CAROTID BODY HYPERTROPHY IN P A T I E N T S W I T H CYSTIC FIBROSIS A N D C Y A N O T I C C O N G E N I T A L H E A R T DISEASE Ernest E. Lack, M.D.*
Abstract Tim carotid bodies from 71 patients ranging in age from 28 weeks' gestation to 30 )'ears were obtained at autopsy. Patients were divided into two groups based on tile presence or absence of chronic hypoxemia. There was a high correlation between tile weight of individual carotid bodies in each case. Among the 12 patients with chronic hypoxemia, eight patients lind carotid bodies heavier than predicted ,,b)" statistical analysis. Of these eight patients, six lind cystic fibrosis and two'had cyanotic heart disease. Morphometric and cell population analyses of tim carotid bodies from these eight patients and from those of the control population indicated tlmt enlargement of the carotid bodies during normal or abnormal growth resuhs fi'om proportionate increases in lobule parenchyma and stroma. There was also an increase in tile width and'length o f the lobules without an increase in the diameter of the cell cords or a change in the size or proportion of the chief cells. Growth and development of tim carotid bodies were studied in a control group of 59 patients without chronic hypoxemia. There were no sex related differences in carotid body weights. The combined weight of the carotid bodies correlated most strongly with body weight, ahhough there was some correlation with age and body length. A regression equation reflecting the data relating to body weight (BW) is: Combined weight of carotid bodies (in rag.) = 0.29 BW (in kg.) + 3.0. Leukemic infiltrates w e r e present in two patients with acute lymphocytic leukelnia, and diffuse lymplmcytic infiltration with nodule formation was present in one patient with mental retardation. Metaplastic cartilage was present in a carotid body of one patient.
Until recentl)" tim greatest interest among pathologists in carotid bodies has concerned neoplastic enlargement. Carotid bodies undergo non-neoplastic enlargement, most notably in patients with
p u l m o n a r y e m p h y s e m a and cor pulmonale 1'2 and in patients dwelling at high altitudes.3.4 Carotid bodies and related branchiomeric paraganglia have been ascribed a h o m e o s t a t i c
*Senior Resident, Departnaent of l'athology,The Chihlren's ttospital Medical Center, Boston. Massachusetts.
39
HUMAN I'ATHOLOGY-VOLUME 8, NUMBER 1 Janua O' 1977 role by sensing fluctuations in blood pH and oxygen tension? ,6 The final common pathway leading to non-neoplastic carotid body enlargement has presumably been chronic hypoxemia. The purpose of this stud)" is to analyze parameters of normal growth of the carotid bodies from late fetal to young adult life and to determine whether there is pathological growth in patients with chronic hypoxemia due to cystic fibrosis of the pancreas or cyanotic congenital heart disease. MATERIALS A N D METHODS
40
Cases for study included 68 patients on whom autopsy examination was perf o r m e d at T h e C h i l d r e n ' s Hospital Medical C e n t e r f r o m J u l y 1974 to J u n e 1975. Their ages ranged from 28 weeks' gestation to 30 )'ears; there were 24 females and 44 males. Two additional cases of cystic fibrosis and one case of cyanotic congenital heart disease were available for microscopic stud)'. The patients were divided into two groups. One group of 12 patients with chronic hypoxemil included nine patients with cystic fibrosis of the pancreas and three patients with cyanotic congenital heart disease. The second group consisting of 59 patients without known chronic hypoxemia was designated as a control group and utilized in studies of normal growth of the carotid body from late fetal to young aduh life. Carotid bodies were obtained for study between one and 21 hours after death by dissection of adventitial tissue in and around tire bifurcation of the common carotid arteries using iridectomy scissors and fine forceps. In most cases the common carotid with its bifurcation was removed, along with approximately 1 cm. long segments of both internal and external branches. Carotid bodies were dissected free of surrounding fat and adventitia by use of a dissecting microscope with periodic immersion of the tissue in nornml saline to prevent dessication. Each carotid body was then separately weighed on a precision scale after careful blotting to remove excess fluid. Carotid bodies from each case were fixed in 10 per cent buffered formalin, except for tissue in one case of Hunter's syndrome that was fixed in cold absolute
alcohol. Carotid bodies from each case were embedded together in paraffin. Sections were cut at 6 microns and stained with hematoxylin and eosin, lead ilematoxylin,r PAS orange G, Bodian axon, and Dominici mast cell stains. The length and width of lobules and width of cell cords were determined in 55 cases by use of an ocular micrometer calibrated with a 2.0 mm. scale with graduations ill 0.1 and 0.01 mm. Recorded values are approximate, since no allowance was made for tissue shrinkage during formalin fixation and routine processing. For purposes of this study a lobule is defined as a subunit of tile carotid body, composed of chief cells arranged in anastolnosing cell cords and cell clusters (zellballen). An effort was made not to record dimensions of structures that, ahhough circumscribed, appeared to be only peripherall)' cut lobules as determined from continuous ribbons of tissue mounted on microscopic slides. An arteriole entering or within a circumscribed collection of cell cords and cell clusters was helpfnl in defining a lobule, but was not present in all instances. An average o f 20 of the largest lobules was measured ira each specimen. In specimens showing adequate preservation, 200 cells were counted and classified as chief cells or sustentacular cells according to morphologic criteria described by Grimley and Glenner. 8 By use of sections showing the greatest cross sectional area in each specimen, camera lucida drawings of carotid bodies and their lobules were made on graph paper by lightly tracing images when projected onto a vertical, stationary, tlat surface. Representative pairs of carotid bodies and their component lobular tissue from each case were carefidly cut out from these tracings on a clean surface with a scalpel blade and forceps. The pieces of paper were weighed separately on a precision scale. In this way the percentage of interlobular tissue in sections was estimated for each pair of carotid bodies. Means and standard deviations of the various observations were compared for possible statistical significance, when appropriate, including such parameters as body weight, age, and body length. Special pathological changes involving carotid bodies were noted.
CAROTID BODY HYPERTROI'IIY--LAcK
RESULTS
Carotid Body Weights In the control population, which included 59 patients, the mean weight of the left carotid body was 4.0 mg. (range, 0.5 to 17.8 nag.; standard deviation, 3.8 mg.) and the right, 3.9 mg. (range 0.1 to 17.6 rag.; standard deviation, 3.7 rag.). The mean combined carotid body weight was 7.9 mg. (standard deviation, 7.4 mg.) for the entire group and was 8.2 mg. (standard deviation, 7.8 mg.) in the 41 males and 7.5 rag. (standard deviation, 6.7 mg.) in the 18 females. T h e mean body weight was 16.8 kg. (range, 1.0 to 87 kg.; standard deviation, 21.9 kg.). There was a high correlation between the weight of the right and the left carotid body in each case (r = 0.91; p < 0.001). The frequency distribution of patients in these cases grouped into arbitrarily de-
fined age intervals is seen in Figure 1. Mean combined weights of carotid bodies, when studied in relation to these age intervals, show a postnatal growth spurt as might accompany the physiological change between intra- and extrauterine life, and progressively increasing values, except in the 12 to 18 )'ear interval (Fig. 2). In this interval, which corresponds to the spurt o f normal adolescent growth, there was a slight but statistically insignificant decrease. The mean combined carotid body weight of the two patients in the age interval 24 to 30 )'ears (26.2 rag.; standard deviation, 13.0 nag.) is similar to that reported in a study of an elderly adult population) The combined weight o f carotid bodies correlated statistically with body weight, age, and body length. There was a greater correlation of combined weight of carotid bodies with body weight (r = 0.85; p < 0.001) than with age ( r = 0.73; p < 0.001) or body length ( r =
10
0
9
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9
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40
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-,-WEEKS-"
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12 ~
6
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Figure I. ttistogram showing frequencydistribution of 71 patients in relation to arbitrarilyconstructed age intervals. [] Cystic fibrosis of tile pancreas. O Cyanoticcongenital heart disease with chronic hypoxemia. 9 Cyanoticcongenitalheart diseasewithot,t chronic hyl)oxemia.9 Sudden infant death syndrome.9 Respiratory distress syndrome (hyalinenaembrane disease).
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HUMAN
PATHOLOGY-VO1.UME
8, N U M B E R
I Jamta O" 1977
40
30
-r
/
2C
10
ttt I l ! 28 40 ~ MONTHS.---WEEKS- | 3 5 12 t
l 2
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Figure 2. Mean and standard deviation of combined weight of carotid bodies in 59 control patients plotted in relation to respective age intervals. Note earl)" postnatal increase i~1 mean combined weight. Intervals in weeks and months reflect gestational age.
42
0.28; p < 0.05). A regression equation was derived for the relation of combined weight of carotid bodies and body we!ght: Combined weight o f carotid bodies (in nag.) = 0.29 BW (in kg.) + 3.0. A muhiple variable regression equation involving any combination of body weight, age, or body length did not improve the predictive value of the coinbined weight of carotid bodies over body weight alone. All 12 of the patients with chronic hypoxemia had digital clubbing, and the nine patients with cystic fibrosis had obstructive and restrictive puhnonary disease with cot- pulmonale. The mean combined weight of the carotid bodies of five patients with cystic fibrosis in the age interval 18 to 24 )'ears was 59.7 nag. (standard deviation, 16.1 nag.; range, 39.9 to 80.3 nag.) as compared with the control population mean combined weight of 18.5 rag. (standard deviation, 10.8 nag.;
range, 3 to 24.0 mg.; Table I). T h e difference in mean values was statistically significant (t = 7.63; p < 0.01). Two patients with cystic fibrosis in this age interval il~dividually had the largest combined carotid body weights encountered in this entire stud), (Figs. 3, 4). The youngest patient with cystic fibrosis was five )'ears old, with a combined carotid body weight of 30.0 mg. -- significantly greater than the mean combined weight of 7.6 mg. (standard deviation, 2.6 rag.; range, 5.1 to 11.1 mg.) for the age interval one to six years. The oldest patient with cystic fibrosis who was 24x/2 )'ears old had a combined carotid body weight of 31.9 mg., a value falling within one standard deviation of the mean established for the age interval 24 to 30 )'ears (Fig. 5). Two patients with cyanotic conglmital heart disease with ages at death of 16 months and 17 )'ears had combined carotid
C A R O T I D B O D Y HYPERTROPHY--LACK
Figure 3. Carotid bodies in a 21 )ear old fenmle with cystic fibrosis of the pancreas diagnosed at seven )'ears of age. They are enlarged and deeply congested. Their combined weight is 70.0 nag.
b o d y weights, respectively, o f 22.5 rag. a n d 49.5 mg., w h i c h were significantly g r e a t e r t h a n the m e a n c o m b i n e d weights o f their respective c o n t r o l po.pulation (p < 0.01). T h e r e m a i n i n g patients with c y a n o t i c
c o n g e n i t a l h e a r t disease were n e w b o r n s , a n d in most, surgical c o r r e c t i o n h a d b e e n a t t e m p t e d (Fig. I). C a r o t i d b o d y weights a n d m i c r o s c o p i c p a r a m e t e r s in these patients a n d in f o u r patients with s u d d e n
Figure 4. Carotid bodies in a 24 )ear ~ female with cystic fibrosis of tile pancreas diagnosed at five and one-half )ears of age. Note that tlney are enlarged and bilaterally bilobed. At the base of the left caroticl body there is a mutrient artery.
43
H U M A N P A T H O L O G Y - V O L U M E 8, NUMBER 1 Jamta O' 1977
Figure 5. Carotid bodies in a 241/2 year old male with cystic fibrosis of the pancreas diagnosed at seven years of age. The right carotid body is bilobed, and the left has a nutrient artery arising from the external carotid artery. Their combined weight is 31.9 nag. i n f a n t d e a t h s y n d r o m e w e r e indistinguishable f r o m those in a g e r e l a t e d patients a n d w e r e i n c l u d e d in t h e c o n t r o l p o p u l a t i o n . I n the 28 to 40 week gestational age g r o u p , which i n c l u d e d seven patients, t h e r e w e r e t h r e e patients with respirator), distress s y n d r o m e (hyaline m e m b r a n e disease). O n e o f t h e s e patients sttrvived
44
f o r five d a y s a n d h a d a c o m b i n e d c a r o t i d b o d y w e i g h t o f 5.9 rag., w h i c h was g r e a t e r t h a n o n e s t a n d a r d deviation a b o v e the m e a n f o r t h a t interval. I n the age interval o n e m o n t h to t h r e e m o n t h s , t h e r e were two p a t i e n t s with p r e v i o n s l y t r e a t e d respirator)" distress s y n d r o m e w h o died f r o m c o m p l i c a t i o n s . O n e o f these patients
Figure 6. Full term male, 30 hours old, with persistent fetal circulation and cyanosis. Both carotid' bodies are deeply congested and are associated with a branching nutrient vessel arising from the base of the bifnri:ation. Their combined weight is 4.5 rag.
CAROTID BODY HYPERTROPHY--LacK had b r o n c h o p n h n o n a r y dysplasia and retrolental fibroplasia. T h e combined carotid body weight in each patient was greater than one standard deviation above the mean for that interval.
Gross Anatomy After separating the internal and external branches o f the c o m m o n carotid artery and exposing the semitransparent adventitial tissue spanning the bifllrcation, carotid bodies appeared as pedunculated, o v o i d , pale pink tissue. U n d e r the dissecting microscope carotid bodies were seen to be intimately attached to adventitia without obvious connection with arterial media. Carotid bodies originated from the base of the bifurcation posteromedially or from the immediately adjacent internal carotid branch. An intricate superficial anastomosing capillary net-
work was present in all cases and occasionall), served as a useful guide in delineating the confines of the carotid body, which in most cases appeared sharply circnmscribed. A lobnlar appearance was c o m m o n , especially in older patients after traction on connecting adventitial strttctures. In some patients a small artery arising from the base of the bifurcation coursed into and often, t h r o u g h the snbstance of the carotid body (Fig. 6). In five cases ( 7 . 5 per cent) the individual carotid bodies appeared unilaterally bilobed, including those in the oldest patient in this study with cystic fibrosis (Fig. 5). T h e patient with cystic fibrosis having the greatest combined carotid body weight (80.3 nag.) had bilaterally bilobed carotid bodies (Fig. 4). In general, carotid bodies were dark pink to tan in the group with cystic fibrosis and cyanotic congenital heart disease.
Figure 7. Carotid body from a 24 hour old umle with hypol)lasticaortic arch showing bifilrcation of an arteriole with each nutrient branch entering tile apex of a Iobule. The adventitial sheath of tile arteriole blends imperceptibly with lobular tissue. (ltematox)lin ~tll~.leosin stain. •
45
HUMAN
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MicroscopicAnatomy
1
Janztmy 1977
lobules, but were not encountered within chief cell cords or cell clusters. The mean lobule width and length in patients in the control population are seen in Figure 8, and values increase steadily with increasing age intervals, a trend that is more evident in the length of the lobules. In general there was greater variability in length than in width of Iobules (i.e., larger standard deviations in the former). Lobule dimensions in patients with cystic fibrosis and cyanotic congenital heart disease were greater than in their age interval matched control group (Table 1). The greatest lobule dimensions were encountered in patients with cystic fibrosis with a mean width of 446.9 microns
In all cases carotid bodies were composed of muhiple Iobules of parenchyma completely surrounded by stroma consisting of vascular neural and connective elements, the amount ofstroma beingscant where lobtdes were compactly arranged and faceted one to the other. In occasional neonatal patients, lobules were distinctly related to small branching arterioles and seemed to blend imperceptibly with the prinfitive appearing cellular adventitial sheath of the nutrient vessel (Fig. 7). As previously noted, ~ mast cells were abundant in perilobular tissue and were associated with neurovascular elements within
700
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Figure 8. Mean a n d standard deviation of Iobule width and length ill 59 control patients plotted in relation to their respective age intervals.
CAROTID BODY HYPERTROPHY-LAcK T A B L E 1.
CAROTID BODY ~IEASUREMENTSIN 12 PATIENTS WITtt CtlRONIC HYPOXEMIA
Combined Weight of Carotid Bodies
Mean Lobule Width
Sex
(rag.)
(tO
Length 01)
F F F F M M M F M
30.0
483 448 529 442 579 421 405 427 315
720 692 1049 781 800 645 682 660 851
252 448 311
403 692 654
Age
O'r.) Cyst~fbros~ 1 2 3 4 5 6 7 8 9
5 11 20 21 '2'2 22 22 24 24V2
39.9 70.0 59.1 49.1 80.3 31.9
Mean Lobule
Cyanotic congenital heart disease 1
IV2
F
22.5
2 3
121/2 17
M F
49.5
(standard deviation, 76.2 microns) and a mean length of 762.2 microns (standard d e v i a t i o n , 128.7 m i c r o n s ; F i g . 9). Two leukemic patients had mono-
nuclear cellular infiltration within and between lobules, probably representing a manifestation of leukemia. One nonleukemic patient had lymphoid nodule
Figure 9. Carotid bodies in a five )ear old female with cystic fibrosis of tile pancreas. Tile mean width of the lol)ules is 483 microns and the mean length, 720 microns. Their comb!ned weight is 30.0 rag. (PAS-orange G stain. •
47
HUMAN P A T H O L O G Y - V O L U M E 8, NUMBER 1 Jamta U 1977
Figure 10. Section of a carotid body in a 29 )-ear old menially retarded female, showing lymphocytic infiltration with nodt, le formation. T h e combined weight of the carotid bodies is 17.0 rag. (Hematoxylin and eosln stain, xl00.)
f o r m a t i o n in addition to lymphocytic infiltration (Fig. 10). In o n e patient there was a solitary metaplastic focus o f hyaline cartilage in perilobular tissue (Fig. 11), and in a n o t h e r patient t h e r e was a solitary focus o f calcification, which was not clearly bone. In several cases ganglion cells with s u r r o t m d i n g satellite cells were enc o u n t e r e d in interlobular tissue. T h e r e were no discernible abnormalities by light microscopy in the carotid bodies in the case o f Hunter's s y n d r o m e . T h e differential weights o f p a p e r tracings provided indirect evidence o f a proportional increase in both stroma and lobnlar tissue with age. T h e mean proportion o f p a p e r r e p r e s e n t i n g stroma in the greatest cross sectional area in the carotid bodies was 58.7 per cent (standard deviation, 8.5 per cent) in the control g r o u p and 61.7 per cent (standard deviation, 4.5 per cent) in the g r o u p with
48
chronic hypoxemia. T h e r e was no significant difference in tile p r o p o r t i o n o f stroma t h r o u g h o u t the control g r o u p . The predominant arrangement of chief cells within lobules was in the form o f anastomosing cell cords and cell clusters (zellballen). T h e diameter o f cell cords was similar in all cases, with a m e a n value o f 28+4 microns. T h e d i a m e t e r o f well p r e s e r v e d chief cells was approximatel)" 12 microns. Cell cord width was usually in the r a n g e o f two to three chief cell diameters. Cell clusters (zellballen), where well developed, were r o u n d to oval and varied considerably in size f r o m case m case and even within individual cases. As previously noted by others, s some axonal filaments a p p e a r e d in Bodian stained sections to e n t e r cell cords and cell clusters and t e r m i n a t e in close proximity to chief cells. Axonal filaments were readily detected in o n e patient with s u d d e n infant
CAROTID BODY HYPERTROPHY-- LACK
Figure 11. Metaplastichyaline cartilage in a carotid body in a six week old female with meningitis.The combined weightof the carotid bodies is 5.4 nag. (ttematoxylinand eosin stain, x 100.)
death syndrome; however, tissue in the remaining three patients was inadequate for proper evaluation. Identification of clfief cells was enhanced by special stains. Lead hematoxylin imparted a bhte-black stain to clfief cell cytoplasm, which in most cases had a finely granular qualit)'. 7 Chief cell cytoplasm was orangeoplfilic with PAS orange G and occasionally showed faint stippled areas of PAS positivity. In cases in which the postmortem interval tended to be prolonged, cytoplasmic staining by lead fiematoxylin or Bodian stain tended to be less intense or absent, and, as previously noted by Heath, Edwards, and Harris, 1 vacuolar change and cytolysis of cell cytoplasm were more conspicuous. Ctfief cell nuclei were rounded and eccentric with granular chromatin and occasionally were densely pyknotic. In contrast, sustentacular cell nuclei were peripherally located in cell cords and cell clusters, were oval and
smaller, and tended to show clnmping of chromatin with prominent nuclear membranes. In very young patients, cell cord and cell cluster formation was somewhat less evident, partly because tile sustentacular elements were plump and primitive in appearance. Tile sustentacular cell cytoplasnl was'indistinct. Differential cell counts, relying largely on nuclear morphology, suggested an approximately equal proportion of sustentacular cells and clfief cells. No obvious sifift in cell population was recognized in the carotid bodies fi'om patients with cystic fibrosis or cyanotic congenital heart disease, compared with those of" age related controls. Finely granular, light yellow pigment was present in the chief cell cytoplasm in patients with cystic fibrosis. Tiffs pigment was not fully characterized but resembled ceroid or lipofnchsin pigment. By comparison tlfis pigment was infrequent in age related controls.
49
HUMAN I'ATHOLOGY-VOLUME 8, NUMBER 1 Jamta U 1977 COMMENT
Patients subject to chronic hypoxemia, whether on a pathological or a ph)'siological basis, have been reported to have enlarged carotid bodies) ~ In the present study the patients with cyanotic congenital heart disease and all but possibly one patient with cystic fibrosis had enlarged carotid bodies, which nticroscopically showed enlargement of lobules. Advanced puhnonary bronchiectasis with variably severe emphysema and cor puhnonale was present in all patients with cystic fibrosis and formed the patlmlogical basis for chronic hypoxemia. The basis of chronic hypoxemia in the remaining patients was physiological with right to left intracardiac slmnting of blood. Most of the cases reported with non-neoplastic carotid body enlargement have been in either elderly patients with puhnonary emphysema and cot pulmonale ''z or in higlt altitude dwellers. 3'4 None o f the patients in tiffs study were high altitude dwellers. In the control population there was a correlation of body weight, age, and body length with combined carotid body weight. A study of carotid bodies in an elderly adult population failed to show such a correlation, t The carotid body has a propensity for growth in a predictable manner in relation to readily measurable body parameters. A high correlation exists between tim weight of individual carotid bodies in each case, suggesting that reliable prediction o f combined weight can be made even if only one carotid body is obtained. Width and length of lobules of carotid bodies increase with age, but the values obtained are more variable than carotid body weights (i.e., the standard deviations are greater for tim former). There is no appreciable influence of sex on weights of the carotid bodies. The slightly better correlation of combined weight of carotid bodies with body weight titan with body length is interesting, since carotid body and related branchiomeric paraganglia have been linked with ventilatory control, n'r' and, in general,' parameters of pulmonary fimction lmve a better correlation with body length. '3 Embryologically the carotid body appears to be nenrectodermally derived but
50
bas an intintate relation with branchial arch mesoderm, '4 which may explain the unnsnal occurrence of hyaline cartilage in one patient. The significance of the lymphocytic infiltration with nodule formation within and arotmd lobules tlmt occurred in one nonleukemic patient is obscure. Infiltrates of this sort lmve been noted in carotid body tumors ''~ and also in other endocrine glands '6 and could represent all antoimmune phenomenon. Enlargement of lobules in carotid bodies of patients with cystic fibrosis and cyanotic congenital heart disease is probably due to a variety of cellular elements, which increase proportionately, including chief cells and sustentacular cells. T h i s hylmrplasia cotfld account for the failure in this stud)' to detect a shift in cell type as was observed in one of six patients with emphysenm and cor pulmonale) As perceived through the light microscope, capillaries increase in number or prominence to maintain a relatively normal cytoarchitecture within Iobules. The enlargement of and hyperplasia witlfin lobules of carotid bodies in patients with cystic fibrosis and cyanotic heart disease is presumably a response to chronic bypoxemia. The four patients with sudden infant death syndrome encountered in this study demonstrated no recognizable morphometric abnormalities of carotid bodies througll light microscopy, but in view of the magnitude of this condition and pathogenetic implications regarding abnormalities in autonomic regulatory processes, more attention needs to be directed toward systematic stud)' of carotid bodies and related paraganglia in these patients, m'8 Further study of carotid bodies is also needed in h)'poxemic infants, including those with the respirator)' distress syndrome.
ACKNOWLEDGMENTS
Tile author would like to thank Dr. Gordon F. Vawter for supervision and critical review of tlm mannscript, Anita Fnlchiero for assistance in biostatistical analysis, and Natalie Daniels f o r histoteclmological preparation of specimens.
CAROTID BODY HYPERTROI'HY--LACK
REFERENCES 1. tteath, D., Edwards, C., and Harris, P.: Postmortem size and structure of the human carotid body. Thorax, 25:129-140, 1970. 2. Edwards, C., Heath, D., and ltarris, P.: The carotid body in emphysema and left ventricular hypertrophy. J. Path., 104:1-13, 1971. 3. Arias-Stella, J.: Human carotid body at high ahitudes. Am. J. Path., 55:150a, 1969. 4. Saldana, M. J., Salem, L. E., and Travezan, R.: High ahitude hypoxia and cl~emodectomas. tluman Path., 4:251-263, 1973. 5. Heymans, C.: Action of drugs on carotid body and sinus. Pharmacol. Rev., 7:119-142, 1955. 6. Joels, N., and Neil, E.: The excitation meclmnism of the carotid body. Brit. Med. Bull., 19:21-24, 1963. 7. Solcia, E., Capella, C., and Vassallo, G.: Lead hematoxylin as a stain for endocrine cells. ttistochemie, 20:116-126, 1969. 8. Grimley, P. M., and Glenner, G. G.: Histology and uhrastructure of carotid body paragangliomas, comparison with the normal gland. Cancer, 20:1473-1488, 1967. 9. l'ryse-Davies, J., and Dawson, I. M. I'.: Some morphologic, histocllemical, and chemical observations on chemodcctomas and the norreal carotid body, including a study of the chromaffin reaction and possible ganglion cell elements. Cancer, 17:185-202, 1964. 10. Winson, M., and Heath, D.: The carotid bodies in anemia. Arch. Pathol., 96:58-60, 1973. !1. Lugliani, R., Whipp, B. J., Seard, C., and Wasserman, K.: Effect of bilateral carotid-
12.
13.
14. 15.
16. 17.
18.
19. 20.
body resectioq on ventilatory control at rest and during exercise in man. New Eng.J. Med., 285:1105-1111, 1971. Davidson, J. T., Whipp, B. J., Wasserman, K., Koyal, S. N., and Lugliani, R.: Role of the carotid bodies in breath-holding. New Eng. J. Med., 290:819-822, 1974. Cook, C. D., and Hamann, J. F.: Relation of hmg volumes to height in healtl W persons between the ages of 5 and 38 )ears. J. Pediat., 59:710-714, 1961. Lattes, R.: Noncbronmffin paraganglioma of ganglion nodosum, carotid body, and aorticarch bodies. Cancer, 3:667-694, 1950. Oberman, H. A., Holtz, F., ShelTer, L. A., and Magielski, J. E.: Chemodectomas (nonchromaffin paragangliomas) of the head and neck. Cancer, 21:838-851, 1968. Lack, E. E.: Lymphoid hypophysitis with end organ iqsu fficiency. Arch. l'athol., 99:215-219, 1975. Valdes-Dapena, M. A.: Sudden unexpected and tmexplained death in infancy-a status report --1973. New Eng. J. Med., 289:1195-1197, 1973. Salk, L., Grel!ong, B. A., and Dietrich,J.: Sudden infant death-cardiac habituation and poor autonomic control. New Eng. J. Med., 291: 219-222, 1974. . Arias-Stella, J., and Valcarccl, J.: Chief cell hyperplasia in the hunmn carotid body at lfigh altitudes. Hum. Pathol., 7:361-373, 1976. Naeye, R., Fisher, R., Ryser, M., and Whalen, 1'.: Carotid bod)" in the sudden infant death syndrome. Science, 191:567-569, 1976.
Tile Prnmenade Apt. 814 South 5225 Pooks ttill Road Bethesda, Maryland 20014
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