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Paracortical alteration in lymphadenopathic and tumor-draining lymph nodes: Histologic study
PARACORTICAL ALTERATION IN L Y M P H A D E N O P A T H I C A N D T U M O R - D R A I N I N G LYMPH NODES: H I S T O L O G I C S T U D Y Hoqjung Ree, M.D.* and Herbert Fanger, M.D.'~
Abstract Histologic studies of 142 enlarged lymph nodes from 124 patients, diagnosed histologically as nonspecific chronic lympbadenitis or reactive hyperplasia, revealed a characteristic nodular alteration in the paracortical area of nodes from the axillary, cervical, and inguinal regions, and rarely in abdominal, mediastinal, and retroperitoneal groups. In 1389 lymph nodes from 100 radical mastectomy specimens similar changes were noted more frequently in the lower than in higher levels o f the tumor-draining axillary nodes. T h e nodule was composed of small lymphocytes associated with postcapillary venules and lfistiocytes-macrophages. T h e latter varied in distribution from a scattered pattern resembling a starry-sky appearance in the initial phase of paracorticai alteration to the replacement o f small lymphocytes in advanced stages. Plasma cells and lymphatic sinuses were characteristically absent from this nodular alteration. An impressive example o f such changes was seen in four cases of dermatopathic lyntphadenitis. Studies of the paracortical area may provide new insight into the pathogenesis of some lymphadenopatlties.
Since the work of Turk t and l'arrott 2' a the paracortical area of the lymph node has been recognized as a thymus-dependent anatomic site related to cell mediated immunity. Alteration of this area has been reported in association with the development of delayed hypersensitivity,1 injection of substances with adjuvanticity,4 skin homograft,s growth of tumor in animals,6' 7 and treatment with antilymphocytic se-
rum. 8-1~ In man, depletion of small iylnphocytes from tile paracortical area was reported in conditions associated with a defect in cell mediated iinmunity--DiGeorge's syndrome, 11 Wiskott-Aldrich syndrome, 12 and lepromatous leprosy) a" ~4 In advanced malignant disease, deficiency of cellular immunity has been noted as a frequent concomitant) 5"t6 However, detailed morphologic studies of paracortical
*Assistant Professor of l'athology, Brown University. Associate l'athologist, Rhode Island ttoslilt:d, l'rovidcnce, Rhode Island. "{'Professor of Medical Science, Brown University. Director-Pathologist, Rhode Island Hospital, Providence, Rhode Island.
363
HUMAN PATHOLOGY--VOLUME 6, NUMBER 3 May 1975 alterations in this condition are exceedingly rare; review of the literature has yielded only one article dealing with this subject, but with essentially negative results) 7 Sinus histiocytosis of lymph nodes has been studied in patients with carcinoma t8 and benign conditions, ~a but these are not related to paracortical change. ht the present study we have examined so-called lymphadenopathic nodes of nonspecific cause from various sites as Well as tumor-draining axillary nodes. O u r studies have revealed a characteristic n o d u l a r alteration in the paracortical areas o f these lymph nodes, providing new insight into the pathogenesis o f certain types of lymphoid alteration, especially dermatopathic lyntphadenitis. MATERIAL A N D METHODS
Two groups of surgically obtained lymplt nodes were used for this stud)'. T h e first consisted of 142 lymph nodes fi'om 124 patients (72 males and 52 females ranging in age f r o m two to 80 )'ears) with histopathologic diagnoses of reactive hyperplasia or nonspecific chronic lymphadenitis, inclnding four cases of dermatopathic iymphadenitis. Tim lymph nodes ranged from 1 to 4 cm. ill diameter. T h e second group consisted o f a total o f 1389
364
lymph nodes fi'om 100 radical mastectomy cases. Only cases containing more than eight examinable lymph nodes were included. L y m p h nodes with t u m o r involving more t h a n one-quarter of a section were eliminated from the study. All specimens were fixed in Zenker's solution, e m b e d d e d in paratlin, and stained with hematoxylin and eosin. OBSERVATIONS
In normal lymph nodes the paracortical area is an inconspicuous, loosely arranged lymphoid tissue with relatively p r o m i n e n t postcapillary venules, lying beneath the cortical follicles (Fig. 1). T h e nodular aheration of the paracortical area (NAPA o r T-nodule*) is associated with the expansion of this area with increased celhdarity: small lymph0cytes and histiocytes-macrophages (Fig. 2). Aggregates of small lymphocytes are frequently found a r o u n d postcapillary venules (containing characteristic high endothelial lining) and occasionally in the walls of the latter (Fig. 3), suggesting the process of migration. Lyre*T is for Thymus-dependent2 or Tertiary cortical nodule? The T-nodule is used in this communication since the nodular aheration is not alwaysconfined to the paracortical area in two dimensional sections.
Figure 1. Lymph node without paracortical alteration. Inconspicuous paracortical area with several postcapillaryvenules (arrows). (• CF: cortical follicle; GC: germinal center; LS: lymphatic sinuses.
L Y M I ' H A D E N O P A T H I C AND T U M O R - D R A I N I N G LYMPH N O D E S - R E E , FANGER
.
' -,,,.-':9
9
.,~ ~ '-..-~.~:'~,
A'-"-..~
" "~.'~.
,:Y, :
,
..
Figure 2. T-nodule: expanded, i{ypercellular paracortical area (arrows). Starry-sky appearance by scattered histiocytes (• 50). CF: cortical follicle; GC: germinal center; arrow head: postcapillary venule.
phoid cells in the T-nodule are small lymphocytes, and no large.lymphoid cells (immunoblasts) are found. Histiocytesmacrophages vary in distribution from scattered macrophages producing a starrysky appearance (Fig. 2) to the replacement of the nodule by proliferating lfistiocytes with depletion of small lymphocytes (Figs. 4, 5). Scattered histiocytes-macropbages usually display abundant cytoplasm and
active phagocytosis evidenced by intracytoplasmic golden brown pigment or vacuoiated bodies. Rarely intracellular pyknotic nuclei are observed, suggesting phagocytosis of l)'mpllocytes (Fig. 6). Histiocytes are usually more prominent at the periphery of T-nodules (Figs. 7, 9), whereas small lymphocytes tend to persist in the central portion, especially around postcapillary venules (Figs. 4, 5). Plasma cells and lyre-
Figure 3. Components of T-nodules: small lymphocytes, histiocytes-macrophages (arrows), postcapillary venules_ Small lymphocytes (arrow heads) migrating through wall of postcapillary venules. (x160.)
365
ItUMAN PATHOLOGY--VOLUME 6, NUMBER 3 Alay 1975
Figure 4. T-nodule showing replacement of small lymphocytes by histiocytes-macrophageswith remainder around postcapillary venulcs (arrows). (•
phatic sinuses are characteristically absent f r o m the T - n o d u l e . Very rarely one observes in the paracortical area aggregates o f lymphoid cells without intermingling histiocytes-macrophages, in which the main c o m p o n e n t seems to be m e d i u m sized
366
lymphocytes instead o f tile T - n o d u l e s ' small lympliocytes. T - n o d u l e s vary from a discrete n o d u l a r form (Fig. 2) to a confluent mass (Figs. 7, 8), frequently encroaching on cortical follicles or medullary structures.
Figure 5. T-nodule showing depletion of small lymphocytes, advanced stage, and proliferation of histiocytes.A few snmll lymphocytes persist around postcapillary venule (arrow). (•
LYMPHADENOI'ATHIC AND TUMOR-DRAINING LYMI'H NODES-REr, FANGER
Figure 6. Macrophage with i~hagocytizedp)'kIlotic nucleus (arrow). (x400.)'
Lymph Nodesfrom Patients with Nonspecific Lymphadenopathy Sixty lymph nodes o f 142 (42 per cent) contained T - n o d u l e s , o f which the incidence and extent varied m a r k e d l y with the location o f the lymph node. T h e changes were g r a d e d as l + (discrete, u p to twice the size o f a cortical follicle), 2 + (confluent, m o r e than three times larger t h a n a cortical
follicle), and 3 + (massive, size e x t e n d i n g o v e r o n e half o f a low power field). T h e results are shown in T a b l e 1. T - n o d u l e s o c c u r r e d more frequently in axillary, cervical, and inguinal lymph nodes than in abdominal, mediastinal, and r e t r o peritoneal groups. A slightly higher incid e n c e was noted in rnesenteric nodes than in o t h e r abdominal nodes, and T - n o d u l e s were e x t r e m e l y rare in the mediastinal and
Figure 7. Confluent T-nodules encroaching on cortical (arrow) and medullary structures (arrow heads). Note absence of lymphatic sinuses (LS) in T-nodt,les and prominence Of histiocytes in periphery of Tonodules. (x25.)
367
H U M A N I ' A T H O L O G Y - - V O L U M E 6, N U M B E R 3
Figure 8.
Ma~" 1975
Massive T-nodule: axillary lymph nodes from radical mastectomy. (x 12.)
L
Figure 9. T-nodular ddpletion of small lymphocytes, especially in periphery with replacement by histiocytes continuous with massive his tiocyticproliferation of dermatopathic lymphadenitis (right). J.F. 64 M. Generalized exfoliative dermatitis. Inguinal node. (xS0.)
368
LYMPHADENOPATHIC T A B L E 1.
AND TUMOR-DRAINING
L Y M P H N O D E S - - R E E , FANGER
NODULAR ALTERATION OF I*ARACoRTICAL AREA (T-NoDULE) IN NONSPECIFIC LYMPnADENOPATIIY
Region
Axillary Cervical Inguinal Abdominal Retroperitoneal Mediastinal
No. Lymph Nodes
17 46 '2'2
27 12 18 142
retroperitoneal groups. One-third of tim specimens had prominent germinal centers, and the latter were also found in over one-third of T-nodule positive lymph nodes. T h e most prominent changes were found in patients with dermatopathic lymphadenitis. In all four cases, T-nodules showing marked histiocytic replacement were found to be continuous with the margin of the "reticulosis," frequently accompanied bY the characteristic splitting pattern of the paracortex (Figs. 10, 11), indicating the progress of the T-nodules into the massive histocytic proliferation of dermatopathic lymphadenitis. The lesion frequently encroached upon the cortical follicles and
(No. Cases)
(14) (38) (18) (27) (12) (15) (124)
--
4 21 8 21 11 l._ff_7 82
+
"2 11 5 3 I __[1 23
++
I I I
5 9 4 3 0 __0.0 21
6 5 5 0 0 __9_0 16
mednllary cords (Figs. 11, 12). Otherwise these Stl:UCtures remained ~essentially tinremarkable with usually prominent germinal centers.
Axillary Lymph Nodes from Radical Mastectomy Specimens T-nodules were found ill 819 (58 per cent) of 1389 lymph nodes fi'om 100 patients, affecting both tumor bearing and nontunlor beating nodes. Tweh'e cases were selected because of reliable topographic levels2~ and the rcsnlts arc shown in Table 2: T-nodnlcs seemed to occur more frequently in lymph nodes of lower levels.
Figure 10. T-nodules at margin of reticulohistiocytic proliferation (lower left) Of dermatopatJfic lymphadeuitis. V.S. 64 F. Psoriasis. Inguinal node. (•
369
H U M A N P A T H O L O G Y - - V O L U M E 6, N U M B E R 3
May 1975
Figure 11. T-nodules at margin of "retictdosis" of dermatopathic lynq)hadenitis (left) splitting paracortex (arrow hea(ls). Note prominent germinal centers in preserved cortical follicles and medullary cords (MC). J.G. 58 F. Generalized exfoliative dermatitis. Axillary node. (•
DISCUSSION
l,Ve have attempted to define the nodular alteration of the paracortical area. T h e nodule is characterized by the presence of three histol0gic components in varying
n u m b e r s - s n m l l lymphocytes, histiocytesmacrophages, and postcapillary v e n u l e s and notable absence of plasma cells and lymphatic sinuses. From our morphologic observations we speculate that the T-nodule may be
-7. )
370
Figure 12. Dermatopathic lymphadenitis: enlarged paracortex (arrow heads) with reticulohistiocytic rei)lacement; encroachment upon cortical areas (small arrows) and occurrence in extraparacortical location (large arrows). J.B. 60 M. Neurodermatitis. Inguinal node. (x20.)
LYMPHADENOI'ATHIC AND TUMOR-DRAINING LYMPH NODES--REE, FANGER TABLE 2. NODULARAL'rERA'nOXOr PARACORTtCALAREA (T-NoDunE) lX AXIH.XRVLVMPU NODES FROM RADICAL ~IASTECTOMY SPECIMENS >:=. NO.
Lymph Nodes Examined
--
No. Nodes Level I I.evel II Level III
69 54 44 167
23 32 36 91
+
(~ )
No. 'Nodes
(33) (59) (81)
24 8 5 37
(%)
No. Nodes
(34) (15) (11)
13 10 3 26
* T w e h e cases submitted by Doctors George V. Coleman and Henry
thynms related on tim basis o f its characteristic paracortical involvementt-3 and the similarity of histologic alterations reported in human cases with defects in cell mediated immunity,n" ~2 Tim T-nodule shares one comnton feature, the paracortical location, with the "tertiary cortical nodule" of Scothorne and McGregor5 and with "the paracortical area" of Cottier et al. 2' and Oort and Turk2 T h e difference, however, lies in the cell composition of the T-nodule: small lymplmcytes and lfistiocytes-macropltages are practically the only nonvascular constituents in the Tmodule, and large or medium sized lymphoid cells are ,tot found. In addition to the paracortical location, the T-nodule is occasionally found in extraparacortical sites, probably representing an extension of the paracortical alteration. These observations lead us to speculate f u r t h e r t h a t the T - n o d u l e m a y represent a stage of a local inmntne reaction associated with some chronic stimulation, which results in the pictnre of small lyml)hocytes being replaced by histiocytesmacrophages. Our observation of the evolvenaent of the T-nodule into the "reticulosis" o f d e r matopathic lymphadenitis suggests the necessity for further studies in pat!ents with this condition from the viewpoint of the T-cell related immune parameter. Such studies niight fiuufish insight into the patlmgenesis of other so-called "nonspecific" lymphadenopatlfies. The basis for the prevalence of the T-nodule in the peripheral (versus tim deep visceral) group of lymph nodes is not clear. Equally nnknown at this moment
Ill
q--I-
No. (%)
Nodes
(19) .(18) (7)
9 4 0 13
(%) (13) (7) (0)
J. Robidoux.
is tlm significance of the graduated alteration seen in tumor-draining lymph nodes fromradical mastectomy specimens. From a histopathologic point of view, however, what seems most impressive is the occurrence of the small lymplmcytespresumably T-cells--in close association with postcapillary venules and histiocytes in the paracortical zone, producing a characteristic histologic pattern. This suggests the possibility of the recognition of altered paracortical l y m p h o i d tissue, even in an extraparacortical location.
ACKNOVVLEDGMENTS
The authors are gratefld to Doctors .lack M. Monchik and Gilbert T. DiLeone for critical review of the manuscript, Sandra Kunz for teclmical assistance, Muriel Giorgio for typing, and Artlmr E. JacqtteS-for photography. Our special 'thanks are extended also to Darlene Burrows.
REFERENCES 1. Oort, J., and Turk, .l- L.: A hislologlcal and autoradiographic study of l)ml~h nodes d u r i n g the developnmnt o f contact sensitivity in the guinea pig. Brit. J. Exper. l'ath., 46:147, 1965. 2. Parrot, D. 31. V., DeSousa, 31. A. B., and East,J.: T h y m u s - d e p e n d e n t areas ill the lymphoid orgalls of neonatally th)'mectomized mice. J. Exper. 3led., 123:191, 1966. 3. DeSousa, 31. A. B., a n d Parrott, D. 31. V.: T h e definition of a gerlninal center areas as distinct from tile thymus-dependent area in the lymphoid tissue of the mouse. In Cottier, H., Odartchenko, N., Schindler, R., and Congdon,
371
tlUMAN
4.
5.
6.
7.
8. 9. 10.
11.
12.
I'ATHOLOGY--VOLUME
6, N U M B E R 3
C. C. (Editors): (,erlninal Centers in hnmune Responses. (Proceedings of a symposiunl held at the University of Bern, Switzerlaud, June 22-24, 1966.) New York, Springer-Verlag, 1967. Taub, R. N., Krantz, A. R., and Dresser, D. W.: The effect of localized injection of adjuvant material on file draining lymph node. I. Histology. I mmnnology, 18:171, 1970. Scothorne, R. J., and McGregor, I. A.: Celhdar changes in lymph nodes and spleen following skin homografting in the rabbit. J. Anat. (Lond.), 89:283, 1955. Alexander, P., Benstcd, J., Delorme, E.J., tlall, J. G., and Hodgett, J.: The cellular immune response to primary sarcomata in rats. lI. Abnormal rest)onses of nodes draining the tt, mor. Proc. Roy. Soc. Lond. B, 174:237, 1967. Edwards, A. J., Sumner, M. R., Rowland, G. F., and Hurd, C. M.: Changes in I)'mphoreticular tissues during growth of a murine adeuocarcinoma. I. ttistolog)' and weight o f l ) m p h nodes, spleen, and thymus. J. Nat. Cancer Inst., 47: 301, 1971. Taub, R. N., and Lance, E. M.: Histopathological effects in mice of heterologous antilymphocyte serum. J. Exp. Med., 128:1281, 1968. Turk, J. L., and Willoughby, D. A.: Central and peripheral effects of antilylnphocyte sera. Lancet, 1:249, 1967". Perkins, W. D., Schwarz, M. R., and Koehler, J. K.: The mechanism of action ofantilymphocytic serum: an electron microscopic stud)'. Clin. Immun. hnmunnl~ath., l:27, 1972. Kretschmer, R., Say, B., Brown, D., and Rosen, F. S.: Congenital aplasia of the thymus gland (DiGeorge's syndrome). New Eng. J. Med., 279:1295, 1968. Cooper, M. D., Chase, H. 1'., Lowman, J. T., Krivit, W., and Good, R. A.: Wiskott-Aldrich s y n d r o m e - a n immunologic deficiency disease
13.
14.
15. 16.
17.
18. 19. 20.
21. 22.
May 1975 involving tile afferent limb of imnmnity. Am.J. Med., 44:499, 1968. Turk, J. L., and Waters, M. F. R.: Imnnnlological basis for depression of cellular inunuuity and tile delayed allergic response in patients with lepromatous leprosy. Lancet, 2:436, 1968. Lira, S. D., Fusaro, R,, aud Good, R. A.: Leprosy. VI. The treatment of leprosy patients with intravenous infusion of leukocytes from normal persons. Clin. hnmun. Immnnopath., 1:122, 1972. Good, R. A.: Relation between immunity and malignancy. Proc. Nat. Acad. Sci. U.S.A., 69:1026, 1972. Tripodi, D., Parks, L. C., and Brugmans, J.: Drug-induced restoration of cutaneous delayed hypersensitivity in ancrgic patients with cancer. New Eng.J. Med., 289:354, 1973. Mohallatce, E. A., Dutz, W., and Saeghi, A.: Paracortical thymus-dependent areas in lymph nodes of patients with nonreticuloendothelial neoplasms. Israel J, Med. Sci., 6:567, 1970. Black, M. M., and Spcer, F. D.: Sinus histiocytosis of lymph nodes in cancer. Snrg. Gynec. Obst., 106:163, 1958. Rosai, J., and Dorfinan, R. F.: Sinus histiocytosis with massive lymphadenot)athy. Arch. Path., 87:63, 1969. McDivitt, R. W., Stewart, F. W., and Berg, J. W.: Atlas of T u m o r l'athology. Metastases and Their Prognostic hnportance. Second series, Fascicle 2. Washington, D.C., Armed Forces Institute of l'athology, 1968. Gowans, J. L., and Knight, E.J.: The route of recirculation of lymphocytes ill the rat. l'roc. Roy. Soc. Lond. B, 159:257, 196;t. Cottier, H., Turk, J., and Sobin, L.: A proposal for a standard system of reporting human lymph node morphology in relation to immunological function. J. Clin. l'ath., 26:317, 1973.
Department of Pathology Rhode Island ttospital Providence, Rhode Island 02902 (Dr. Reel
372
Abstract Histologic studies of 142 enlarged lymph nodes from 124 patients, diagnosed histologically as nonspecific chronic lympbadenitis or reactive hyperplasia, revealed a characteristic nodular alteration in the paracortical area of nodes from the axillary, cervical, and inguinal regions, and rarely in abdominal, mediastinal, and retroperitoneal groups. In 1389 lymph nodes from 100 radical mastectomy specimens similar changes were noted more frequently in the lower than in higher levels o f the tumor-draining axillary nodes. T h e nodule was composed of small lymphocytes associated with postcapillary venules and lfistiocytes-macrophages. T h e latter varied in distribution from a scattered pattern resembling a starry-sky appearance in the initial phase of paracorticai alteration to the replacement o f small lymphocytes in advanced stages. Plasma cells and lymphatic sinuses were characteristically absent from this nodular alteration. An impressive example o f such changes was seen in four cases of dermatopathic lyntphadenitis. Studies of the paracortical area may provide new insight into the pathogenesis of some lymphadenopatlties.
Since the work of Turk t and l'arrott 2' a the paracortical area of the lymph node has been recognized as a thymus-dependent anatomic site related to cell mediated immunity. Alteration of this area has been reported in association with the development of delayed hypersensitivity,1 injection of substances with adjuvanticity,4 skin homograft,s growth of tumor in animals,6' 7 and treatment with antilymphocytic se-
rum. 8-1~ In man, depletion of small iylnphocytes from tile paracortical area was reported in conditions associated with a defect in cell mediated iinmunity--DiGeorge's syndrome, 11 Wiskott-Aldrich syndrome, 12 and lepromatous leprosy) a" ~4 In advanced malignant disease, deficiency of cellular immunity has been noted as a frequent concomitant) 5"t6 However, detailed morphologic studies of paracortical
*Assistant Professor of l'athology, Brown University. Associate l'athologist, Rhode Island ttoslilt:d, l'rovidcnce, Rhode Island. "{'Professor of Medical Science, Brown University. Director-Pathologist, Rhode Island Hospital, Providence, Rhode Island.
363
HUMAN PATHOLOGY--VOLUME 6, NUMBER 3 May 1975 alterations in this condition are exceedingly rare; review of the literature has yielded only one article dealing with this subject, but with essentially negative results) 7 Sinus histiocytosis of lymph nodes has been studied in patients with carcinoma t8 and benign conditions, ~a but these are not related to paracortical change. ht the present study we have examined so-called lymphadenopathic nodes of nonspecific cause from various sites as Well as tumor-draining axillary nodes. O u r studies have revealed a characteristic n o d u l a r alteration in the paracortical areas o f these lymph nodes, providing new insight into the pathogenesis o f certain types of lymphoid alteration, especially dermatopathic lyntphadenitis. MATERIAL A N D METHODS
Two groups of surgically obtained lymplt nodes were used for this stud)'. T h e first consisted of 142 lymph nodes fi'om 124 patients (72 males and 52 females ranging in age f r o m two to 80 )'ears) with histopathologic diagnoses of reactive hyperplasia or nonspecific chronic lymphadenitis, inclnding four cases of dermatopathic iymphadenitis. Tim lymph nodes ranged from 1 to 4 cm. ill diameter. T h e second group consisted o f a total o f 1389
364
lymph nodes fi'om 100 radical mastectomy cases. Only cases containing more than eight examinable lymph nodes were included. L y m p h nodes with t u m o r involving more t h a n one-quarter of a section were eliminated from the study. All specimens were fixed in Zenker's solution, e m b e d d e d in paratlin, and stained with hematoxylin and eosin. OBSERVATIONS
In normal lymph nodes the paracortical area is an inconspicuous, loosely arranged lymphoid tissue with relatively p r o m i n e n t postcapillary venules, lying beneath the cortical follicles (Fig. 1). T h e nodular aheration of the paracortical area (NAPA o r T-nodule*) is associated with the expansion of this area with increased celhdarity: small lymph0cytes and histiocytes-macrophages (Fig. 2). Aggregates of small lymphocytes are frequently found a r o u n d postcapillary venules (containing characteristic high endothelial lining) and occasionally in the walls of the latter (Fig. 3), suggesting the process of migration. Lyre*T is for Thymus-dependent2 or Tertiary cortical nodule? The T-nodule is used in this communication since the nodular aheration is not alwaysconfined to the paracortical area in two dimensional sections.
Figure 1. Lymph node without paracortical alteration. Inconspicuous paracortical area with several postcapillaryvenules (arrows). (• CF: cortical follicle; GC: germinal center; LS: lymphatic sinuses.
L Y M I ' H A D E N O P A T H I C AND T U M O R - D R A I N I N G LYMPH N O D E S - R E E , FANGER
.
' -,,,.-':9
9
.,~ ~ '-..-~.~:'~,
A'-"-..~
" "~.'~.
,:Y, :
,
..
Figure 2. T-nodule: expanded, i{ypercellular paracortical area (arrows). Starry-sky appearance by scattered histiocytes (• 50). CF: cortical follicle; GC: germinal center; arrow head: postcapillary venule.
phoid cells in the T-nodule are small lymphocytes, and no large.lymphoid cells (immunoblasts) are found. Histiocytesmacrophages vary in distribution from scattered macrophages producing a starrysky appearance (Fig. 2) to the replacement of the nodule by proliferating lfistiocytes with depletion of small lymphocytes (Figs. 4, 5). Scattered histiocytes-macropbages usually display abundant cytoplasm and
active phagocytosis evidenced by intracytoplasmic golden brown pigment or vacuoiated bodies. Rarely intracellular pyknotic nuclei are observed, suggesting phagocytosis of l)'mpllocytes (Fig. 6). Histiocytes are usually more prominent at the periphery of T-nodules (Figs. 7, 9), whereas small lymphocytes tend to persist in the central portion, especially around postcapillary venules (Figs. 4, 5). Plasma cells and lyre-
Figure 3. Components of T-nodules: small lymphocytes, histiocytes-macrophages (arrows), postcapillary venules_ Small lymphocytes (arrow heads) migrating through wall of postcapillary venules. (x160.)
365
ItUMAN PATHOLOGY--VOLUME 6, NUMBER 3 Alay 1975
Figure 4. T-nodule showing replacement of small lymphocytes by histiocytes-macrophageswith remainder around postcapillary venulcs (arrows). (•
phatic sinuses are characteristically absent f r o m the T - n o d u l e . Very rarely one observes in the paracortical area aggregates o f lymphoid cells without intermingling histiocytes-macrophages, in which the main c o m p o n e n t seems to be m e d i u m sized
366
lymphocytes instead o f tile T - n o d u l e s ' small lympliocytes. T - n o d u l e s vary from a discrete n o d u l a r form (Fig. 2) to a confluent mass (Figs. 7, 8), frequently encroaching on cortical follicles or medullary structures.
Figure 5. T-nodule showing depletion of small lymphocytes, advanced stage, and proliferation of histiocytes.A few snmll lymphocytes persist around postcapillary venule (arrow). (•
LYMPHADENOI'ATHIC AND TUMOR-DRAINING LYMI'H NODES-REr, FANGER
Figure 6. Macrophage with i~hagocytizedp)'kIlotic nucleus (arrow). (x400.)'
Lymph Nodesfrom Patients with Nonspecific Lymphadenopathy Sixty lymph nodes o f 142 (42 per cent) contained T - n o d u l e s , o f which the incidence and extent varied m a r k e d l y with the location o f the lymph node. T h e changes were g r a d e d as l + (discrete, u p to twice the size o f a cortical follicle), 2 + (confluent, m o r e than three times larger t h a n a cortical
follicle), and 3 + (massive, size e x t e n d i n g o v e r o n e half o f a low power field). T h e results are shown in T a b l e 1. T - n o d u l e s o c c u r r e d more frequently in axillary, cervical, and inguinal lymph nodes than in abdominal, mediastinal, and r e t r o peritoneal groups. A slightly higher incid e n c e was noted in rnesenteric nodes than in o t h e r abdominal nodes, and T - n o d u l e s were e x t r e m e l y rare in the mediastinal and
Figure 7. Confluent T-nodules encroaching on cortical (arrow) and medullary structures (arrow heads). Note absence of lymphatic sinuses (LS) in T-nodt,les and prominence Of histiocytes in periphery of Tonodules. (x25.)
367
H U M A N I ' A T H O L O G Y - - V O L U M E 6, N U M B E R 3
Figure 8.
Ma~" 1975
Massive T-nodule: axillary lymph nodes from radical mastectomy. (x 12.)
L
Figure 9. T-nodular ddpletion of small lymphocytes, especially in periphery with replacement by histiocytes continuous with massive his tiocyticproliferation of dermatopathic lymphadenitis (right). J.F. 64 M. Generalized exfoliative dermatitis. Inguinal node. (xS0.)
368
LYMPHADENOPATHIC T A B L E 1.
AND TUMOR-DRAINING
L Y M P H N O D E S - - R E E , FANGER
NODULAR ALTERATION OF I*ARACoRTICAL AREA (T-NoDULE) IN NONSPECIFIC LYMPnADENOPATIIY
Region
Axillary Cervical Inguinal Abdominal Retroperitoneal Mediastinal
No. Lymph Nodes
17 46 '2'2
27 12 18 142
retroperitoneal groups. One-third of tim specimens had prominent germinal centers, and the latter were also found in over one-third of T-nodule positive lymph nodes. T h e most prominent changes were found in patients with dermatopathic lymphadenitis. In all four cases, T-nodules showing marked histiocytic replacement were found to be continuous with the margin of the "reticulosis," frequently accompanied bY the characteristic splitting pattern of the paracortex (Figs. 10, 11), indicating the progress of the T-nodules into the massive histocytic proliferation of dermatopathic lymphadenitis. The lesion frequently encroached upon the cortical follicles and
(No. Cases)
(14) (38) (18) (27) (12) (15) (124)
--
4 21 8 21 11 l._ff_7 82
+
"2 11 5 3 I __[1 23
++
I I I
5 9 4 3 0 __0.0 21
6 5 5 0 0 __9_0 16
mednllary cords (Figs. 11, 12). Otherwise these Stl:UCtures remained ~essentially tinremarkable with usually prominent germinal centers.
Axillary Lymph Nodes from Radical Mastectomy Specimens T-nodules were found ill 819 (58 per cent) of 1389 lymph nodes fi'om 100 patients, affecting both tumor bearing and nontunlor beating nodes. Tweh'e cases were selected because of reliable topographic levels2~ and the rcsnlts arc shown in Table 2: T-nodnlcs seemed to occur more frequently in lymph nodes of lower levels.
Figure 10. T-nodules at margin of reticulohistiocytic proliferation (lower left) Of dermatopatJfic lymphadeuitis. V.S. 64 F. Psoriasis. Inguinal node. (•
369
H U M A N P A T H O L O G Y - - V O L U M E 6, N U M B E R 3
May 1975
Figure 11. T-nodules at margin of "retictdosis" of dermatopathic lynq)hadenitis (left) splitting paracortex (arrow hea(ls). Note prominent germinal centers in preserved cortical follicles and medullary cords (MC). J.G. 58 F. Generalized exfoliative dermatitis. Axillary node. (•
DISCUSSION
l,Ve have attempted to define the nodular alteration of the paracortical area. T h e nodule is characterized by the presence of three histol0gic components in varying
n u m b e r s - s n m l l lymphocytes, histiocytesmacrophages, and postcapillary v e n u l e s and notable absence of plasma cells and lymphatic sinuses. From our morphologic observations we speculate that the T-nodule may be
-7. )
370
Figure 12. Dermatopathic lymphadenitis: enlarged paracortex (arrow heads) with reticulohistiocytic rei)lacement; encroachment upon cortical areas (small arrows) and occurrence in extraparacortical location (large arrows). J.B. 60 M. Neurodermatitis. Inguinal node. (x20.)
LYMPHADENOI'ATHIC AND TUMOR-DRAINING LYMPH NODES--REE, FANGER TABLE 2. NODULARAL'rERA'nOXOr PARACORTtCALAREA (T-NoDunE) lX AXIH.XRVLVMPU NODES FROM RADICAL ~IASTECTOMY SPECIMENS >:=. NO.
Lymph Nodes Examined
--
No. Nodes Level I I.evel II Level III
69 54 44 167
23 32 36 91
+
(~ )
No. 'Nodes
(33) (59) (81)
24 8 5 37
(%)
No. Nodes
(34) (15) (11)
13 10 3 26
* T w e h e cases submitted by Doctors George V. Coleman and Henry
thynms related on tim basis o f its characteristic paracortical involvementt-3 and the similarity of histologic alterations reported in human cases with defects in cell mediated immunity,n" ~2 Tim T-nodule shares one comnton feature, the paracortical location, with the "tertiary cortical nodule" of Scothorne and McGregor5 and with "the paracortical area" of Cottier et al. 2' and Oort and Turk2 T h e difference, however, lies in the cell composition of the T-nodule: small lymplmcytes and lfistiocytes-macropltages are practically the only nonvascular constituents in the Tmodule, and large or medium sized lymphoid cells are ,tot found. In addition to the paracortical location, the T-nodule is occasionally found in extraparacortical sites, probably representing an extension of the paracortical alteration. These observations lead us to speculate f u r t h e r t h a t the T - n o d u l e m a y represent a stage of a local inmntne reaction associated with some chronic stimulation, which results in the pictnre of small lyml)hocytes being replaced by histiocytesmacrophages. Our observation of the evolvenaent of the T-nodule into the "reticulosis" o f d e r matopathic lymphadenitis suggests the necessity for further studies in pat!ents with this condition from the viewpoint of the T-cell related immune parameter. Such studies niight fiuufish insight into the patlmgenesis of other so-called "nonspecific" lymphadenopatlfies. The basis for the prevalence of the T-nodule in the peripheral (versus tim deep visceral) group of lymph nodes is not clear. Equally nnknown at this moment
Ill
q--I-
No. (%)
Nodes
(19) .(18) (7)
9 4 0 13
(%) (13) (7) (0)
J. Robidoux.
is tlm significance of the graduated alteration seen in tumor-draining lymph nodes fromradical mastectomy specimens. From a histopathologic point of view, however, what seems most impressive is the occurrence of the small lymplmcytespresumably T-cells--in close association with postcapillary venules and histiocytes in the paracortical zone, producing a characteristic histologic pattern. This suggests the possibility of the recognition of altered paracortical l y m p h o i d tissue, even in an extraparacortical location.
ACKNOVVLEDGMENTS
The authors are gratefld to Doctors .lack M. Monchik and Gilbert T. DiLeone for critical review of the manuscript, Sandra Kunz for teclmical assistance, Muriel Giorgio for typing, and Artlmr E. JacqtteS-for photography. Our special 'thanks are extended also to Darlene Burrows.
REFERENCES 1. Oort, J., and Turk, .l- L.: A hislologlcal and autoradiographic study of l)ml~h nodes d u r i n g the developnmnt o f contact sensitivity in the guinea pig. Brit. J. Exper. l'ath., 46:147, 1965. 2. Parrot, D. 31. V., DeSousa, 31. A. B., and East,J.: T h y m u s - d e p e n d e n t areas ill the lymphoid orgalls of neonatally th)'mectomized mice. J. Exper. 3led., 123:191, 1966. 3. DeSousa, 31. A. B., a n d Parrott, D. 31. V.: T h e definition of a gerlninal center areas as distinct from tile thymus-dependent area in the lymphoid tissue of the mouse. In Cottier, H., Odartchenko, N., Schindler, R., and Congdon,
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C. C. (Editors): (,erlninal Centers in hnmune Responses. (Proceedings of a symposiunl held at the University of Bern, Switzerlaud, June 22-24, 1966.) New York, Springer-Verlag, 1967. Taub, R. N., Krantz, A. R., and Dresser, D. W.: The effect of localized injection of adjuvant material on file draining lymph node. I. Histology. I mmnnology, 18:171, 1970. Scothorne, R. J., and McGregor, I. A.: Celhdar changes in lymph nodes and spleen following skin homografting in the rabbit. J. Anat. (Lond.), 89:283, 1955. Alexander, P., Benstcd, J., Delorme, E.J., tlall, J. G., and Hodgett, J.: The cellular immune response to primary sarcomata in rats. lI. Abnormal rest)onses of nodes draining the tt, mor. Proc. Roy. Soc. Lond. B, 174:237, 1967. Edwards, A. J., Sumner, M. R., Rowland, G. F., and Hurd, C. M.: Changes in I)'mphoreticular tissues during growth of a murine adeuocarcinoma. I. ttistolog)' and weight o f l ) m p h nodes, spleen, and thymus. J. Nat. Cancer Inst., 47: 301, 1971. Taub, R. N., and Lance, E. M.: Histopathological effects in mice of heterologous antilymphocyte serum. J. Exp. Med., 128:1281, 1968. Turk, J. L., and Willoughby, D. A.: Central and peripheral effects of antilylnphocyte sera. Lancet, 1:249, 1967". Perkins, W. D., Schwarz, M. R., and Koehler, J. K.: The mechanism of action ofantilymphocytic serum: an electron microscopic stud)'. Clin. Immun. hnmunnl~ath., l:27, 1972. Kretschmer, R., Say, B., Brown, D., and Rosen, F. S.: Congenital aplasia of the thymus gland (DiGeorge's syndrome). New Eng. J. Med., 279:1295, 1968. Cooper, M. D., Chase, H. 1'., Lowman, J. T., Krivit, W., and Good, R. A.: Wiskott-Aldrich s y n d r o m e - a n immunologic deficiency disease
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Department of Pathology Rhode Island ttospital Providence, Rhode Island 02902 (Dr. Reel
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