Volume 20, Number 2, 1992
T O X I C O ~ PATHOLOGY ~;IC ISSN.0192-6233
Copyright 0 1992 by the Society of Toxicologic Pathologists
Printed in U.S.A.
BRIEF COMMUNICATION Mesenteric Lymph Node Hemangiomas of Wistar Rats* JAMES'F.REINDEL, MARKA. DOMINICK, AND ALEXW. GOUGH Parke-Davis PfiarmaceriticalResearch Disision, Wartier-Lantbert Company, Anti Arbor, hficfiigan 48105 ABsrRACr Vascular tumors in rodent mesenteric lymph nodes are uncommon. Fifty-seven of these neoplasms were identified in control and treated Wistar rats from 6 tumor bioassays. Tumor incidence ranged from 0.75% to 5.50% and was higher in males than females (2:l). Lesions, noted as incidental necropsy findings o r in routine histologic sections, were typically solitary and restricted to nodal and perinodal tissue. Additional solitary vascular tumors were identified in skin o f 3 rats and pararenal lymph node of 1 rat. Distinct metastases were not evident. When apparent grossly, affected nodes were red to purple, hemorrhagic, and/or enlarged. Histologically, all tumors were composed of variably sized, endothelial-cell-lined, blood-filled spaces separated by variable amounts of poorly cellular stroma. Nodal effacement was common in larger tumors. Approximately half of the tumors had features of typical cavernous hemangiomas. The remaining tumors had slightly more aggressive features consisting of single or multiple foci of lymph node capsule invasion, presence of tumor cells in muscular blood vessels, or cellular atypia with variable mitotic activity. Death due to tumor rupture and consequent hernoperitoneum occurred in 1 rat only. Keywords. Lymph node; vascular tumor
Primary vascular neoplasms of lymph nodes in animals or humans are rare and have received little attention in the medical literature (1, 6, 7). Indeed, most overviews of lymph node pathology of domestic and laboratory animals or man do not mention this tumor type as a primary lymph node neoplasm. We have noted a relatively common occurrence of these tumors in mesenteric lymph nodes of barrier-maintained male and female Wistar rats in recent 2-year carcinogenicity studies. Vascular tumors arising from mesenteric nodes far exceeded the incidence of these tumors in any other lymph node and, in most bioassays, exceeded the incidence in any other tissue. Incidence and microscopic features of 57 cases of these tumors in aged Wistar rats from 6 2-year carcinogenicity bioassays are reported.
male Wistar rats (Charles River Laboratories, Wilmington, MA, and Hilltop Laboratories, Scottdale, PA) were compiled and reevaluated from 6 2-year carcinogenicity studies. Portions of 2 tumors from 1 bioassay were fixed in 2.5% glutaraldehyde, postfixed in 1% osmium tetroxide, and embedded in Epon-Araldite resin. Three blocks of each tumor were sectioned, stained with uranyl acetate and lead citrate, and examined ultrastructurally.
MATERIALSAND METHODS Gross and histopathologic data from 57 cases of vascular tumors of mesentenc lymph nodes from bamer-maintained control and treated male and fe-
* Address correspondence lo: Dr. James F. Reindel, ParkeDavis Pharmaceutical Research Division, Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48 105.
268
RESULTS Analysis of tumor incidence data from individual bioassays indicated no significant drug-related effects $&occurrence of these vascular tumors. Cumulative tumor inkidence for rats assigned to control groups from all bioassays was 15/585 (2.6Y0). Of these, 11/320 were male (3.4%) and 4/265 were female (1.5%). Cumulative tumor incidence for rats receiving drug treatment from all bioassays was 421 1885 (2.2%), indicating no apparent treatment related effect on tumor frequency. Incidence of mesenteric lymph node vascular tumors from all rats (control and treated) per bioassay ranged from 0.8% to 5.5% (Table I). Cumulative incidence for males (3.2%) was greater than for fe-
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Vol. 20, No. 2, 1992
MESENTERIC LYMPH NODE HEMANGIOMAS OF WISTAR RATS
269
FIG. 1.- Well-circumscribed mesenteric lymph node hemangioma containing vascular spaces of varying size and prominent cellular stroma. Nodal architecture is effaced, and a thin rim of compressed lymphoid tissue is evident along the tumor margins. H&E. x 20.
males (1.2%). Incidence of vascular tumors in mesenteric lymph nodes exceeded that of other lymph nodes and generally that of other tissues (Table 11).
Gross pa tho log^ Pathologic features ofnodal vascular tumors from these bioassays are summarized in Table 111. Tu-
mors were identifiedgrossly in 42 of 57 cases (73.7%). When identified grossly, lymph nodes were dark, red to purple, hemorrhagic, congested, and/or enlarged. Others were described as nodules or masses. Additional vascular neoplasms at other sites were noted in 4 of these rats. Three rats each had additional isolated cutaneous vascular tumor (2 heman-
FIG.2.-Focal capsular penetration by a more aggressive variant of vascular tumor. Vascular spaces containing blood cells are present between mesenteric adipocytes. H&E. x 64.
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REINDEL ET AL
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TOXICOLOGIC PATHOLOGY
TABLE I.- Incidence of mesentenc hemangiomas in six carcinogenicity studies.
Bioassay
Sex
1
M F M F M
2
3
No.of animals
No. of mesenteric LN hemangiomas
200 200 200 200 325 325 200 200 200 200 220 1345 1125
3 0 15 7 6 4 7 I 6 2 6 43 14
F
4
M F M F M M
5
6a Total
F
lncidence
1.5
0.0
7.5 3.5 1.8 1.2 3.5 0.5 3.0 I .o 2.7 3.2 1.2
Histopathology results only available for males. Cumulative tumor incidence for control rats was 15/640 (2.3%)and for rats receiving drug treatment was 4211830 (2.3%). a
TABLE 11.-Incidence and location" of all vascular tumors in six carcinogenicity studies. Bioassay (No. of animals) Location
Mesentenc LN Spleen Skin Uteruslvagina Lymph node Skeletal muscle Liver Prostate Thymus Testis Abdomen (soft tissue)
l ( 1 8 ) 2(243 3(16) 4(14) 5(19) 6(10)
3 5 4 4
2
2 1 2 2
2
1
3 2 1
0
8 3
8 3 4
1
2 1 1
1
6
1 1
1 1
I
1
Only primary site of metastatic hemangiosarcomas tabulated. Multicentric occurrence of vascular tumors occurred in four rats.
FIG.3.-Tumor regions with minimal cellular atypia (A) vs regions with more pronounced cellular atypia (B). Mitosis (arrow), anisocytosis, anisokaryosis, prominent nucleoli, and exaggerated cytoplasmic basophilia occurred in atypical regions. H&E. x 288.
TABLE 111.-Pathologic features of mesenteric lymph node hemangiomas. No. of mesenteric LN heman~omas
Gross pathology No gross xiodal abnormality Gross abnormality (dark, red, purple, hemorrhagic, congested, enlarged, nodule, mass) Hemoperitoneum Histopathology Extension outside nodal capsule Cellular atypia Cortical cornpressiodeffacement Muscular vessel invasiodabnormalities
'
%
15
26.3
42 la
73.7 1.8
33 17 29 3
57.9 29.8 50.9 5.3
Tumor rupture as cause of death.
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Vol. 20, No. 2, 1992
MESENTERIC LYMPH NODE HEMANGIOMAS OF WISTAR RATS
271
FIG.I.-Tumor cells lining variably sized vascular spaces. The large vascular space is partitioned by thin projections of endothelial cell processes. H&E. x 3,075.
giomas and 1 hemangiosarcoma without distant metastasis), and 1 rat had a pararenal lymph node hemangioma. Metastases to lung, liver, or spleen were not evident in any rat.
Histopat hology Hemangiomas were generally well circumscribed and contained variable-sized vascular spaces surrounded by an often prominent cellular stroma (Fig.. 1). Marked cortical compression or nodal effacement occurred in approximately 50% of the tumors. Extension of tumor outside the lymph node capsule (Fig. 2) was the most common feature, suggesting a more aggressive behavior of this tumor. Tumor cells or pronounced vasoform intimal abnormalities were evident in lumina of perinodal muscular blood vessels in 3 cases. Cells lining cavernous vascular spaces were generally uniformly flattened to plump cells with oval nuclei (Fig. 3A). Slight to moderate cellular atypia
typified by anisocytosis, anisokaryosis, exaggerated cytoplasmic basophilia, and/or increased mitosis were identified in regions of 17 tumors (Fig. 3B). Multinucleated cells and multilayering of sinusoidal endothelial cells were also evident in regions of some tumors.
Electron Microscopy ,T~Q tumors, examined ultrastructurally, were composed offlattened cells lining variably sized vascular spaces (Fig. 4). Many endothelial cells had long, thin, irregular, filipodial-like processes that extended into subjacent collagenous stroma or vascular lumina. There was conspicuous overlapping of processes between adjacent cells forming multilayered stacks (Fig. 5). Tight junctions between processes were common. Subplasmalemmal and cytoplasmic pinocytotic vesicles were numerous. Cytoplasm contained small amounts of rough endoplasmic reticulum and abundant polysomes. Nu-
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272
REINDEL ET AL
TOXICOLOGIC PATHOLOGY
FIG.5.-Tumor cells containing numerous polysomes and pinocytotic vesicles, small amounts of rough endoplasmic reticulum, few mitochondria, and many intercellular junctions. Multilayered stacks of cell processes are evident. H&E. x 9,250.
clei were oval to slightly irregular with prominent peripheral heterochromatin. Inconspicuous nucleoli were evident in some cells. Areas of tumors in which cavernous .vascular spaces were sparse or absent had abundant collagenous stroma containing isolated tumor cells or cell clusters with cleft-like, vestigial vascular spaces. Other cells within the collagenous matrix contained numerous lysosomes typical of macrophages. Still other cells had poorly defined cytologic features and thus could not be specifically identified. DISCUSSION Controversy has existed over whether vascular proliferations of mesenteric lymph nodes represent true neoplasms or vascular malformations (hamar-
tomas) (2). Based on our retrospective review of 57 tumors, we concluded that there was little justification for their classification as vascular malformations. Their histologic characteristics and biologica1,:behavior were typical of vascular tumors. Furthermore, proriferations . of this type have not been identified in young Wistar rats at our laboratory as would be expected if they represented developmental malformations. When classified as tumors, these proliferations have been called lymphangiomas, hemangiomas, or hemangiosarcomas (5). Because all tumors reviewed consisted of vascular spaces containing erythrocytes, there was no justification for classifying them as lymphangiomas. Hemorrhage into vascular spaces of lymphatic tumors was discounted as the source
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Vol. 20, No. 2, 1992
MESENTERIC LYMPH NODE HEMANGIOMAS OF WISTAR RATS
of erythrocytes in these spaces because the distribution of red blood cells was relatively uniform throughout most vascular spaces, and evidence of hemorrhage into remaining nodal tissue, tumor interstitium, or perinodal tissue was lacking or minimal. Categorization of these tumors as hemangiomas or low grade hemangiosarcomas based on morphologic criteria alone was difficult. In support of the benign nature of these tumors was their biologic behavior. These tumors were generally incidental findings at necropsy. In only 1 case did rupture of a larger tumor cause death. Furthermore, the absence of tumor metastases to liver, lung, or spleen during a 2-year bioassay supports our contention that these tumors were benign despite features of atypia in some tumors. The benign nature of the tumors is also supported by findings in 2 lifetime carcinogenicity studies of a closely related Han-Wistar rat strain, and in 1 lifetime carcinogenicity study of the BDII/Han rat (3-5). In those studies, incidence of mesenteric lymph node vascular tumor was as high as 73.3% in males and 43.3%in females, yet no metastases were seen. Deaths attributed to tumor rupture and consequent hemoperitoneum occurred rarely. There was some discrepancy in nomenclature applied to the tumors in those studies; however, tumors originally reported as lymphangiomas were later classified as hemangiomas (5). The high incidence of this tumor type in mesenteric lymph nodes appears to be restricted to Wistar rats and related rat strains (BDII/Han, Han/Wistar). In fact, we found no reports of mesenteric lymph node vascular tumors in other rat strains. Reasons for the predilection of this site for vascular tumor development in Wistar rats are not known. In summary, vascular tumors in mesenteric lymph nodes of Wistar rats were considered hemangiomas
273
with or without foci of atypia. Biologically, these tumors were benign and did not metastasize, even when features of atypia or extracapsular extension of tumor were present.
ACKNOWLEDGMENTS We acknowledge Walter Bobrowski for technical assistance and Lori Kunkel for secretarial assistance in preparation of this manuscript. This work was presented in part as a poster at the Society of Toxicologic Pathologists Tenth International Symposium, Monterey, California, June 2-6, 199 1.
REFERENCES 1. Almagro UA, Choi H, and Rouse T M (1985). Hemangioma in a lymph node. Arch. Pathol. Lab. bled. 109: 576-5 78. 2. Carter RL (1973). Tumours of soft tissues. In: Patliology of Tiunours in Laboratory Animals, Vol. l , VS Turusov et a1 (eds). International Agency for Research on Cancer, Switzerland, pp. 151-168. 3. Deerberg F, Pittermann W, and Rapp K (1978). Longevity study in Han:Wistar rats: Experience in maintaining aging rats for gerontological investigations. Znterdisc. Top. Gerorttol. 13: 66-74. 4. Deerberg F, Rapp K, Rehm S, and Pittermann W (1 980). Genetic and environmental influences on lifespan and diseases in Han:Wistar rats. Mech. Ageing Dev. 14: 333-343. 5 . Kaspareit-Rittinghausen J, Deerberg F, and Rapp K (1987). Mortality and incidence of spontaneous neoplasms in BDII-Han rats. Zentralirtsf Versuclzstierzd1t 30: 209-2 16. 6. Kasznica J, Sideli RV, and Collins MH (1989). Lymph node hemangioma. Arch. Pathol. Lab. bled. 113: 8 0 4 807. 7. Silva EG, Phillips MJ, Langer B, and Ordenez NG (1986). Spindle and histiocytoid (epithelioid) hemangioendothelioma. Primary in lymph node. Ant. J. Clin. Pathol. 85: 73 1-735.
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T O X I C O ~ PATHOLOGY ~;IC ISSN.0192-6233
Copyright 0 1992 by the Society of Toxicologic Pathologists
Printed in U.S.A.
BRIEF COMMUNICATION Mesenteric Lymph Node Hemangiomas of Wistar Rats* JAMES'F.REINDEL, MARKA. DOMINICK, AND ALEXW. GOUGH Parke-Davis PfiarmaceriticalResearch Disision, Wartier-Lantbert Company, Anti Arbor, hficfiigan 48105 ABsrRACr Vascular tumors in rodent mesenteric lymph nodes are uncommon. Fifty-seven of these neoplasms were identified in control and treated Wistar rats from 6 tumor bioassays. Tumor incidence ranged from 0.75% to 5.50% and was higher in males than females (2:l). Lesions, noted as incidental necropsy findings o r in routine histologic sections, were typically solitary and restricted to nodal and perinodal tissue. Additional solitary vascular tumors were identified in skin o f 3 rats and pararenal lymph node of 1 rat. Distinct metastases were not evident. When apparent grossly, affected nodes were red to purple, hemorrhagic, and/or enlarged. Histologically, all tumors were composed of variably sized, endothelial-cell-lined, blood-filled spaces separated by variable amounts of poorly cellular stroma. Nodal effacement was common in larger tumors. Approximately half of the tumors had features of typical cavernous hemangiomas. The remaining tumors had slightly more aggressive features consisting of single or multiple foci of lymph node capsule invasion, presence of tumor cells in muscular blood vessels, or cellular atypia with variable mitotic activity. Death due to tumor rupture and consequent hernoperitoneum occurred in 1 rat only. Keywords. Lymph node; vascular tumor
Primary vascular neoplasms of lymph nodes in animals or humans are rare and have received little attention in the medical literature (1, 6, 7). Indeed, most overviews of lymph node pathology of domestic and laboratory animals or man do not mention this tumor type as a primary lymph node neoplasm. We have noted a relatively common occurrence of these tumors in mesenteric lymph nodes of barrier-maintained male and female Wistar rats in recent 2-year carcinogenicity studies. Vascular tumors arising from mesenteric nodes far exceeded the incidence of these tumors in any other lymph node and, in most bioassays, exceeded the incidence in any other tissue. Incidence and microscopic features of 57 cases of these tumors in aged Wistar rats from 6 2-year carcinogenicity bioassays are reported.
male Wistar rats (Charles River Laboratories, Wilmington, MA, and Hilltop Laboratories, Scottdale, PA) were compiled and reevaluated from 6 2-year carcinogenicity studies. Portions of 2 tumors from 1 bioassay were fixed in 2.5% glutaraldehyde, postfixed in 1% osmium tetroxide, and embedded in Epon-Araldite resin. Three blocks of each tumor were sectioned, stained with uranyl acetate and lead citrate, and examined ultrastructurally.
MATERIALSAND METHODS Gross and histopathologic data from 57 cases of vascular tumors of mesentenc lymph nodes from bamer-maintained control and treated male and fe-
* Address correspondence lo: Dr. James F. Reindel, ParkeDavis Pharmaceutical Research Division, Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48 105.
268
RESULTS Analysis of tumor incidence data from individual bioassays indicated no significant drug-related effects $&occurrence of these vascular tumors. Cumulative tumor inkidence for rats assigned to control groups from all bioassays was 15/585 (2.6Y0). Of these, 11/320 were male (3.4%) and 4/265 were female (1.5%). Cumulative tumor incidence for rats receiving drug treatment from all bioassays was 421 1885 (2.2%), indicating no apparent treatment related effect on tumor frequency. Incidence of mesenteric lymph node vascular tumors from all rats (control and treated) per bioassay ranged from 0.8% to 5.5% (Table I). Cumulative incidence for males (3.2%) was greater than for fe-
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Vol. 20, No. 2, 1992
MESENTERIC LYMPH NODE HEMANGIOMAS OF WISTAR RATS
269
FIG. 1.- Well-circumscribed mesenteric lymph node hemangioma containing vascular spaces of varying size and prominent cellular stroma. Nodal architecture is effaced, and a thin rim of compressed lymphoid tissue is evident along the tumor margins. H&E. x 20.
males (1.2%). Incidence of vascular tumors in mesenteric lymph nodes exceeded that of other lymph nodes and generally that of other tissues (Table 11).
Gross pa tho log^ Pathologic features ofnodal vascular tumors from these bioassays are summarized in Table 111. Tu-
mors were identifiedgrossly in 42 of 57 cases (73.7%). When identified grossly, lymph nodes were dark, red to purple, hemorrhagic, congested, and/or enlarged. Others were described as nodules or masses. Additional vascular neoplasms at other sites were noted in 4 of these rats. Three rats each had additional isolated cutaneous vascular tumor (2 heman-
FIG.2.-Focal capsular penetration by a more aggressive variant of vascular tumor. Vascular spaces containing blood cells are present between mesenteric adipocytes. H&E. x 64.
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REINDEL ET AL
270
TOXICOLOGIC PATHOLOGY
TABLE I.- Incidence of mesentenc hemangiomas in six carcinogenicity studies.
Bioassay
Sex
1
M F M F M
2
3
No.of animals
No. of mesenteric LN hemangiomas
200 200 200 200 325 325 200 200 200 200 220 1345 1125
3 0 15 7 6 4 7 I 6 2 6 43 14
F
4
M F M F M M
5
6a Total
F
lncidence
1.5
0.0
7.5 3.5 1.8 1.2 3.5 0.5 3.0 I .o 2.7 3.2 1.2
Histopathology results only available for males. Cumulative tumor incidence for control rats was 15/640 (2.3%)and for rats receiving drug treatment was 4211830 (2.3%). a
TABLE 11.-Incidence and location" of all vascular tumors in six carcinogenicity studies. Bioassay (No. of animals) Location
Mesentenc LN Spleen Skin Uteruslvagina Lymph node Skeletal muscle Liver Prostate Thymus Testis Abdomen (soft tissue)
l ( 1 8 ) 2(243 3(16) 4(14) 5(19) 6(10)
3 5 4 4
2
2 1 2 2
2
1
3 2 1
0
8 3
8 3 4
1
2 1 1
1
6
1 1
1 1
I
1
Only primary site of metastatic hemangiosarcomas tabulated. Multicentric occurrence of vascular tumors occurred in four rats.
FIG.3.-Tumor regions with minimal cellular atypia (A) vs regions with more pronounced cellular atypia (B). Mitosis (arrow), anisocytosis, anisokaryosis, prominent nucleoli, and exaggerated cytoplasmic basophilia occurred in atypical regions. H&E. x 288.
TABLE 111.-Pathologic features of mesenteric lymph node hemangiomas. No. of mesenteric LN heman~omas
Gross pathology No gross xiodal abnormality Gross abnormality (dark, red, purple, hemorrhagic, congested, enlarged, nodule, mass) Hemoperitoneum Histopathology Extension outside nodal capsule Cellular atypia Cortical cornpressiodeffacement Muscular vessel invasiodabnormalities
'
%
15
26.3
42 la
73.7 1.8
33 17 29 3
57.9 29.8 50.9 5.3
Tumor rupture as cause of death.
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Vol. 20, No. 2, 1992
MESENTERIC LYMPH NODE HEMANGIOMAS OF WISTAR RATS
271
FIG.I.-Tumor cells lining variably sized vascular spaces. The large vascular space is partitioned by thin projections of endothelial cell processes. H&E. x 3,075.
giomas and 1 hemangiosarcoma without distant metastasis), and 1 rat had a pararenal lymph node hemangioma. Metastases to lung, liver, or spleen were not evident in any rat.
Histopat hology Hemangiomas were generally well circumscribed and contained variable-sized vascular spaces surrounded by an often prominent cellular stroma (Fig.. 1). Marked cortical compression or nodal effacement occurred in approximately 50% of the tumors. Extension of tumor outside the lymph node capsule (Fig. 2) was the most common feature, suggesting a more aggressive behavior of this tumor. Tumor cells or pronounced vasoform intimal abnormalities were evident in lumina of perinodal muscular blood vessels in 3 cases. Cells lining cavernous vascular spaces were generally uniformly flattened to plump cells with oval nuclei (Fig. 3A). Slight to moderate cellular atypia
typified by anisocytosis, anisokaryosis, exaggerated cytoplasmic basophilia, and/or increased mitosis were identified in regions of 17 tumors (Fig. 3B). Multinucleated cells and multilayering of sinusoidal endothelial cells were also evident in regions of some tumors.
Electron Microscopy ,T~Q tumors, examined ultrastructurally, were composed offlattened cells lining variably sized vascular spaces (Fig. 4). Many endothelial cells had long, thin, irregular, filipodial-like processes that extended into subjacent collagenous stroma or vascular lumina. There was conspicuous overlapping of processes between adjacent cells forming multilayered stacks (Fig. 5). Tight junctions between processes were common. Subplasmalemmal and cytoplasmic pinocytotic vesicles were numerous. Cytoplasm contained small amounts of rough endoplasmic reticulum and abundant polysomes. Nu-
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272
REINDEL ET AL
TOXICOLOGIC PATHOLOGY
FIG.5.-Tumor cells containing numerous polysomes and pinocytotic vesicles, small amounts of rough endoplasmic reticulum, few mitochondria, and many intercellular junctions. Multilayered stacks of cell processes are evident. H&E. x 9,250.
clei were oval to slightly irregular with prominent peripheral heterochromatin. Inconspicuous nucleoli were evident in some cells. Areas of tumors in which cavernous .vascular spaces were sparse or absent had abundant collagenous stroma containing isolated tumor cells or cell clusters with cleft-like, vestigial vascular spaces. Other cells within the collagenous matrix contained numerous lysosomes typical of macrophages. Still other cells had poorly defined cytologic features and thus could not be specifically identified. DISCUSSION Controversy has existed over whether vascular proliferations of mesenteric lymph nodes represent true neoplasms or vascular malformations (hamar-
tomas) (2). Based on our retrospective review of 57 tumors, we concluded that there was little justification for their classification as vascular malformations. Their histologic characteristics and biologica1,:behavior were typical of vascular tumors. Furthermore, proriferations . of this type have not been identified in young Wistar rats at our laboratory as would be expected if they represented developmental malformations. When classified as tumors, these proliferations have been called lymphangiomas, hemangiomas, or hemangiosarcomas (5). Because all tumors reviewed consisted of vascular spaces containing erythrocytes, there was no justification for classifying them as lymphangiomas. Hemorrhage into vascular spaces of lymphatic tumors was discounted as the source
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Vol. 20, No. 2, 1992
MESENTERIC LYMPH NODE HEMANGIOMAS OF WISTAR RATS
of erythrocytes in these spaces because the distribution of red blood cells was relatively uniform throughout most vascular spaces, and evidence of hemorrhage into remaining nodal tissue, tumor interstitium, or perinodal tissue was lacking or minimal. Categorization of these tumors as hemangiomas or low grade hemangiosarcomas based on morphologic criteria alone was difficult. In support of the benign nature of these tumors was their biologic behavior. These tumors were generally incidental findings at necropsy. In only 1 case did rupture of a larger tumor cause death. Furthermore, the absence of tumor metastases to liver, lung, or spleen during a 2-year bioassay supports our contention that these tumors were benign despite features of atypia in some tumors. The benign nature of the tumors is also supported by findings in 2 lifetime carcinogenicity studies of a closely related Han-Wistar rat strain, and in 1 lifetime carcinogenicity study of the BDII/Han rat (3-5). In those studies, incidence of mesenteric lymph node vascular tumor was as high as 73.3% in males and 43.3%in females, yet no metastases were seen. Deaths attributed to tumor rupture and consequent hemoperitoneum occurred rarely. There was some discrepancy in nomenclature applied to the tumors in those studies; however, tumors originally reported as lymphangiomas were later classified as hemangiomas (5). The high incidence of this tumor type in mesenteric lymph nodes appears to be restricted to Wistar rats and related rat strains (BDII/Han, Han/Wistar). In fact, we found no reports of mesenteric lymph node vascular tumors in other rat strains. Reasons for the predilection of this site for vascular tumor development in Wistar rats are not known. In summary, vascular tumors in mesenteric lymph nodes of Wistar rats were considered hemangiomas
273
with or without foci of atypia. Biologically, these tumors were benign and did not metastasize, even when features of atypia or extracapsular extension of tumor were present.
ACKNOWLEDGMENTS We acknowledge Walter Bobrowski for technical assistance and Lori Kunkel for secretarial assistance in preparation of this manuscript. This work was presented in part as a poster at the Society of Toxicologic Pathologists Tenth International Symposium, Monterey, California, June 2-6, 199 1.
REFERENCES 1. Almagro UA, Choi H, and Rouse T M (1985). Hemangioma in a lymph node. Arch. Pathol. Lab. bled. 109: 576-5 78. 2. Carter RL (1973). Tumours of soft tissues. In: Patliology of Tiunours in Laboratory Animals, Vol. l , VS Turusov et a1 (eds). International Agency for Research on Cancer, Switzerland, pp. 151-168. 3. Deerberg F, Pittermann W, and Rapp K (1978). Longevity study in Han:Wistar rats: Experience in maintaining aging rats for gerontological investigations. Znterdisc. Top. Gerorttol. 13: 66-74. 4. Deerberg F, Rapp K, Rehm S, and Pittermann W (1 980). Genetic and environmental influences on lifespan and diseases in Han:Wistar rats. Mech. Ageing Dev. 14: 333-343. 5 . Kaspareit-Rittinghausen J, Deerberg F, and Rapp K (1987). Mortality and incidence of spontaneous neoplasms in BDII-Han rats. Zentralirtsf Versuclzstierzd1t 30: 209-2 16. 6. Kasznica J, Sideli RV, and Collins MH (1989). Lymph node hemangioma. Arch. Pathol. Lab. bled. 113: 8 0 4 807. 7. Silva EG, Phillips MJ, Langer B, and Ordenez NG (1986). Spindle and histiocytoid (epithelioid) hemangioendothelioma. Primary in lymph node. Ant. J. Clin. Pathol. 85: 73 1-735.
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