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Lymphadenopathy in childhood
LYMPHADENOPATHY CHILDHOOD
IN
Long Term Follow-up in Patients with Nondiagnostic Lymph Node Biopsies* Joh z M.
Kissane, M.D.,? and Gordon N. Gephardt,.M.D.~
Abstract In a retrospective study o f peripheral lymph n o d e biopsies in clfildren with a d e n o p a t h y , 37 o f 100 biopsies over a 15 year period were nondiagnostic (either "no pathologic diagnosis" or "reactive hyperplasia"). T h e vital status o f 34 o f these patients was ascertained five to 20 )'cars later. Twenty-five were alive and in normal health at the end o f the stud)'. Nine were not well; six o f these have died. In only two o f the fatalities does it seem likely that f u r t h e r sampling at the time o f the nondiagnostic biopsy would have provided a diagnosis. F o u r patients, all boys who p r e s e n t e d with t h r o m b o c y t o p e n i a , are dead after variable clinical courses.
T h e pathologic anatomist faces perhaps no s t e r n e r challenge than the interpretation o f lymph nodes f r o m patients in whom clinical and laboratory evahmtions have failed to provide a diagnosis. In an appreciable n u m b e r o f such cases a specific phenoxnenologic diagnos!s c a n n o t be made and the tissue is r e p o r t e d as either "no pathologic diagnosis" or "reactive hyperplasia." Studies in adults suggest that the patients who carry these diagnoses are at g r e a t e r than r a n d o m risk o f subsequently developing an anatomically diagnosable lesion o f the l y m p h o i d system. T h e r e a p p e a r to be no data that bear u p o n this p r o b l e m in children. T h e present study was directed
toward two questions: What is tim diagnostic yield o f lymph node biopsy in pediatric patients, and what is the long term prognosis in children in whom nondiagnostic lymph n o d e biopsy is performed?
MATERIALS AND METHODS
Clinical records at St. Louis Children's Hospital relating to p r o c e d u r e s involving peripheral l)'mpll nodes between J a n u a r y 1, 1950, and D e c e m b e r 31, 1965, were reviewed. This interval was selected as affording a reasonabl)" sizable g r o u p o f patients for long t e r m follow-up. It was
*Portions of this work were presented at tile interim meeting, Pediatric l'athology Club, Texas Children's Hospital, Houston, Texas, September 20-21, 1973. #Professor of Pathology and of Pathology in Pediatrics, Washington UniversitySchool of Medicine. Associate l'athologist, Barnes and Attiliated Ilospitals and St. Louis Children's llospital. Director of Pathologic Anatomy, St. Louis Children's ttospital. Consuhant in Pathology, Jewish tiospltal of St. Louis, St. Louis, Missouri. +At the time of this stud) Dr. Gephardt was a fourth )ear medical student, Washington University School of Medicine, St. I.ouis, Missouri. Presently Intern in Pathology, University of Rochester and Strang Memorial Hospital, Rochester, New York.
431
HUMAN PATHOLOGY--VOLUME 5, NUMBER 4 July 1974 recognized that many patients presented before the availability o f m o d e r n diagnostic p r o c e d u r e s - e v e n before the recognition of certain relevant disease entities. It was not the purpose o f this study, however, to establish possible or even probable diagnoses in the light o f current concepts but rather to examine the long term natnral history of nondiagnostic lymph node biopsies in pediatric patients. Cases were excluded from this study in which lymph nodes became available in the course of an extirpative or essentially therapeutic procedure. 9 Also excluded were cases in which an anatomic diagnosis was established by examination of tissue other than lymlHl nodes d u r i n g the relevant hosl)ital stay. This stricture was applied becanse diagnostic p r o c e d u r e s are applied to puzzling cases in a variable sequence, d e p e n d i n g u p o n such circumstances, irrelevant to the disease process, as availability of Consuhants, scheduling of operating rooms, and days of performance of certain laboratory procedures. Microsections from all biopsies were reviewed, employing special stains as indicated, without knowledge of follow-up information. Information regarding the cnrrent state of heahh o f every patient in whom lymph node biopsy had been nondiagnostic was sought by letters to attending physicians, to referring physicians, to pathologists in the metropolitan St. Louis area, to bttreaus of death registration in Missouri and Illinois, and to parents. These !nquiries were s u p p l e m e n t e d when necessary by letters a n d telephone communications with parents at their last known address. In man)' instances, one of us (GG) visited the n e i g h b o r h o o d of last known residence and inte[rogated neighbors, local shopkeelmrs, or others regarding the patient's present or most recent known address. Medical records, pathology reports, and microsections f r o m patients subsequently u n d e r medical observation were reviewed.*
RESULTS
One h u n d r e d patients met the criteria for inchtsion in this study. Anatomic diagnoses in these 100 patients are classified in Table 1. In nine patients unequivocal morphologic features of acute inflammation were recognizable in the biopsy of the lymph node. All nine are alive and in normal health four to 14 )'ears after biopsy. In 28 patients, lymph nodes biopsies showed microscopic features of granulomatous inflammation. In 15 of these, acid fast bacilli were identified morphologically. I n three the tissues were interpreted as "consistent with cat scratch disease." In one there was a clinical history of a scratch by a pet cat. Twenty-six cases were afforded anatomically specific diagnoses. These encompassed a fairly representative group of diagnoses a m o n g infants and children with l y m p h a d e n o p a t h y (Table 2). In 39 lyxnph node biopsies from 37 patients, "no pathologic diagnosis" or "reactive hyperplasia" was the microscopic interpretation. Further attention was directed toward these 37 patients. A m o n g these 37 patients, the average age was seven )'ears (range, nine months to 13 years)~ Twenty-five were boys and 12, girls. Twenty-eight were white a n d nine, black. In most cases the duration of adenopathy was two months or less, but this historical feature varied from a few weeks to 12 months. Symptoms and signs are tabulated in Table 3. Most patients had been immunized against diphtheria, pertussis, tetanus, and smallpox, b u t dates and pm;ticulars were rarely recorded. No patient was receiving anticonvulsant medication. O n e patient had a cousin said to have leukemia. T h e r e was no other family history of helnatologic disease, l y m p h a d e n o p a t h y , Or death in childhood,
ANATOMICDIAGNOSISIN PERIPIIERALLvm'Ii NODE BIOPSIES
T A B L E 1.
432
*The very large mmlber of professional and lay people who cooperated with the purposes of this study l)recludes their individual designation. The anthors wish to acknowledge the contribution of physicians who promptly and willingly submitted clinical records, of pathologists whotnade available reports, slides, and paraffin blocks, and, finally, of parents to the objectives of Ibis study.
Acute inflammation 9Granulomalous inllammation Specific diagnoses "tlyperplasia" or no diagnosis
9 9_8 26 37 10 0
LYMPHADENOI'ATHY IN CHILDHOOD--KISSANE, GEPIIARDT TABLE 2.
SPrcIVlC DIAGNOSISIN
26 DIAGNOSTIC PERII'tIERAL LYMI'H
NODE BIOPSIES l.)mphocytlc lymphoma Hodgkin's disease Histiocytic lymphoma "'Malignant reticuloendot heliosis" Metastatic tumor Acinic carcinoma Neuroblastoma Sarcoma, unclassified Malignant tumor, unclassified Eosinophilic granuloma
6 13 1 1
1 1 1 I
4 I
26
but family histories were o f t e n f r a g m e n tary or p e r f n n c t o r y . l'hysical e x a m i n a t i o n revealed generalized lyml>lladenopatily in six patients a n d regional o r localized l y m p h a d e n o p a t h y in 31. Raslles o r c u t a n e o n s lesions were n o t e d in f o u r patients. In only o n e patient was tim e r u p t i o n characterized as " e c z e m a t o u s " o r "scaly." O n e patient had abscesses o f the scalp; o n e lind otitis media. S p l e n o m e g a l y Ctwo f i n g e r b r e a d t h s " to 11 cm.) was p r e s e n t in f o u r patients a n d h e p a t o m e g a l y ("two f i n g e r b r e a d t h s " to 3 cm.) in four. C u t a n e o u s petechiae were n o t e d in two patients a n d gingival bleeding in one. T h e s e observations, except for h e p a t o m e g a l y 2 cln. below the costal m a r gin in o n e patient, were all in patients with c u r r e n t o r previous t h r o m b o c y t o p e n i a . L a b o r a t o r y studies revealed h e m o globin levels less titan 10.0 gm. p e r 100 ml. in five patients. In o n e o f these t h e r e were f o u r nucleated e r y t h r o c y t e p r e c u r s o r s p e r T A B L E 3. SYMPTOMS AND SIGNS IN 37 PATIENTS WITtt NONDIAGNOSTIG LYMI'II NODE BIOPSIES
Rash Fever Splenonlegaly I lepatomegaly Recurrent respiratory infection Allergies Asthma Purpura Exposure to unpasteurized milk Exposure to tuberculosis Previous thrombocytopenia tlistory of cat scratch tlistory of mumps
No.
%
4 4 4 4 3 3 2 3 3 2 2 1 1
11 l1 11 l1 8 8 6 8 8 6 6 3 3
100 leukocytes in tim p e r i p h e r a l blood smear. O n e patient had only 3000 leukocytes p e r cu. ram. All others had leukocyte counts g r e a t e r than 4000 p e r cu. m m . F o u r lind leukocyte counts g r e a t e r tlmn 12,000 p e r cu. m m . , all with a left slfift, a n d n o n e g r e a t e r tlmn 29,000 p e r cu. ram. Relative n e n t r o p e n i a was r e c o r d e d in o n e case. Platelets were nsually evaluated in stained films o f p e r i p h e r a l blood as " n o r real" or " a d e q u a t e . " Formal platelet counts were decreased in f o u r patients, r a n g i n g f r o m 1200 to 181,000 p e r cu. ram. B o n e n m r r o w aspiration was perf o r m e d in eight o f 37 patients with n o n diagnostic biopsies o f p e r i p h e r a l lyxnpll nodes. Five m a r r o w exanfinations were i n t e r p r e t e d as " n o r m a l , " two as " e r y t h r o j d llyperplasia," a n d one as "generalized hyperplasia." Microscopic e x a m i n a t i o n s o f clots o b t a i n e d at n m r r o w aspiration in m a n y o f these cases c o n f i r m e d the diagnosis t e n d e r e d f r o m e x a m i n a t i o n o f m a r row smears. T u b e r c u l i n skin tests were r e c o r d e d in 15 o f 37 patients. O n e was positive. T w e l v e patients received c u t a n e o u s tests with histoplasmin; all were negative. VDRL, Kahn, o r Kline tests were r e c o r d e d in nine cases a n d were negative in all. T w o sickle cell screening tests were p e r f o r m e d , a n d both were negative. T w o patients lind LE tests; both were negative: Chest roentg e n o g r a m s were obtained in 17 o f the 37 patients. Seven e x a m i n a t i o n s were rep o r t e d as negative, f o u r as showing mediastinal o r hilar adenopatily, f o u r as showing pneulnonitis of one o r m o r e lobes, a n d two as revealing p r i m a r y G b o n complexes. Skull x-ray films in t h r e e patients were nornml. T h e sites o f the 39 lympll nodes f r o m which biopsy specimens were taken in the 37 cases are tabulated in T a b l e 4. Most
T A B L E 4. SITES o r 39 NONDIAGNOSTIC LY.XtPtI NODE BIOPSIES IN 37 CASES
Cervical Axillary l'reauricular Inguinal Not slated Total
No.
%
21 11 3 '2 2 39
54 26 8 6 B 100
433
tlUMAN PATHOLOGY--VOLUME 5, NUMBER 4 July 1974 cases were examples o f regionally localized e n l a r g e m e n t ' o f cervical lymph nodes. Axillary, preauricular, and ingninal adenopathies were n m c h less c o m m o n . L y m p h nodes r e m o v e d at biopsy varied f r o m 0.8 to 5.0 cm. in greatest diameter. T h e average d i a m e t e r was 1.6 cm. Few nodes e x c e e d e d 2.0 cm. in greatest diameter. Cultures o f excised nodes for mycobacteria were obtained in six cases; o n e was positive. Four nodes were c u h u r e d for fungi; all were negative. Six were cultured routinely; one culture grew out a few colonies o f M. pyogenes Par. aureus, but the patient remains alive, in good h e a h h without t r e a t m e n t 16 )'ears after biopsy. T i m clinical status o f patients subjected to nondiagnostic lymph n o d e biopsies within the terms o f the stud)' was ascertained in 34 o f the 37 cases. O f the three patients who were lost to follow-up at tim termination o f the stud)', two were known to have been alive a n d well four and 14V2 )'ears after biopsy. No follow-up i n f o r m a t i o n is available for the third patient. 9 This r e p o r t t h e r e f o r e is based u p o n the courses o f 34 o f 37 patients followed f r o m biopsy o f p e r i p h e r a l lymph nodes to the termination o f the study. General aspects o f follow-up stud)' are summarized in T a b l e 5. O f the 34 patients subjected to nondiagnostic lymph n o d e biopsies and followed to the end o f the study, 25 were known to be alive and in normal health five to 20 years after biopsy. In riine pa-
T A B L E 5.
FOLLOW-UPtN 37 PATIENTSWITH NONDIAGNOSTICLYMPtt NODE BIOPSIES
434
Alive and well 5 to 20 )ears later T h r e e lost to follow-up (two alive and well four and 141/2 )ears later) Recurrent adenopathy, once called Brill-Symmers disease, alive and well 16Y2 )'ears later Recurrent a d e n o p a t h y with u p p e r respirator)' infections, IgA def., five )'ears later Atypical mycobacterial infections; Hodgkin's disease 18 )ears later Alive after treatment. Dead Thrombocytopenia 4 Lymphon m 1 Leukemia . . 1
25 3
1
1
1 6
tients subjected to nondiagnostic biopsy o f p e r i p h e r a l lymph nodes, subsequent courses have involved morbidit)' relevant to tim l y m p h o i d system. T h r e e surviving patients have been subjected to r e p e a t e d clinical, laboratory, and m o r p h o l o g i c stndies. T h e s e three cases are s u m m a r i z e d in the following paragraphs.
Case I
This young man is alive and well 16 )'ears after nondiagnostic lymph node biopsy. When tlte patient was tliree and one-half )'ears old, a biopsy specimen was taken from a preauricular mass. The pathologic diagnosis was reactive hyperplasia of l)'mph nodes and acute and chronic inflammation of the iJarotid salivary gland. Three years later biopsy of an enlarged cervical lymph node was undertaken at anotlter hospital. The possibility Of Brill-Synmaers disease was raised but apparently not made the basis for therapy. Twice in the next two )'ears the child was hospitalized elsewhere for study of tlte cervical lymphadenopathy. One biopsy specimen was interpreted as nonspecific lymphadenitis. Examination of bone marrow was "normal." A chest roentgenogram showed "hilar calcification." Tile patient has experienced repeated episodes of cervical adenopathy, not always associated with infections. He has recentl)" been studied at the age of 19 )'cars at a local hospital, 16 )'ears after nondiagnostic lymph node biopsy. No adenopathy Was present. Urinalysis, hemogram, chest roentgenogram, total and fractional serum protein studies, and blood chemistries were normal. Case 2
Tiffs five year old boy was admitted with asymptomatic generalized adenopathy. Biopsy of a cervical node showed follicular hyperplasia (Fig. 1). Tile patient remains well five )'ears later. Generalized adenopathy Ires accompanied upper respirator)" infections. Recently tlte pa- . tient lias been sltown to have isolated deficiency of IgA.
Cose 3 In this case the clinical course has been remarkable. At tile age of two years this white male child presented witlt generalized lymphadenopathy and an eryflmmatous skin rash but no other remarkable findings: His father, a physician, was undeftreatment for tuberculosis.
L Y M P H A D E N O P A T H Y IN CHILDHOOD--KIsSA,~E, GEPtIARDT
Figure 1, Case '2. Follicular hyperl~lasia in cervical I)mph node of five )ear old boy subsequently shown to have isolated deficienc)" of IgA. (x200.) Biopsy o f left axillary lymph node showed only hyperplasia (Fig. 2A). Nine months later the child was readmitted with pain and swelling in tile knees and right elbow. Sktdl roentgenograms showed osteoI)'tic lesions, and x-ray films o f tile extrentities showed lesions in the right ulna and in both femurs. Biopsies of lesions o f an ulna and Of the calvarium were interpreted as being "consistent with Hand-Schfiller-Christian disease." Radiation therapy was begun. Biopsy material that was cultured eventually grew out an atypical Mycobacterium, and a guinea pig injected with material from the biopsy developed gram/lomas in the spleen. T h e child received several courses o f then available antituberculosis medications. T h r o u g h tbe next eight )'ears he developed many osseous and subcutaneous abscesses from which mycobacteria of the Battey type were repeatedly recovered. After a course of isoniazid, paraanainosalicylic acid, and kanamycin, these aspects of the patient's course were suppressed and he remained well and in good health until nine )'ears later, when at the age of 20 )'ears a pelvic mass developed, which was diagnosed elsewhere as Hodgkin's disease. A staging laparotom)' was performed elsewhere, and the results o f examination of material from this procedure were consistent with the diagnosis o f Hodgkin's disease, lymphocyte depletion type. T h e pathologist at the other center, in retrospect, entertains the diagnosis of histiocytic lymphoma on the
basis o f tissues available from the staging procedure (Fig. 2B). At the end o f our study the patient remains alive and well at termination o f a course o f irradiation. The next group of patientspresents two f e a t u r e s in c o m m o n . All f o u r w e r e male a n d all f o u r p r e s e n t e d with t h r o m b o - ' cytopeni,'i f o r which, in t h r e e cases, s p l e n e c t o m y was p e r f o r m e d . O t h e r features in the n a t u r a l histories o f these patients a r e h e t e r o g e n e o u s . Case 4 This white male was admitted at eight )ears o f age with features o f tllrombocytopenic p u r p u r a and Coombs" positive hemolytic anemia. Splenectom)" was performed. Hemolytic crises recurred but responded to transfusions and steroid tberap)'. Chronic infections o f tbe mastoid, paranasal sinnses, and middle ear persisted. T h e final three )'ears o f the patient's life were dominated b)" a progressive incapacitating disease o f the central nervous system involving both the u p p e r and the lower motor neuron systems and featuring diarrhea and pulmonary, middle ear, and urinary tract infections. T h e serum gamma globulin level was once measured as 1.6 gin. per 100 ml. A specific diagnosis was never established, and the patient died at the age of 15 )'ears o f complications ofbis nenrologic disease. Autopsy was not performed.
435
H U M A N I ' A T H O L O G Y - - V O L U M E 5, NUMBER 4 July 1974
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Figure 2. Case 3. A, Follicular ID-perplasia of axillary I)mlfll node at age two years, showing fifllicular hyperl~lasia. (x200.) B, Spleeq at 20 years of age, showing malig,mnt lympho,na. (x500.)
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Case 5 This iwo and one-half year old wliite male was admitted with fever, adenopathy, hepatosplenomegaly, thrombocytopenia, anemia, and eosinophilia. Tuberculin and histoplasmin tests were negative. T h e bone marrow was generally hyperplastic. A chest roentgenogram showed right hilar adenopathy. A:~illary lymph node biopsy showed reactive hyperplasia. Routine and fimgal cuhures were negative. Tile patient was discharged following a normal hemogram. Subsequent clinical information is not available, but the patient is known to have died at five and one-lmlf }'ears o f age. NO atttopsy was performed, but causes of death are recorded as "1itseudomonas aeruginosa and Monilia albicans septicemia."
Case 6
436
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Tiffs two year old white boy had been nornml at birth but developed symptoms o f thrombocytopenic p u r p u r a during the last six
++ 9 months of his life. Clinical manifestations did not improve after splenectomy elsewhere. He was referred to the St. Lotfis Children's Hospital where he improved after treatment with steroids and antibiotics. Tile child was discharged home and died two w e e k s later. Autopsy findings included bronchopneumonia and lymphoid hyperplasia.
Case 7 This white male was admitted at age 12 }'ears with thrombocytopenia, cervical adenopathy, and mild eosinophilia. Sptenectomy was performed, and a peripheral lymph node was interpreted as sho~[ing "reactive hyperplasia" (Fig. 3A). Bone marrow examination showed many eosinophils and megakaryocytes but was nondiagnostic. During the next eight }'ears of his life the patient underwent fotlr clocumented episodes o f bacterial meningitis, two o f them pnetnnococcal. Lymphadenopathy persisted and on two occasions was diagnosed elsewhere by
L Y M I ' H A D E N O I ' A T H Y IN CHILDHOOD--KIssA.x~:, GZVHA~Da" various pathologists as Hodgkin's disease. One episode o f lymphadenopatl W followed spider bites of both legs (Fig. 3B). T h e patient died in another city at the age of 25 )'ears o f a ruptured cerebral aneur)'sm. Peripheral lymphoid tissue was described at autopsy only as hyperplastic (Fig. 3C). I n c o n t r a s t with these cases, two patients p r o g r e s s e d relatively r a p i d l y to a fatal t e r m i n a t i o n a f t e r a n o n d i a g n o s t i c l y m p h n o d e biopsy.
9
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This 13 )'ear old white boy was admitted with left cervical adenopath)" and hepatosplenomegaly. A hemogram revealed 0nly anemia. Chest roentgenographic examination showed bilateral hilar adenopathy. Although. the patient was febrile, a source o f infection was not demonstrated. Biopsies of axillary and cervical lymph nodes were interpreted as showing lwperplasia. T h e patient was' discharged.
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IIUMAN I'ATHOLOGY--VOLUME 5, NUMBER 4 j~,ty 1974 Three weeks later lie returned with a hemorrhagic rash over the trunk, hepatosplenomegaly, and cervical l)'mphadenopathy. A chest roentgenogram showed pleural effusion. Cytologic examination of the pleural aspirate revealed malignant cells. A biopsy of nodules in the anterior chest wall was interpreted as.showing malignant lymphoma. The patient died in spite of radiation therapy and treatment with methotrexate and adrenocorticosteroids. Autopsy disclosed histiocytic I)mphoma, widel)' distributed. Case 9
This white female infant was admitted at three weeks of age I)ecause of the spitting up of feedings. Gestation and delivery had bcen normal. At 12 days of age the baby dcveloped an erythematous pustular cutaneous eruption and began to spit up her feedings, l'hysical examination was not revealing except for pt,stular lesions on the scalp, neck, and perineum and generalized shotty, lyml~hadenol~athy. A peripheral blood count showed 18 per cent eosinophils, 2 per cent juvenile neutrophils, 8 per cent "stab cells," 14 per cent segmented neutrophils, 46 per cent i)'ml~hoc)'tes, and 12 per cent monocytes. After antibiotic therap)" and transfusions, the infant's condition improved. A lymph node biopsy was nondiagnostic. After two months in tile hospital she was discharged. A week later she was readmitted with moderately severe diarrhea. Her condition deteriorated and she died one week ariel" readmission. The pathologic diagnosis at autopsy was acute leukemia.
DISCUSSION
438
In this series o f retrospectively studied cases, approximately one-fourth of the childreu subjected .to noildiagnostic lymph node biopsies in the course of investigation of lyml)hadenopathy suffered prolonged morbidity and, over two decades, a mortality of about 18 per cent. In a recent stud)" of nondiagnostic lymph node biopsies in adult males, Saltzstein I followed three grottps of patients, distingttished on the basis of clinical indications for the original biopsy. A m o n g 25 patients with initially nondiagnostic biopsies of lymph nodes in whom the indication was I)'ml)hadenol)athy alone, six (I 7 per cent) were later diagnosed as having a related a n a -
tomically specific disease. O f 23 patients ill whom lympll node biopsy constituted part of a wide ranging diagnostic study for miscellaneous indications (most of them, fever o f u n d e t e r m i n e d origin or suspected collagen-vascular disease), 15 (57 per cent) later were afforded a specific diagnosis. In 45 patients, clinically or radiographicall)" demonstrated p u l m o n a r y disease p r o m p t e d tile biopsy. O f these patients, 37 (79 per cent) were later shown to have a pertinent disease, unusually carcinoma or specific inllamnmtion. T h e r e appears to be no corresponding study o f the diagnostic yield and uhimate course over prolonged periods in children subjected to nondiagnostic I)'mpll node biopsy. It is apparent fi'om o u r study that the indications for lymph node biopsy in aduhs differ from those in children, and results are comparable only in the approximately one-third of a d u h patients in whom the indication for biopsy is lymp h a d e n o p a t h y of indeterminate etiology. In Sahzstein's series, moreover, when an anatomically specific diagnosis was ultimately achieved in six of 35 patients with obscure lymphadenopathy, that diagnosis became clinically apparent within six months in five of the six cases. Dawson and associates 2 analyzed 158 "diflicuh" lymph node biopsies in patients o f . unstated ages, presumably mostly aduhs. In seven cases the "blind" pathologic diagnosis was reactive hyperplasia in patients who eventually died of nmlignant lymllhoma; six of them died within three }'ears after nondiagnostic l)'ml~la node biopsy. In our group o f patients in w i m m investigation of lymlflmdenopathy inchtded nondiagnostic lyml)h node biopsy, three-fourths (7,1 per cent) were alive and in good heahh five to 20 )'ears aftevbiopsy. T w o of the three patients not available for follow-up evaluation at the end of the study were known to have been alive and" well four and 14V2 years after biopsies. Nine patients (26 per cent) did not regain normal good health after occurrence of the l)'nq~iladenopatl W that occasioned tim biopsy. T h r e e o f these patients are alive. T h e nature of the underlying disease process and, indeed, the ultimate prognosis in case 1 remain obscure. T h e natural history, with prolonged lyml)hadenopathy
LYMI'HADENOPATHY IN CHILDHOOD--KIssANE, GEI'I'IARDT
and infiltration o f organs (parotid glaud), suggests "sinus histiocytosis" described by A z o u r y and Reed z and elaborated by Rosai and D o r f m a n . 4 Iu o u r case I, Itowever, the pathologic picture was tltat o f nonspecific follicular hyperplasia ratlter than "sinus Itistiocytosis." We can v e n t u r e no projection as to this patient's uhimate course nor, in fact, can we speculate as to the n a t n r e o f the u n d e r l y i n g disease. T h e patient in case 2 laas been d e m o n strated to suffer fi'ont isolated deficiency o f IgA. Generalized l y m p h a d e n o p a t l t y iu the course o f respirator)' infections has been described iu patients with symptomatic deficiency o f IgA. 5 Patient 3 snffered m a n y atypical mycobacterial infectious and has uhintately d e v e l o p e d lytnphoreticular nmlignant disease. No specific immunologic deficiency s y n d r o m e has beeu definable eitlter clinically or morphologically in tlte ninny available samples o f lymphoid tissue. F o u r patients (cases 4 to 7) a p p e a r unified by their presentation with throntbocytopenia witlt or withottt deficiencies in otlter circulating cell lines and by their susceptibility to infection and male sex. T h e s e tltree features collectively suggest tire Wiskott-Aldricit syndrome, but patients in o u r g r o u p lind all been norntal in the postnatal period. In only one was a rash described as eczematous (a scaly dermatitis over the foreltead in a 12t/2 )'ear old). Ahhouglt features o f the Wiskott-Aldriclt s y n d r o m e have been described in a living patient 24 )'ears'old, G attd rapid deterioration after splenectonty is p r o l n ! n e n t in tire ltistories o f patients with the Wiskott-Aldrich s y n d r o m e , we are not able to s u p p o r t that diagnosis s t r o n g l y in this g r o u p o f patients eitlter on retrospective clinical g r o u n d s or f r o m study o f available lylnph nodes. Case 7 strongly resembles cases 1 and 2 in tlte r e p o r t o f Canale and Smith. 7 L y m p h a d e n o p a t h y and susceptibility to infihration in tlmt r e p o r t were associated with d e m o n strable inability o f the involved patients to f o r m antipnettxnococcal antibodies. It is obvious retrospectively tlmt ntany, p e r h a p s most, o f those patients who did not recover relatively p r o m p t l y after non-
diagnostic biopsy o f 1)'ml~h nodes must Itave suffered " from abnornmlities in cellular o r b u m 6 r a l reactions to infection. It was not the p u r p o s e o f tlfis study to attempt to establish retrospectively tlte diagnosis o f a specific form o f i m m u n o logic deficiency disease i n any case but ratiter to p r e s e n t the natnral Itistory o f pediatric patieuts witlt l y m p h a d e n o p a t i W in wltom biopsy o f peripheral lymplt nodes was initially nondiagnostic. T w o patients in o u r series o f cases o f nondiagnostic lymph n o d e biopsies proc e e d e d rapidly to a fatal termination o f a neoplastic disease. Tire patient iu case 8 rapidly p r e s e n t e d the picture o f histiocytic l y m p h o m a , and patient 9 died o f a somewhat peculiar blastic leukemia a few weeks after nondiagnostic lymplt n o d e biopsy. In both cases f u r t h e r salnpling or diagnostic perseverance probably would have provided an anatomic diagnosis d u r i n g the first ltospitalization. Only tltese two cases a p p e a r to c o r r e s p o n d to Sahzstein's cases o f l y m p h a d e n o p a t h y in adults in wltom anatonfically specific diagnoses became possible relatively promptly.
REFERENCES
1. Saltzstein, S-. L.: "File fate of patients with nondiagnostic lymt)h node biopsies. Snrgery, 58: 659, 1965. 2. Dawson, P. J., Cooper R. A., and Rambo, D. N.: Diagnoses of malignant lymphoma, a clinicopathological analysis of 158 dilficuh lymph node biopsies. Cancer, 17:1405, 1964. 3. Azoury, F. J., and Reed, R.J.: Histiocytosis. New Engl. J. Med., 274:928, 1966. 4. Rosai, J., and Dorfinan, R. F.: Sinus histiocytosis with nmssive l)'nq)hadenopathy, a pseudo l)mphomatous benign disorder. Analysis of 34 cases. Cancer, 30:1174, 1972. 5. Heremans, I. F., and Crabbe, P. A.: IgA deficiency: general consideration and relation to hunmn diseases. In Bergsma, D. (Editor): Immune Deficiency Diseases in Man. Birth Defects. Original Article Series. Vol. IV, No. 1, p. 298, 1968. 6. Meadl, M. A., Watson, J. I., and Rose, B.: The Wiskott-Aldrich syndrome; immunopathologic meclmnisms and a long-term survival. Ann. Intern. Med., 68:1050, 1968. 7. Canale, V. C., and Smith, C. H.: Chronic lymphadenopathy simulating malignant lymphoma. J. l'ediat., 70:891, 1967. 660 South Euclid Avenue St. Lotfis, Missouri 63110 (Dr. Kissane)
439
IN
Long Term Follow-up in Patients with Nondiagnostic Lymph Node Biopsies* Joh z M.
Kissane, M.D.,? and Gordon N. Gephardt,.M.D.~
Abstract In a retrospective study o f peripheral lymph n o d e biopsies in clfildren with a d e n o p a t h y , 37 o f 100 biopsies over a 15 year period were nondiagnostic (either "no pathologic diagnosis" or "reactive hyperplasia"). T h e vital status o f 34 o f these patients was ascertained five to 20 )'cars later. Twenty-five were alive and in normal health at the end o f the stud)'. Nine were not well; six o f these have died. In only two o f the fatalities does it seem likely that f u r t h e r sampling at the time o f the nondiagnostic biopsy would have provided a diagnosis. F o u r patients, all boys who p r e s e n t e d with t h r o m b o c y t o p e n i a , are dead after variable clinical courses.
T h e pathologic anatomist faces perhaps no s t e r n e r challenge than the interpretation o f lymph nodes f r o m patients in whom clinical and laboratory evahmtions have failed to provide a diagnosis. In an appreciable n u m b e r o f such cases a specific phenoxnenologic diagnos!s c a n n o t be made and the tissue is r e p o r t e d as either "no pathologic diagnosis" or "reactive hyperplasia." Studies in adults suggest that the patients who carry these diagnoses are at g r e a t e r than r a n d o m risk o f subsequently developing an anatomically diagnosable lesion o f the l y m p h o i d system. T h e r e a p p e a r to be no data that bear u p o n this p r o b l e m in children. T h e present study was directed
toward two questions: What is tim diagnostic yield o f lymph node biopsy in pediatric patients, and what is the long term prognosis in children in whom nondiagnostic lymph n o d e biopsy is performed?
MATERIALS AND METHODS
Clinical records at St. Louis Children's Hospital relating to p r o c e d u r e s involving peripheral l)'mpll nodes between J a n u a r y 1, 1950, and D e c e m b e r 31, 1965, were reviewed. This interval was selected as affording a reasonabl)" sizable g r o u p o f patients for long t e r m follow-up. It was
*Portions of this work were presented at tile interim meeting, Pediatric l'athology Club, Texas Children's Hospital, Houston, Texas, September 20-21, 1973. #Professor of Pathology and of Pathology in Pediatrics, Washington UniversitySchool of Medicine. Associate l'athologist, Barnes and Attiliated Ilospitals and St. Louis Children's llospital. Director of Pathologic Anatomy, St. Louis Children's ttospital. Consuhant in Pathology, Jewish tiospltal of St. Louis, St. Louis, Missouri. +At the time of this stud) Dr. Gephardt was a fourth )ear medical student, Washington University School of Medicine, St. I.ouis, Missouri. Presently Intern in Pathology, University of Rochester and Strang Memorial Hospital, Rochester, New York.
431
HUMAN PATHOLOGY--VOLUME 5, NUMBER 4 July 1974 recognized that many patients presented before the availability o f m o d e r n diagnostic p r o c e d u r e s - e v e n before the recognition of certain relevant disease entities. It was not the purpose o f this study, however, to establish possible or even probable diagnoses in the light o f current concepts but rather to examine the long term natnral history of nondiagnostic lymph node biopsies in pediatric patients. Cases were excluded from this study in which lymph nodes became available in the course of an extirpative or essentially therapeutic procedure. 9 Also excluded were cases in which an anatomic diagnosis was established by examination of tissue other than lymlHl nodes d u r i n g the relevant hosl)ital stay. This stricture was applied becanse diagnostic p r o c e d u r e s are applied to puzzling cases in a variable sequence, d e p e n d i n g u p o n such circumstances, irrelevant to the disease process, as availability of Consuhants, scheduling of operating rooms, and days of performance of certain laboratory procedures. Microsections from all biopsies were reviewed, employing special stains as indicated, without knowledge of follow-up information. Information regarding the cnrrent state of heahh o f every patient in whom lymph node biopsy had been nondiagnostic was sought by letters to attending physicians, to referring physicians, to pathologists in the metropolitan St. Louis area, to bttreaus of death registration in Missouri and Illinois, and to parents. These !nquiries were s u p p l e m e n t e d when necessary by letters a n d telephone communications with parents at their last known address. In man)' instances, one of us (GG) visited the n e i g h b o r h o o d of last known residence and inte[rogated neighbors, local shopkeelmrs, or others regarding the patient's present or most recent known address. Medical records, pathology reports, and microsections f r o m patients subsequently u n d e r medical observation were reviewed.*
RESULTS
One h u n d r e d patients met the criteria for inchtsion in this study. Anatomic diagnoses in these 100 patients are classified in Table 1. In nine patients unequivocal morphologic features of acute inflammation were recognizable in the biopsy of the lymph node. All nine are alive and in normal health four to 14 )'ears after biopsy. In 28 patients, lymph nodes biopsies showed microscopic features of granulomatous inflammation. In 15 of these, acid fast bacilli were identified morphologically. I n three the tissues were interpreted as "consistent with cat scratch disease." In one there was a clinical history of a scratch by a pet cat. Twenty-six cases were afforded anatomically specific diagnoses. These encompassed a fairly representative group of diagnoses a m o n g infants and children with l y m p h a d e n o p a t h y (Table 2). In 39 lyxnph node biopsies from 37 patients, "no pathologic diagnosis" or "reactive hyperplasia" was the microscopic interpretation. Further attention was directed toward these 37 patients. A m o n g these 37 patients, the average age was seven )'ears (range, nine months to 13 years)~ Twenty-five were boys and 12, girls. Twenty-eight were white a n d nine, black. In most cases the duration of adenopathy was two months or less, but this historical feature varied from a few weeks to 12 months. Symptoms and signs are tabulated in Table 3. Most patients had been immunized against diphtheria, pertussis, tetanus, and smallpox, b u t dates and pm;ticulars were rarely recorded. No patient was receiving anticonvulsant medication. O n e patient had a cousin said to have leukemia. T h e r e was no other family history of helnatologic disease, l y m p h a d e n o p a t h y , Or death in childhood,
ANATOMICDIAGNOSISIN PERIPIIERALLvm'Ii NODE BIOPSIES
T A B L E 1.
432
*The very large mmlber of professional and lay people who cooperated with the purposes of this study l)recludes their individual designation. The anthors wish to acknowledge the contribution of physicians who promptly and willingly submitted clinical records, of pathologists whotnade available reports, slides, and paraffin blocks, and, finally, of parents to the objectives of Ibis study.
Acute inflammation 9Granulomalous inllammation Specific diagnoses "tlyperplasia" or no diagnosis
9 9_8 26 37 10 0
LYMPHADENOI'ATHY IN CHILDHOOD--KISSANE, GEPIIARDT TABLE 2.
SPrcIVlC DIAGNOSISIN
26 DIAGNOSTIC PERII'tIERAL LYMI'H
NODE BIOPSIES l.)mphocytlc lymphoma Hodgkin's disease Histiocytic lymphoma "'Malignant reticuloendot heliosis" Metastatic tumor Acinic carcinoma Neuroblastoma Sarcoma, unclassified Malignant tumor, unclassified Eosinophilic granuloma
6 13 1 1
1 1 1 I
4 I
26
but family histories were o f t e n f r a g m e n tary or p e r f n n c t o r y . l'hysical e x a m i n a t i o n revealed generalized lyml>lladenopatily in six patients a n d regional o r localized l y m p h a d e n o p a t h y in 31. Raslles o r c u t a n e o n s lesions were n o t e d in f o u r patients. In only o n e patient was tim e r u p t i o n characterized as " e c z e m a t o u s " o r "scaly." O n e patient had abscesses o f the scalp; o n e lind otitis media. S p l e n o m e g a l y Ctwo f i n g e r b r e a d t h s " to 11 cm.) was p r e s e n t in f o u r patients a n d h e p a t o m e g a l y ("two f i n g e r b r e a d t h s " to 3 cm.) in four. C u t a n e o u s petechiae were n o t e d in two patients a n d gingival bleeding in one. T h e s e observations, except for h e p a t o m e g a l y 2 cln. below the costal m a r gin in o n e patient, were all in patients with c u r r e n t o r previous t h r o m b o c y t o p e n i a . L a b o r a t o r y studies revealed h e m o globin levels less titan 10.0 gm. p e r 100 ml. in five patients. In o n e o f these t h e r e were f o u r nucleated e r y t h r o c y t e p r e c u r s o r s p e r T A B L E 3. SYMPTOMS AND SIGNS IN 37 PATIENTS WITtt NONDIAGNOSTIG LYMI'II NODE BIOPSIES
Rash Fever Splenonlegaly I lepatomegaly Recurrent respiratory infection Allergies Asthma Purpura Exposure to unpasteurized milk Exposure to tuberculosis Previous thrombocytopenia tlistory of cat scratch tlistory of mumps
No.
%
4 4 4 4 3 3 2 3 3 2 2 1 1
11 l1 11 l1 8 8 6 8 8 6 6 3 3
100 leukocytes in tim p e r i p h e r a l blood smear. O n e patient had only 3000 leukocytes p e r cu. ram. All others had leukocyte counts g r e a t e r than 4000 p e r cu. m m . F o u r lind leukocyte counts g r e a t e r tlmn 12,000 p e r cu. m m . , all with a left slfift, a n d n o n e g r e a t e r tlmn 29,000 p e r cu. ram. Relative n e n t r o p e n i a was r e c o r d e d in o n e case. Platelets were nsually evaluated in stained films o f p e r i p h e r a l blood as " n o r real" or " a d e q u a t e . " Formal platelet counts were decreased in f o u r patients, r a n g i n g f r o m 1200 to 181,000 p e r cu. ram. B o n e n m r r o w aspiration was perf o r m e d in eight o f 37 patients with n o n diagnostic biopsies o f p e r i p h e r a l lyxnpll nodes. Five m a r r o w exanfinations were i n t e r p r e t e d as " n o r m a l , " two as " e r y t h r o j d llyperplasia," a n d one as "generalized hyperplasia." Microscopic e x a m i n a t i o n s o f clots o b t a i n e d at n m r r o w aspiration in m a n y o f these cases c o n f i r m e d the diagnosis t e n d e r e d f r o m e x a m i n a t i o n o f m a r row smears. T u b e r c u l i n skin tests were r e c o r d e d in 15 o f 37 patients. O n e was positive. T w e l v e patients received c u t a n e o u s tests with histoplasmin; all were negative. VDRL, Kahn, o r Kline tests were r e c o r d e d in nine cases a n d were negative in all. T w o sickle cell screening tests were p e r f o r m e d , a n d both were negative. T w o patients lind LE tests; both were negative: Chest roentg e n o g r a m s were obtained in 17 o f the 37 patients. Seven e x a m i n a t i o n s were rep o r t e d as negative, f o u r as showing mediastinal o r hilar adenopatily, f o u r as showing pneulnonitis of one o r m o r e lobes, a n d two as revealing p r i m a r y G b o n complexes. Skull x-ray films in t h r e e patients were nornml. T h e sites o f the 39 lympll nodes f r o m which biopsy specimens were taken in the 37 cases are tabulated in T a b l e 4. Most
T A B L E 4. SITES o r 39 NONDIAGNOSTIC LY.XtPtI NODE BIOPSIES IN 37 CASES
Cervical Axillary l'reauricular Inguinal Not slated Total
No.
%
21 11 3 '2 2 39
54 26 8 6 B 100
433
tlUMAN PATHOLOGY--VOLUME 5, NUMBER 4 July 1974 cases were examples o f regionally localized e n l a r g e m e n t ' o f cervical lymph nodes. Axillary, preauricular, and ingninal adenopathies were n m c h less c o m m o n . L y m p h nodes r e m o v e d at biopsy varied f r o m 0.8 to 5.0 cm. in greatest diameter. T h e average d i a m e t e r was 1.6 cm. Few nodes e x c e e d e d 2.0 cm. in greatest diameter. Cultures o f excised nodes for mycobacteria were obtained in six cases; o n e was positive. Four nodes were c u h u r e d for fungi; all were negative. Six were cultured routinely; one culture grew out a few colonies o f M. pyogenes Par. aureus, but the patient remains alive, in good h e a h h without t r e a t m e n t 16 )'ears after biopsy. T i m clinical status o f patients subjected to nondiagnostic lymph n o d e biopsies within the terms o f the stud)' was ascertained in 34 o f the 37 cases. O f the three patients who were lost to follow-up at tim termination o f the stud)', two were known to have been alive a n d well four and 14V2 )'ears after biopsy. No follow-up i n f o r m a t i o n is available for the third patient. 9 This r e p o r t t h e r e f o r e is based u p o n the courses o f 34 o f 37 patients followed f r o m biopsy o f p e r i p h e r a l lymph nodes to the termination o f the study. General aspects o f follow-up stud)' are summarized in T a b l e 5. O f the 34 patients subjected to nondiagnostic lymph n o d e biopsies and followed to the end o f the study, 25 were known to be alive and in normal health five to 20 years after biopsy. In riine pa-
T A B L E 5.
FOLLOW-UPtN 37 PATIENTSWITH NONDIAGNOSTICLYMPtt NODE BIOPSIES
434
Alive and well 5 to 20 )ears later T h r e e lost to follow-up (two alive and well four and 141/2 )ears later) Recurrent adenopathy, once called Brill-Symmers disease, alive and well 16Y2 )'ears later Recurrent a d e n o p a t h y with u p p e r respirator)' infections, IgA def., five )'ears later Atypical mycobacterial infections; Hodgkin's disease 18 )ears later Alive after treatment. Dead Thrombocytopenia 4 Lymphon m 1 Leukemia . . 1
25 3
1
1
1 6
tients subjected to nondiagnostic biopsy o f p e r i p h e r a l lymph nodes, subsequent courses have involved morbidit)' relevant to tim l y m p h o i d system. T h r e e surviving patients have been subjected to r e p e a t e d clinical, laboratory, and m o r p h o l o g i c stndies. T h e s e three cases are s u m m a r i z e d in the following paragraphs.
Case I
This young man is alive and well 16 )'ears after nondiagnostic lymph node biopsy. When tlte patient was tliree and one-half )'ears old, a biopsy specimen was taken from a preauricular mass. The pathologic diagnosis was reactive hyperplasia of l)'mph nodes and acute and chronic inflammation of the iJarotid salivary gland. Three years later biopsy of an enlarged cervical lymph node was undertaken at anotlter hospital. The possibility Of Brill-Synmaers disease was raised but apparently not made the basis for therapy. Twice in the next two )'ears the child was hospitalized elsewhere for study of tlte cervical lymphadenopathy. One biopsy specimen was interpreted as nonspecific lymphadenitis. Examination of bone marrow was "normal." A chest roentgenogram showed "hilar calcification." Tile patient has experienced repeated episodes of cervical adenopathy, not always associated with infections. He has recentl)" been studied at the age of 19 )'cars at a local hospital, 16 )'ears after nondiagnostic lymph node biopsy. No adenopathy Was present. Urinalysis, hemogram, chest roentgenogram, total and fractional serum protein studies, and blood chemistries were normal. Case 2
Tiffs five year old boy was admitted with asymptomatic generalized adenopathy. Biopsy of a cervical node showed follicular hyperplasia (Fig. 1). Tile patient remains well five )'ears later. Generalized adenopathy Ires accompanied upper respirator)" infections. Recently tlte pa- . tient lias been sltown to have isolated deficiency of IgA.
Cose 3 In this case the clinical course has been remarkable. At tile age of two years this white male child presented witlt generalized lymphadenopathy and an eryflmmatous skin rash but no other remarkable findings: His father, a physician, was undeftreatment for tuberculosis.
L Y M P H A D E N O P A T H Y IN CHILDHOOD--KIsSA,~E, GEPtIARDT
Figure 1, Case '2. Follicular hyperl~lasia in cervical I)mph node of five )ear old boy subsequently shown to have isolated deficienc)" of IgA. (x200.) Biopsy o f left axillary lymph node showed only hyperplasia (Fig. 2A). Nine months later the child was readmitted with pain and swelling in tile knees and right elbow. Sktdl roentgenograms showed osteoI)'tic lesions, and x-ray films o f tile extrentities showed lesions in the right ulna and in both femurs. Biopsies of lesions o f an ulna and Of the calvarium were interpreted as being "consistent with Hand-Schfiller-Christian disease." Radiation therapy was begun. Biopsy material that was cultured eventually grew out an atypical Mycobacterium, and a guinea pig injected with material from the biopsy developed gram/lomas in the spleen. T h e child received several courses o f then available antituberculosis medications. T h r o u g h tbe next eight )'ears he developed many osseous and subcutaneous abscesses from which mycobacteria of the Battey type were repeatedly recovered. After a course of isoniazid, paraanainosalicylic acid, and kanamycin, these aspects of the patient's course were suppressed and he remained well and in good health until nine )'ears later, when at the age of 20 )'ears a pelvic mass developed, which was diagnosed elsewhere as Hodgkin's disease. A staging laparotom)' was performed elsewhere, and the results o f examination of material from this procedure were consistent with the diagnosis o f Hodgkin's disease, lymphocyte depletion type. T h e pathologist at the other center, in retrospect, entertains the diagnosis of histiocytic lymphoma on the
basis o f tissues available from the staging procedure (Fig. 2B). At the end o f our study the patient remains alive and well at termination o f a course o f irradiation. The next group of patientspresents two f e a t u r e s in c o m m o n . All f o u r w e r e male a n d all f o u r p r e s e n t e d with t h r o m b o - ' cytopeni,'i f o r which, in t h r e e cases, s p l e n e c t o m y was p e r f o r m e d . O t h e r features in the n a t u r a l histories o f these patients a r e h e t e r o g e n e o u s . Case 4 This white male was admitted at eight )ears o f age with features o f tllrombocytopenic p u r p u r a and Coombs" positive hemolytic anemia. Splenectom)" was performed. Hemolytic crises recurred but responded to transfusions and steroid tberap)'. Chronic infections o f tbe mastoid, paranasal sinnses, and middle ear persisted. T h e final three )'ears o f the patient's life were dominated b)" a progressive incapacitating disease o f the central nervous system involving both the u p p e r and the lower motor neuron systems and featuring diarrhea and pulmonary, middle ear, and urinary tract infections. T h e serum gamma globulin level was once measured as 1.6 gin. per 100 ml. A specific diagnosis was never established, and the patient died at the age of 15 )'ears o f complications ofbis nenrologic disease. Autopsy was not performed.
435
H U M A N I ' A T H O L O G Y - - V O L U M E 5, NUMBER 4 July 1974
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.o
9
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+
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Figure 2. Case 3. A, Follicular ID-perplasia of axillary I)mlfll node at age two years, showing fifllicular hyperl~lasia. (x200.) B, Spleeq at 20 years of age, showing malig,mnt lympho,na. (x500.)
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Case 5 This iwo and one-half year old wliite male was admitted with fever, adenopathy, hepatosplenomegaly, thrombocytopenia, anemia, and eosinophilia. Tuberculin and histoplasmin tests were negative. T h e bone marrow was generally hyperplastic. A chest roentgenogram showed right hilar adenopathy. A:~illary lymph node biopsy showed reactive hyperplasia. Routine and fimgal cuhures were negative. Tile patient was discharged following a normal hemogram. Subsequent clinical information is not available, but the patient is known to have died at five and one-lmlf }'ears o f age. NO atttopsy was performed, but causes of death are recorded as "1itseudomonas aeruginosa and Monilia albicans septicemia."
Case 6
436
'
Tiffs two year old white boy had been nornml at birth but developed symptoms o f thrombocytopenic p u r p u r a during the last six
++ 9 months of his life. Clinical manifestations did not improve after splenectomy elsewhere. He was referred to the St. Lotfis Children's Hospital where he improved after treatment with steroids and antibiotics. Tile child was discharged home and died two w e e k s later. Autopsy findings included bronchopneumonia and lymphoid hyperplasia.
Case 7 This white male was admitted at age 12 }'ears with thrombocytopenia, cervical adenopathy, and mild eosinophilia. Sptenectomy was performed, and a peripheral lymph node was interpreted as sho~[ing "reactive hyperplasia" (Fig. 3A). Bone marrow examination showed many eosinophils and megakaryocytes but was nondiagnostic. During the next eight }'ears of his life the patient underwent fotlr clocumented episodes o f bacterial meningitis, two o f them pnetnnococcal. Lymphadenopathy persisted and on two occasions was diagnosed elsewhere by
L Y M I ' H A D E N O I ' A T H Y IN CHILDHOOD--KIssA.x~:, GZVHA~Da" various pathologists as Hodgkin's disease. One episode o f lymphadenopatl W followed spider bites of both legs (Fig. 3B). T h e patient died in another city at the age of 25 )'ears o f a ruptured cerebral aneur)'sm. Peripheral lymphoid tissue was described at autopsy only as hyperplastic (Fig. 3C). I n c o n t r a s t with these cases, two patients p r o g r e s s e d relatively r a p i d l y to a fatal t e r m i n a t i o n a f t e r a n o n d i a g n o s t i c l y m p h n o d e biopsy.
9
,m,
Cose
This 13 )'ear old white boy was admitted with left cervical adenopath)" and hepatosplenomegaly. A hemogram revealed 0nly anemia. Chest roentgenographic examination showed bilateral hilar adenopathy. Although. the patient was febrile, a source o f infection was not demonstrated. Biopsies of axillary and cervical lymph nodes were interpreted as showing lwperplasia. T h e patient was' discharged.
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IIUMAN I'ATHOLOGY--VOLUME 5, NUMBER 4 j~,ty 1974 Three weeks later lie returned with a hemorrhagic rash over the trunk, hepatosplenomegaly, and cervical l)'mphadenopathy. A chest roentgenogram showed pleural effusion. Cytologic examination of the pleural aspirate revealed malignant cells. A biopsy of nodules in the anterior chest wall was interpreted as.showing malignant lymphoma. The patient died in spite of radiation therapy and treatment with methotrexate and adrenocorticosteroids. Autopsy disclosed histiocytic I)mphoma, widel)' distributed. Case 9
This white female infant was admitted at three weeks of age I)ecause of the spitting up of feedings. Gestation and delivery had bcen normal. At 12 days of age the baby dcveloped an erythematous pustular cutaneous eruption and began to spit up her feedings, l'hysical examination was not revealing except for pt,stular lesions on the scalp, neck, and perineum and generalized shotty, lyml~hadenol~athy. A peripheral blood count showed 18 per cent eosinophils, 2 per cent juvenile neutrophils, 8 per cent "stab cells," 14 per cent segmented neutrophils, 46 per cent i)'ml~hoc)'tes, and 12 per cent monocytes. After antibiotic therap)" and transfusions, the infant's condition improved. A lymph node biopsy was nondiagnostic. After two months in tile hospital she was discharged. A week later she was readmitted with moderately severe diarrhea. Her condition deteriorated and she died one week ariel" readmission. The pathologic diagnosis at autopsy was acute leukemia.
DISCUSSION
438
In this series o f retrospectively studied cases, approximately one-fourth of the childreu subjected .to noildiagnostic lymph node biopsies in the course of investigation of lyml)hadenopathy suffered prolonged morbidity and, over two decades, a mortality of about 18 per cent. In a recent stud)" of nondiagnostic lymph node biopsies in adult males, Saltzstein I followed three grottps of patients, distingttished on the basis of clinical indications for the original biopsy. A m o n g 25 patients with initially nondiagnostic biopsies of lymph nodes in whom the indication was I)'ml)hadenol)athy alone, six (I 7 per cent) were later diagnosed as having a related a n a -
tomically specific disease. O f 23 patients ill whom lympll node biopsy constituted part of a wide ranging diagnostic study for miscellaneous indications (most of them, fever o f u n d e t e r m i n e d origin or suspected collagen-vascular disease), 15 (57 per cent) later were afforded a specific diagnosis. In 45 patients, clinically or radiographicall)" demonstrated p u l m o n a r y disease p r o m p t e d tile biopsy. O f these patients, 37 (79 per cent) were later shown to have a pertinent disease, unusually carcinoma or specific inllamnmtion. T h e r e appears to be no corresponding study o f the diagnostic yield and uhimate course over prolonged periods in children subjected to nondiagnostic I)'mpll node biopsy. It is apparent fi'om o u r study that the indications for lymph node biopsy in aduhs differ from those in children, and results are comparable only in the approximately one-third of a d u h patients in whom the indication for biopsy is lymp h a d e n o p a t h y of indeterminate etiology. In Sahzstein's series, moreover, when an anatomically specific diagnosis was ultimately achieved in six of 35 patients with obscure lymphadenopathy, that diagnosis became clinically apparent within six months in five of the six cases. Dawson and associates 2 analyzed 158 "diflicuh" lymph node biopsies in patients o f . unstated ages, presumably mostly aduhs. In seven cases the "blind" pathologic diagnosis was reactive hyperplasia in patients who eventually died of nmlignant lymllhoma; six of them died within three }'ears after nondiagnostic l)'ml~la node biopsy. In our group o f patients in w i m m investigation of lymlflmdenopathy inchtded nondiagnostic lyml)h node biopsy, three-fourths (7,1 per cent) were alive and in good heahh five to 20 )'ears aftevbiopsy. T w o of the three patients not available for follow-up evaluation at the end of the study were known to have been alive and" well four and 14V2 years after biopsies. Nine patients (26 per cent) did not regain normal good health after occurrence of the l)'nq~iladenopatl W that occasioned tim biopsy. T h r e e o f these patients are alive. T h e nature of the underlying disease process and, indeed, the ultimate prognosis in case 1 remain obscure. T h e natural history, with prolonged lyml)hadenopathy
LYMI'HADENOPATHY IN CHILDHOOD--KIssANE, GEI'I'IARDT
and infiltration o f organs (parotid glaud), suggests "sinus histiocytosis" described by A z o u r y and Reed z and elaborated by Rosai and D o r f m a n . 4 Iu o u r case I, Itowever, the pathologic picture was tltat o f nonspecific follicular hyperplasia ratlter than "sinus Itistiocytosis." We can v e n t u r e no projection as to this patient's uhimate course nor, in fact, can we speculate as to the n a t n r e o f the u n d e r l y i n g disease. T h e patient in case 2 laas been d e m o n strated to suffer fi'ont isolated deficiency o f IgA. Generalized l y m p h a d e n o p a t l t y iu the course o f respirator)' infections has been described iu patients with symptomatic deficiency o f IgA. 5 Patient 3 snffered m a n y atypical mycobacterial infectious and has uhintately d e v e l o p e d lytnphoreticular nmlignant disease. No specific immunologic deficiency s y n d r o m e has beeu definable eitlter clinically or morphologically in tlte ninny available samples o f lymphoid tissue. F o u r patients (cases 4 to 7) a p p e a r unified by their presentation with throntbocytopenia witlt or withottt deficiencies in otlter circulating cell lines and by their susceptibility to infection and male sex. T h e s e tltree features collectively suggest tire Wiskott-Aldricit syndrome, but patients in o u r g r o u p lind all been norntal in the postnatal period. In only one was a rash described as eczematous (a scaly dermatitis over the foreltead in a 12t/2 )'ear old). Ahhouglt features o f the Wiskott-Aldriclt s y n d r o m e have been described in a living patient 24 )'ears'old, G attd rapid deterioration after splenectonty is p r o l n ! n e n t in tire ltistories o f patients with the Wiskott-Aldrich s y n d r o m e , we are not able to s u p p o r t that diagnosis s t r o n g l y in this g r o u p o f patients eitlter on retrospective clinical g r o u n d s or f r o m study o f available lylnph nodes. Case 7 strongly resembles cases 1 and 2 in tlte r e p o r t o f Canale and Smith. 7 L y m p h a d e n o p a t h y and susceptibility to infihration in tlmt r e p o r t were associated with d e m o n strable inability o f the involved patients to f o r m antipnettxnococcal antibodies. It is obvious retrospectively tlmt ntany, p e r h a p s most, o f those patients who did not recover relatively p r o m p t l y after non-
diagnostic biopsy o f 1)'ml~h nodes must Itave suffered " from abnornmlities in cellular o r b u m 6 r a l reactions to infection. It was not the p u r p o s e o f tlfis study to attempt to establish retrospectively tlte diagnosis o f a specific form o f i m m u n o logic deficiency disease i n any case but ratiter to p r e s e n t the natnral Itistory o f pediatric patieuts witlt l y m p h a d e n o p a t i W in wltom biopsy o f peripheral lymplt nodes was initially nondiagnostic. T w o patients in o u r series o f cases o f nondiagnostic lymph n o d e biopsies proc e e d e d rapidly to a fatal termination o f a neoplastic disease. Tire patient iu case 8 rapidly p r e s e n t e d the picture o f histiocytic l y m p h o m a , and patient 9 died o f a somewhat peculiar blastic leukemia a few weeks after nondiagnostic lymplt n o d e biopsy. In both cases f u r t h e r salnpling or diagnostic perseverance probably would have provided an anatomic diagnosis d u r i n g the first ltospitalization. Only tltese two cases a p p e a r to c o r r e s p o n d to Sahzstein's cases o f l y m p h a d e n o p a t h y in adults in wltom anatonfically specific diagnoses became possible relatively promptly.
REFERENCES
1. Saltzstein, S-. L.: "File fate of patients with nondiagnostic lymt)h node biopsies. Snrgery, 58: 659, 1965. 2. Dawson, P. J., Cooper R. A., and Rambo, D. N.: Diagnoses of malignant lymphoma, a clinicopathological analysis of 158 dilficuh lymph node biopsies. Cancer, 17:1405, 1964. 3. Azoury, F. J., and Reed, R.J.: Histiocytosis. New Engl. J. Med., 274:928, 1966. 4. Rosai, J., and Dorfinan, R. F.: Sinus histiocytosis with nmssive l)'nq)hadenopathy, a pseudo l)mphomatous benign disorder. Analysis of 34 cases. Cancer, 30:1174, 1972. 5. Heremans, I. F., and Crabbe, P. A.: IgA deficiency: general consideration and relation to hunmn diseases. In Bergsma, D. (Editor): Immune Deficiency Diseases in Man. Birth Defects. Original Article Series. Vol. IV, No. 1, p. 298, 1968. 6. Meadl, M. A., Watson, J. I., and Rose, B.: The Wiskott-Aldrich syndrome; immunopathologic meclmnisms and a long-term survival. Ann. Intern. Med., 68:1050, 1968. 7. Canale, V. C., and Smith, C. H.: Chronic lymphadenopathy simulating malignant lymphoma. J. l'ediat., 70:891, 1967. 660 South Euclid Avenue St. Lotfis, Missouri 63110 (Dr. Kissane)
439