the presence (systemic mastocytosis; SM) or absence (malignant mastocytosis; MM) of skin involvement
* , ** , ***, tP
Lymph node findings in generalized mastocytosis H.-P-HORNY, E.KAISERLING, M.R.PARWARESCH* & K.LENNERT* Institutes of Pathology, Universityaf Tiibingen, Tiibingen and *University of Kiel, Kiel, Germany Date of submission 21 January 1992 Accepted for publication 10 June 1992
HORNY H.-P., KAISERLING E.. PARWARESCH M . R . & LENNERT K.
(1992) Histopathology 21, 439-446
Lymph node findings in generalized mastocytosis Lymph nodes from 2 1 cases of generalized mastocytosis were studied histologically to confirm or exclude mast cell infiltration, and to investigate their micro-architecture. Mast cell infiltrates were detected in 17 (80%)of the lymph nodes and were found mainly in the medullary cords and sinuses. Diffuse infiltration was seen in 14 cases and focal infiltration in three cases. The following pathological findings were frequently observed: germinal centre hyperplasia (n= 14), which is probably a nonspecific finding;and hyperplasia of small blood vessels, which sometimes resembled high endothelial venules (14),eosinophilia (8), plasmacytosis (7)and collagen fibrosis (6),all of which may well be related to the effectsof mediators released by mast cells. Infiltrates of acute or chronic myeloid leukaemia were seen in six lymph nodes. Division of the cases into two prognostically different groups, i.e. systemic mastocytosis, in which the skin lesions of urticaria pigmentosa are present and the prognosis is favourable,and malignant mastocytosis, in which there is no cutaneous involvement and the prognosis is poor, revealed that all six lymph nodes exhibiting leukaemic infiltrates came from the malignant mastocytosis group: eosinophilia, plasmacytosis and fibrosis were seen significantly more often in malignant than in systemicmastocytosis, but blood vessel hyperplasia and germinal centre hyperplasia were encountered with the same high frequency in both groups: and mast cell atypia tended to be more pronounced in malignant mastocytosis; this diagnosis could therefore easily be missed without naphthol AS-D chloroacetate esterase staining. In four lymph nodes no mast cell infiltrates could be detected, although two of these exhibited eosinophilia, plasmacytosis and fibrosis. As only one example of the lymphadenopathic variant of generalized mastocytosis was found amongst 18 1 archive and published cases reviewed, this would appear to be very rare. Keywords: lymph node, malignant mastocytosis, mast cell, systemic mast cell disease, systemic mastocytosis
Introduction Mastocytosis is defined as a disease in which there is an abnormal (reactive or neoplastic) increase in mast cell numbers in certain tissues’, although this definitionmay be considered etymologically not completelycorrect. The diagnosis depends on characteristic histopathological findings and should not be based solely on the signs and symptoms associated with mast cell degranulation. The organs commonly involved in generalized mastocytosis and showing typical histological changes are bone liverap9 and skinlo; lymph nodes have been reported to be involved less often and show a complex histological picture’-’l. Since no widely Dedicated to Pr0f.Dr.Dr.h.c.A.Ebhle. Tubingen, Germany. on the occasion of his 70th birthday. Address for correspondence: Dr H.-P. Horny. Institut fiir Pathologie der Universitat, Liebermeisterstr. 8, D-7400 Tiibingen. Germany.
accepted classificationof tumorous proliferation of mast cells exists, it is di8ticult to compare the histopathological and clinical findings of different investigators’. The distinction between pure cutaneous mastocytosis (in most cases urticaria pigmentosa) and generalized variants is well recognized. We have also identified two different subtypes of generalized mastocytosis: systemic mastocytosis, in which the cutaneous lesions of urticaria pigmentosa are present and the prognosis is generally favourable, and malignant mastocytosis, in which there is no cutaneous involvement and the disease is usually rapidly fatal’2*13.Further subgroups of mastocytosis have been identified by some authors, e.g. mastocytosis with chronic ne~tropenia’~ and lymphadenopathic mastocytosis with eosinophilia, which is regarded as an aggressive form of generalized mastocytosis characterized by the rapid development of lymphadenopathy”. We have analysed the clinical and histomorphological 439
440
H.-P.Horny et al.
lymph node findings in our cases of generalizedmastocytosis in order to c o n h or exclude mast cell infiltration, to describe the topographical distribution and the morphological spectrum of changes in the micro-architecture of enlarged lymph nodes in generalized mastocytosis, to establish histological criteria for differentiating between systemic and malignant mastocytosis and to confirmor exclude the existence of a lymphadenopathic variant of generalized mastocytosis.
Materials and methods Clinical and histopathological lymph node findings in generalized mastocytosis were assessed in 53 cases of our own and 128 cases reported in the literature. The case reports have been listed separately in ‘appendicesto the references’ in three previously published papers concerning liver, spleen and blood findings in generalized mastocyt~sis~*~*’~. Cases for which there was no information about lymph nodes were rejected. The diagnosis of generalized mastocytosis had been confirmed histologically (mostly in trephine biopsies taken from the iliac crest) in all of our 53 cases. As detailed el~ewhere~*’~, the cases were divided into two groups depending upon the presence or absence of skin involvement resembling urticaria pigmentma-systemic and malignant mastocytosis, respectively.Since the group of patients investigated was almost the same as that recently described in a study reporting liver findings in generalid mastocyto~is~, the general clinical features (age, sex, actuarial survival) will not be described further. The site from which the enlarged lymph nodes had been removed and the presence or absence of mast cell infiltrates in the lymph nodes were recorded for each case. Statistical analysis was performed using the x2 test. Twenty-one lymph nodes (from 2 1 patients) were available for histological evaluation: 19 were biopsy specimens and two were autopsy specimens. All tissue samples had been fixed in 5% buffered formalin and embedded in paraffln. Sections, 4 pm thick, were cut and subjected to the following stains and enzyme reactions: haematoxylin and eosin (H& E), Giemsa, the periodic
Table 1. Lymph node findings in 53 archive cases and 128 published cases of histologically/cytologicallyconfirmed generalized mastocytosis (GM).The cases are subdividedaccording to the presence (systemic mastocytosis: SM) or absence (malignant mastocytosis; MM) of skin involvement. Data for the archive cases are given in parentheses ~~
Number SM l 2 8 ( 2 9 ) MM 53 (24) GM 181 (53)
~
~~~~
1
2
3
4
5
66(18) lO(3) 76 (21)
2 (1) 2(0) 4 (1)
22(2) 5(1) 27(3)
l(1) 3(3) 4(4)
37(7) 33(17) 70(24)
1 =No lymphadenopathy,no information about mast cell (MC) intiltration;2 =no lymphadenopathy,MC infiltration excluded histologically; 3 =lymphadenopathy, no information about MC infiltration; 4 =lymphadenopathy, MC infiltration excluded histologically; 5 =lymphadenopathy,MC infiltration c o n h e d histologically.
acid-Schiff reaction, Gomori’s silver impregnation and the naphthol AS-D chloroacetate esterase reaction. The latter is strongly positive in mast cells: these cells can easily be distinguished from mature neutrophils, which are also stained, by their round or ovoid nuclei16. The following were recorded for each of these lymph nodes: site: density and localization of mast cell infiltration; number of eosinophils, plasma cells and neutrophils; degree of collagen fibrosis; presence or absence of germinal centre hyperplasia; and presence or absence of leukaemic infiltrates.
Results GENERAL ASPECTS
Amongst our own 53 archive cases, localized or generalized lymphadenopathy had been recorded as present in 31 and absent in 22 (Table 1).The actual site of the enlarged lymph node had been noted in only nine cases--retroperitonea1(2), generalized (2), axillary (2).
Figure 1. Systemic mastocytosis; inguinal lymph node (case. SM 19). There is idtration of the medullary cords by dense aggregates of strongly metachromatic mast cells. A dilated sinus with loosely scattered mast cells is seen at the centre. Giemsa. x 560. Figure 2. Systemlc mastocgtosfs: axillary lymph node (case SM 33). There is dltruse inliltration of the lymphoreticular t i m e by spindle-shaped. loosely scattered, moderately metachromatic mast cells. Note the marked proliferation of small blood vessels amongst the mast cells. Sometimes mast cells appear to form an endothellum-likelining (centre). Gienwa. x 560. Figure 3. Systemic mastocytosis: inguinal lymph node (case SM 32). a There is focal inliltration of the lymph node by dense clusters of mast cells. which exhibit b strong red cytoplasmic staining in the naphthol AS-D chloroacetate esterase reaction. Naphthol AS-D chloroacetate esterase reaction. a x 340, b x 560.
(Figures 1-3)
442
H.-P. Horny et aJ.
Total number of nodes LN with confirmed MC inliltration Predominant localization of MC infiltrates Medullary cords Sinuses LN with eosinophilia LN with plasmacytosis LN with fibrosis W with hyperplasia of small blood vessels LN with germinal centre hyperplasia LN with leukaemic infiltration
SM
MM
GM
8 7
13 10
21 17
7 0 2* 1** 2***
6 6
Of
6 4 6* 6** 5*** 8
13 4 8 7 7
8
14
6t
6
14
Table 2. Summary of histopathological findings in 21 lymph nodes (CN) removed from 21 patients with generalized mastocytosis (GM). The cases are subdivided according to the presence (systemic mastocytosis; SM) or absence (malignant mastocytosis; MM) of skin involvement
* , ** , ***, tP
