led me to present to this society a brief report on the tumors ofthis

TUMORS OF THE AUTONOMIC NERVOUS SYSTEMBY MONT R. REID, M.D.

OF CINCINNATI, OHIO

THE accidental finding during the past year, in two cases of chronicappendicitis, of what appears microscopically to be carcinomatous growthsof the appendix, and the rather recent conception that such tumors haveoram.>o- s w . N =w b*-&aU ,.-

FIG. I.-"Carcinoid" tumor of the appendix. Low power magnification. Note the similarity to Figure 8.

their origin in the chromaffin tissue of the autonomic nervous system, haveled me to present to this Society a brief report on the tumors of thisnervous system.

On August 5, 1927, Doctor Zinninger, our Resident Surgeon, operated upon a whitewoman, aged thirty years, for cholelithiasis associated with an hydrops of the gall-bladder.Before performing the cholecystectomy he removed the appendix because "it was bounddown by adhesions and its tip obliterated." The external appearance of the appendixresulted in the operator's usual diagnosis of chronic appendicitis. Our pathologist, DoctorConway, reported on the histological study of the appendix as follows: "The sectionfrom the distal portion of the appendix shows the muscular and outer coats to beapparently normal. The mucosa, however, presents a picture which is entirely unusual.The entire lumen is filled with a mass of epithelial cells. These cells are grouped insmall areas irregularly placed and resting upon a dense fibrous tissue framework. The

516

TUMORS OF THE AUTONOMIC NERVOUS SYSTEM

cells appear to be of epithelial origin, containing large darkly stained nuclei and a mod-erate amount of lightly stained cytoplasm. The cells are closely packed and their nucleiare generally uniform in shape and size. There is no infiltration of the outer coats ofthe appendix by this growth. It is limited entirely to the mucosa of the appendix."The pathologist's comment was that the growth resembled an adenoma. The histologicalappearance of this tumor, the ability of the cells to take up a silver stain and its resem-blance to the 325 previously reported cases leave no doubt that it belongs to the group of"carcinoid" or "argentifine" tumors, or paragangliomata of the appendix.

The second case was a young girl, aged twenty-two years, who was operated uponby me on March IO, I928. Six days previously she developed, for the first time, the

...S^.a. . w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~........

*--i., . . Xi

FIG. 2.-High power magnification of a paraganglioirna of the appenldix. Same case as shown in Figure I.

typical symptoms and signs of an attack of acute appendicitis. When she-came undermy observation twenty-eight hours later, it was evident that the attack was rapidlysubsiding. Five days later the re-occurrence of slight local pain and tenderness causedus to operate. To our surprise the distal third of the appendix contained a yellowishnecrotic-appearing segment about one-half centimetre in length, which apparently wascovered by a very thin layer of fibrin. The rest of the appendix seemed to be normal andthere was no zone of acute inflammation about this segment. There were no adhesions.On opening the appendix the involved segment presented a yellowish-white surfacewhich was rather tough. It resembled tuberculous tissue but was uniform in color andwas obviously not necrotic tissue. Microscopically the growth is a typical "carcinoid"tumor of the appendix. The cells reduce silver from an ammoniacal solution. In thisinstance the growth involved the entire thickness of the appendiceal wall.

The color of the growth in this case was almost identical with the medulla of thesuprarenal gland and was strikingly like that observed in a few cases of carotid bodytumors that I have removed.

In considering the neoplasms of the autonomic nervous system, theembryological development of this system must be borne in mind. Through

517

MONT R. REID

the cells composing the primitive neural tube, the so-called neurocyte, theautonomic system is related to the somatic nervous system. Certain undif-ferentiated cells called neuroblasts migrate ventrally from the neural tubegiving origin to the sympathetic ganglia and to the chromaffin tissue. Thisin the human is located for the most part in the medulla of the suprarenalbut is found in the so-called carotid, aortic, cardiac, tympanic and coccygealglands, and in the gelben zellen of the Crypts of Lieberkuhn in the gastro-intestinal tract.

Tumors of the autongmic.-pervous system may be conveniently classifiedas: Neurocytoma, neuroblastoma, ganglioneuroma, paraganglioma, neuroma.

From the neural epithelium arises the neurocytoma, a single case of which,

FIG. 3.--Carcinloid" tumor (paraganglioma) of the appendix. The color of the lesion was yellowish.

aiigin the neighborhood of the gasserian ganglion, was reported byMarchand. The neuroblasts, however, give rise to neoplasms more frequently.

Neuroblastomat is the name most commonly applied to the malignant tumorthat apparently arises from the neuroblasts or undifferentiated cells fromwhich the autonomic and chromaffin systems develop. Other terms are:

Ganglioma embryonale sympathicum (Pick). Sympathicoblastoma (Pick andBielschowsky, Bailey). Sympathigomnon (Herxheimer).

This neoplasm occurs predominantly in infancy or early childhood, severalhaving been congenital. Twenty-five, or 8o per cent. of the patients, wereless than two and one-half years old, but three cases (Ritter and Meltzer)have recently been reported in patients over forty years of age.

The site of predilection is in the suprarenal gland, as shown by the factthat in twenty-seven of the cases the primary growth was found within thisorgan. In one case, both suprarenals were involved. In the remaining cases,the primary sites were in the sympathetic chain, the coccygeal gland, theuterus, upper jejunum and the nasal cavity.

The primary growth in neuroblastoma is usually quite small, though occa-

sionally it may become very large. From very small, primary tumors (8 mm.diameter in one case) metastases in the liver, lungs, lymph g'lands, etc., mayoccur and reach a considerable size. The smaller tumors may be confined to

518


the medulla and thus present simply as an enlargement of the suprarenalgland. The larger tumors and metastases are nodular masses of rather firmconsistency. Gross section shows them to be surrounded by a thin layer offibrous tissue and to contain numerous thin-walled vessels. The cut surfaceis glistening white in color and soft in consistency and from it a pearly juicecan be expressed. Intermingled with the glairy white tumor tissue are avariety of colors-orange, red and black, such as are often seen in xanthoma-which are due to hemorrhage, the blood pigment being in various stages

4K eIL~~~~~~~~~~~~~~~~~~~~~~~~~

FIG. 4.-Histological appearance of a neuroblastoma.

of degeneration. In the larger nodules central necrosis occurs, giving riseto cavities filled with clear or brownish fluid.

Microscopically the tumors are alveolar in topography, the septa con-sisting of delicate connective tissue and thin-walled blood-vessels. Thecytology of the tumor cells is somewhat variable, all stages of cells fromneuroblasts proper to more mature and even differentiated ganglion cellsbeing found in certain tumors. The predominant cells in the pure neuro-blastoma are small, being little larger than the lymphocytes, and contain arelatively large, deeply chromatic nucleus with but a minute amou'nt ofprotoplasm. In the most typical growths, certain of these cells are arrangedin rings surrounding a central mass of fibres, the so-called "rosette" forma-tion, a structure particularly characteristic of this type of neoplasm.

The cytology seems to vary with the rapidity of progress of the growthand the age of the host. Thus the more rapidly growing tumors occurringin the new-born or very young infants, are made up almost entirely of the

51-9

MONT R. REID

small neuroblast type of cell, while in -older patients or less malignant growths,mature ganglion cells with fibril formation may be seen (Landau). Indeed,neuroblastomata and ganglioneuromata may occur in juxtaposition or maybe intermingled in the same tumor. These fibrils' have been thought to benerve fibres, but their failure to stain with silver tannate by appropriatemethods argues against this point of view.

Metastases from the primary growth 'extend first to the neighboringlymph-nodes, and thence to the liver, bony thorax' and bones of the calvarium

FIG. .-Histologicalappearanc of a ganglion a.Noe t lae gngln cls.W

FIG.a.-Histological appearance of a ganglioneuroma. Note the large ganglion cells.

and orbit, the spread being apparently by the lymphatic channels. But thewidespread liver and lung metastases such as are seen following disseminationby way of the blood stream also occur.

In a small percentage of the cases the presence of a tumor in the supra-renal medulla is heralded by the symptoms of Addison's disease, notablyasthenia and cutaneous pigmentation. However, in the larger proportionof the cases the- growth has given little evidence of its presence until wide-spread metastases have produced pressure effects either in the abdomen orintra-cranial contents.

Two clinical types have been differentiated; the one which because ofintra-cranial or retro-orbital metastases, presents with exophthalmos, epilepti-form seizures or paralyses, and a second group, in which progressive enlarge-ment of the abdomen is the first symptom.

The primary diagnosis of neuroblastoma in the absence of a biopsy isalmost impossible, but this growth should be suspected, particularly in young

520


children, when a mass is found in the region-of the suprarenal gland withcharacteristic metastases, or the liver' is markedly enlarged without markedascites. The presence of Addison's syndrome would. be of definite aid inthe early diagnosis but this unfortunately is presint m- but a small- numberof the cases.

The prognosis in these cases is distinctly bad, only one patient, reportedby Lehman in I917, having been successfully operated upon.- In that instance,the tumor was confined to the suprarenal gland, which had become enlargedand pedunculated and could thus be completely excised.

In all but a few of the reported cases the tumor had already reached sucha size or had metastasized so widely, that Mcomplete removal was impossible, but inthe one really operable case, the tumor was'successfully removed. No statistics areavailable upon the effect of radiation onthese tumors.

Ganglioneuroma is a relatively benignneoplasm arising from the ganglionic ele--ments of the autonomic nervous system.In contrast to the neuroblastomata, the _ganglioneuromata occur more commonlyin adults, the average age in fifty-twocases being nineteen years. The youngestreported patient was four years of age andthe oldest seventy-six. Sixty-two per cent.of the cases occurred in f emales, while FIG. 6.-Paraganglioma of the carotidbody (carotid body tumor). Duration of tu-only thirty-eight per cent. were in males. mor eleven years. A diagnosis of carotidaneurism was made six years before removalOf twenty-nine cases in which the side of the tumorwas indicated, twenty-five occurred on the left side of the body.

These tumors vary considerably in size, the reported cases varying fromthe size of a hen's egg to that of a child's head or larger. In Sauerbruch'scase (reported by Brunner) the tumor measured I7 x I2 X 8 cm.

Due to their large fibrous content they are firm in consistency, presentingin the gross many of the characteristics of a fibroma. In some instances,the outer layers of the tumor compose a very firm, almost cartilaginous shellenclosing a mass of softer tissue. The cut surface is gray and glistening andappears to be relatively avascular, with fibrous tissue septa dividing' thetumor into smaller lobules. Microscopically these neoplasms show a rathercoarse, reticular arrangement of fibrous tissue in the interstices of whichare contained strands of non-medullated and medullated nerve fibres. In themajority of cases the former type predominates. Intermingled-with thesefibres are found multipolar ganglion cells varying in -number -in differenttumors and many of them showing signs of degenerative changes, s'uch asvacuolization, etc.

521

MONT R. REID

The ganglioneuromata are usually benign, as shown by the fact thatthey are of slow growth and may reach a considerable size before givingrise to symptoms. In Sato's case, the tumor was known to have beenpresent for sixteen years before its operative removal, and several authors(Borst, Beneke, Ohse, Braun, Kreche and Brunner) have reported casesin which the tumor was as large as a child's head or larger. Also, in at leastone case (Busse-Kredel), re-investigation of a ganglioneuroma, incompletelyremoved at operation five years previously, failed to reveal any recurrence.

In certain of the re-ported cases, ganglioneu-romata seem to havepossessed malignant char-acteristics. Thus, in Bene-ke's case cell types andtopography suggestive ofneuroblastoma werefound, and Berner andM iller found metastasesfrom such a tumor in theneighboring lymph-nodes.Jacobstahl noted liver met-astases, and Seefelder de-scribed metastases from apelvic ganglioneuroma tothe lymph-nodes, bonesand soft parts.

These cases have beentaken to indicate malig-

FIG. 7.-Carotid body tumor removed from the patient shown in nant d e g e n e r a t i o n ofFigUre 6. Figure 6. ganglioneuromata. How-

ever, since combinations of neuroblastoma and ganglioneuroma are known toexist, it would seem more rational to consider these cases as neuroblastomatain parts of which more mature elements, i.e., differentiated ganglion cells, areto be found. Indeed, it-seems altogether likely that we have all gradationsbetween pure neuroblastomata and pure ganglioneuromata and that the degreeof benignancy corresponds quite accurately with the degree of differentiationto be found in the individual tumors.

The rather rare occurrence of ganglioneuromata in connection withperipheral nerves may be due to anomalous development, but is alsoto be explained on the basis of Alt's work in which he found numerousganglion cells in the brachial and lumbo-sacral plexuses in dogs, cats, etc.The diffuse subcutaneous distribution in the case of Kredel-Beneke mayhave originated from the perivascular plexuses in which Glaser has demon-strated ganglion cells.

Ganglioneuromata produce relatively few symptoms and are often found522


in the course of some secondary condition. They sometimes produce. paralysisby pressure. Thus deQuervain noted ptosis and anisocoria in a cervical case,and Busse has described Kredel's case in which a similar tumor in the lumbarregion produced paralysis of the leg, bladder and rectum. Occasionally, asin Loretz's case, a tumor springing from the 'gray ramus may invade thespinal canal through the intervertebral foramina, and produce 'pressure onthe cord or cauda equina while at the same time assuming proportions retro-peritoneally or behind the pleura.

Since these tumors produce no intrinsically characteristic symptoms onecan readily understand why a defi-nite diagnosis in the absence ofhistological examination has neverbeen made. Pressure symptomsattributable to the autonomic sys-tem should suggest such a diagno-sis but since so many other and ~ ..+-more common lesions may produce I-sympathetic paralysis, such evi--dence is only contributory. Oftwenty cases operated upon, sev- fenteen were cured at the time ofthe last report, while only threedied, two from direct effects of themoperation and one due to malig- jnant changes in the tumor withmetastases. In contrast to theneuroblastomata we see, there- .¢fore, that the ganglioneuromata 4

are quite benign in their course > .s.and offer a relatively good prog- FIG. 8.-Histological section of the carotid body tumornosis. shown in Figure 7.

Paraganglioma.-While one branch of the neuroblast tree gives rise tothe sympathetic ganglion cells, the other differentiates into the cells which,by virtue of their chemical affinity for the salts of chromium, are spokenof as chromaffin cells. To the organs composed of chromaffin tissue, Kohnhas given the name of paraganglia, and neoplasms of this tissue are calledparagangliomata (Alezais and Peyron).

While, theoretically, paragangliomata may arise from any of the collec-tions of chromaffin tissue, the greater number, by far, arise in the suprarenalmedulla, the carotid gland, and the Gelben Zellen of the gastro-intestinal tract.

The paragangliomata of the suprarenal medulla are relatively rare; onlyabout seventeen cases have been recorded since the first case was reported byBerdey in I892. All reported cases have been quite benign and symptomless,being for the most part autopsy curiosities. As a rule, the tumors are small,varying from the size of a pinhead to aggregations a few centimetres in

523

MONT R. REID

diameter. In the gross the tumor appears as an enlargement of the supra-renal gland, which on section, is seen to be due to a brownish-gray mass dis-tending the cortex. Microscopically, the tumors are composed of epithelialcells which are arranged in cords along delicately anastomosing capillariesand which, when stained with chrome salts, take a brownish color.

In certain cases, notably those reported by Hedinger, Manasse, Marchettiand Suzuki and Zechmer, sympathetic ganglion cells and their less matureprecursors have been found in the tumors, and, in these cases, the tumorwas invading the cortex in a way which would indicate at least potential

malignancy. The association ofparaganglioma of the adrenal med-ulla with neurofibromatosis in

Aedit3i4 fourteen reported instances (Herx-heimer-Kawa shima, Suzuki andZeckmer) is an interesting clinicalobservation.

More numerous and far morer ! q _ important from the surgical stand-

point are the paragangliomata ofthe carotid gland. Marchand, inI89I, was the first to call attentionto this tumor, while Paltauf, in

FIG. g.-The dotted line indicates how the bifurca-tion of the carotid artery was embedded in a paragan- I892, reported four additionalglioma of the carotid gland. cases and, through his paper,establislhed the condition as a- cliniical entity. A survey of the literaturereveals some Iii reported cases.

Tumors of the carotid gland are found largely in adult life. The averageage is forty-one years, with the extremes in age of seven and seventy-fouryears. Only six such tumors have been reported in patients under twentyyears of age.

In most instances the tumors had been present for some time before opera-tion; in but fourteen instances had the tumor been present less than one yearand in almost 6o per cent. of the cases, a mass had been noted for more thanthree years. Three patients dated the appearance of the growth from a timemore than thirty years previous to operation. In many of the cases, how-ever, in which the tumor had been present for more than a year or so, amore rapid growth during the months preceding operation was noted.

For the' most part the growth of the tumor is symptomless until it comes tocause pressure on the surrounding nerves or upon the pharynx or cesophagus.Relatively small tumors may press upon certain nerves. The vagus wasmost commonly involved (fourteen times); the hypoglossal next (seventimes) ; the cervical sympathetic (five times) ; the glossopharyngeal (fivetimes) ; and spinal accessory (twice). In some instances the patient maycomplain of pain in the throat, ear or base of the skull, or there may beatrophy of the corresponding half of the tongue or dysphagia. The latter

524


symptom may also be due to protrusion of the growth into the pharynx. Pres-sure upon the sympathetic chain may also give rise to anisocoria or enoph-thalmos, and in a few instances there has been aphonia and dyspncea due topressure from large tumors.

Tumors of the carotid body have been variously regarded as perithelio-mata, endotheliomata, epitheliomata, perithelial angiosarcomata or adenomata,due no doubt to slight variations in the histological structure. However, whilehyperplasia or neoplastic growth of the structural elements of the carotidbody aside from the chro- : _maffin tissue does occur,the behavior of these tu-mors and th'e general sim-ilarity of their gross andh stoogi a1appearancehistological appeaance

would seem to indicatethat in most carotid bodytumors, we are dealing 4l*with a certain pathologi-cal entity. 'Certain case's,notably two of those of iGilford and Dobromy- Jslov's case seem to have ibeen sarcomata, while Gil- -it`iford has also reported acase which was probably

"aft

a carcinoma.Grossly, these tumors FIG. io.-The gelben zellen in the Crypts of Lieberkuhn of the

present as nodular masses appendix, darkly stained with silver. (After Forbus.)which are of firm consistency and even texture, characteristics which promptedthe suggestion of the appelation of "potato tumors" by Hutchinson and Gil-ford. On section, they are usually well encapsulated with fibrous tissue andthe cut surface usually presents a yellow or orange color, varying to redwith the vascularity of the tumor. In many instances, the great vascularityhas suggested angio-sarcoma or even aneurism. The adjacent lymph-nodesare occasionally agglomerated with the tumor but are rarely involved bythe growth.

Histologically, an alveolar topography is quite characteristic, the growthbeing composed of polyhedral granular cells arranged in compact groups andsurrounded by hyperplastic capillary endothelium. The amount of stromavaries but is often scanty, the characteristic cells being in intimate contactwith the capillary endothelium.

Because of the site of the carotid gland, tumors arising from it presenta rather definite clinical picture and important neighboring structures so soonbecome involved that the surgical attack upon these tumors furnishes a verydifficult problem.

525

MONT R. REID

Keen, writing on these tumors, mentions the following points whichmay aid'in the diagnosis:' (i) The position at the bifurcation of the carotidartery, (2) movability laterally but not vertically, (3) ovoid shape,_ (4) smoothand not lobulated, (5) single, (6) transmitted pulsation, (7) bruit and thrill,(8) bulging of the wall -of the pharynx, (9) pupils' occasionally constricted,(Io) slow growth, (II) long duration, (I2) a rather firm elastic consistency.Speaking negatively he says they are: (i) Not tender, (2) not painful and(3) the deformity is the main complaint.

The position of the artery in these cases deserves further comment.Whereas other cervical growths may dislocate the artery, they usually leaveit freely movable. In carotid body tumors the carotid artery is caught, fixedand carried lateralward so that it lies in a groove on the lateral or antero-lateral'aspect of the tumor.

Since many of these tumors are extremely vascular, a palpable pulsationand associated bruit are frequently evident, and have been commented uponin twenty-two cases.

The surgical removal of carotid body tumors is fraught with a considerabledanger and difficulty, because the frequent involvement of the carotid arteryin the substance of the growth necessitates the ligation or excision of thisvessel or even the entire neurovascular bundle. Of forty-three cases in whichit was necessary to ligate the carotid artery, nineteen or forty-four per cent.died. In addition, two other patients suffered hemiplegia. The concomitantligation of the common carotid and internal jugular in fifteen cases wasattended with a mortality of 54 per cent.

The mortality in the collected cases was about 40 per cent., certainly ahigh rate for an operation performed in the greater number of instances forcosmetic reasons. Such considerations have led several surgeons-Da Costa,Reclus and others, to advise against operation in the simple cases where adefinite diagnosis' has not been made before fixation and involvement of theneurovascular bundle has taken place.

Obendorfer (I907), separated from the true carcinomata of thegastro-intestinal tract, a group of neoplasms to which he applied the nameof carcinoid tumnors, which, according to our classification, are calledparagangliomata.

Hubschmann in I910 (Reviue. med. de la-Suisse rom., i9i0, vol. xxx,p. 317), suggested that these tumors had their origin in the so-called "GelbenZellen" of the Crypts of Lieberkuhn, the chromaffin character of which hadbeen proven by Schmidt in I905. Gosset and Masson in' I9I4, (Pressemed., vol. xxii), studied these cells and the carcinoid tumors and concludedthat the tumor cells are probably identical with the chromaffin tissue of theparaganglia.- While the idea of the origin of the carcinoid tumors fromchromaffin tissue has not been universally accepted, the findings of Gossetand -Masson have been confirmed' by other authors, notably by Hasegawa(I923), Damsch (I924), and Forbus (I925), and the weight of evidence

526


seems to point to their endocrine origin. As such, they deserve considerationamong the tumors of tissue related to the autonomic nervous system.

Pathologically, these tumors present as single or multinodular enlarge-ments, occurring most commonly in the appendix and ileum, but being alsofound elsewhere in the gastro-intestinal tract. Occasionally they appear as abulbous enlargement of the distal portion of the appendix. The incidenceof their occurrence in appendices removed at operation is estimated at 0.4per cent. The tumors are found in the submucosa but may extend into themuscularis or more rarely into the mesentery. Microscopically they aremade up of rather round, oval or low cylindrical cells with round or ovalnuclei, which stain quite deeply but do not exhibit much variation in sizenor many mitotic figures. These cells are found in nests or alveoli, sur-rounded by interlacing trabeculai of fibrous or smooth muscle tissue. Becauseof the peculiar ability of certain of the cells to reduce silver from ammoniacalsolution, the name of argentaffine tumors has been suggested. Clinically,these tumors are quite benign and seldom, if ever, produce symptomsof themselves.

Neuromata may develop in the sympathetic nerves just as well as in theperipheral nerves. Massary and Valser (Soc. med. des Hopitaux, January29, I923), reported a case of a tumor in the wall of the stomach, which theyconsidered to have been derived from Schwann's syncytium, and because ofthe identity of this tissue with the central neuroglia, they regarded it as aglioma. The neuromata of the sympathetic nerves have been studied byMasson (Thesis, Paris, I909), and Quirin (Thesis, Paris, I92I) has describedthe embryonal sympathomata. Both these classes of neoplasms present asnon-malignant tumors, which occur more commonly in the uterus than inother viscera.

Careful study by Masson and by Askanazy, of the proliferation of thenerve elements about the margins of gastric ulcers and in the walls of previ-ously inflammed appendices-particularly those of the chronic obliterativetype-has convinced these authors that, in some instances, such an overgrowthmay reach a true neoplastic grade. Dupuy (International Clinics, vol. iv,December 25, p. I64) has described a case of ulceration and chronic perfora-tion of the gastric wall, in which there was a considerable hyperplasia of thecells and fibres composing Auerbach's plexus.

Leriche, Bettman and others, who have performed periarterial sym-pathectomy on the iliac arteries or upon the abdominal aorta, for intractablepelvic pain, base the rationale of the operation upon the idea that the painis caused by neuromata formed in connection with the pelvic or uterine nerves-such as have been demonstrated in the uterus by Masson.

SUMMARY OF THE TUMORS OF THE AUTONOMIC NERVOUS SYSTEM

i. In the appendix .................... 3252. In the carotid body .................... III3. In the suprarenal medulla ....... ............. 70

527

MONT R. REID

4. In the small intestine ................................... I75. In the stomach .................. ................. 26. In the central nervous system ............................... I87. In the cervical sympathetic chain ........................... 88. In the thoracic sympathetic chain ........................... II9. In the abdominal sympathetic chain ............. ............ 27

IO. Miscellaneous tumors ................................... 2I

With the two cases of "carcinoid" tumors of the appendix reported in thispaper, we have collected 325 cases of paragangliomata of the appendix. Inreviewing the literature, we have found twenty-five cases in which theappendiceal growth was definitely -a carcinoma, some of which were of thecolloid type. At the Mayo Clinic the incidence of appendiceal tumors ,was0.44 per cent. among the first 5000 cases of appendectomy reported; o.6 percent. among the next 3039 cases. One case of the sixty-four appendicealtumors reported from this clinic was definitely malignant. Stewart andTaylor report a "carcinoid"' tumor of the appendix that caused a metastaticnodule in the pelvis, and claim to have found in the literature seventeen casesof "carcinoid" tumors associated with metastases. I agree with Forbus whodoubts if true paragangliomata of the appendix and gastro-intestinal tractever metastasize. This author has called attention to a peculiar adeno-car-cinoma which superficially resembles "carcinoid" tumors but does not giveany of the characteristic chemical or staining reactions. It will, however,produce extensive metastases.We have collected III reported cases of carotid body tumors which, we

believe had their origin from the chromaffin cells. This does not includethe few cases of malignant tumors that have apparently developed in thestroma of this gland. Of the i iI cases, IIO may be classified as paragang-liomata and one as neuroblastoma. Birniois states that no improvement hasresulted from radiotherapy and also, that no distant metastases have everbeen observed. Collison and Machenty mention one case from the litera-ture, in which metastases to the liver occurred. We could not find the originalreport of this case.

Of the seventy tumors of the suprarenal medulla, forty appear to beneuroblastomata-; thirteen ganglioneuromata; and seventeen paragangliomata.The neuroblastomata were highly malignant, the other tumors were rela-tively benign.

Of the small intestine there are reported two neuroblastomata and fifteenparagangliomata ("carcinoid" tumors).

One neuroma and one peripheral glioma (neuroblastoma) are reportedas occurring in the stomach.

There are eighteen tumors of the autonomic nervous system, which havebeen located in the region of the central nervous system-five neuroblasto-mata and thirteen ganglioneuromata. -Of the ganglioneuromata, three werein the cerebrum; two in the cerebellum; two in the tuber cinerium; one in the

-528


medulla; one in the gasserian ganglion; one in the pineal body; two in thedura and ependyma; and one in the spinal canal.

Eight tumors of the cervical sympathetic chain have been recorded-twoneuroblastomata and six ganglioneuromata.

Eleven tumors of the thoracic sympathetic chain have been reported-three neuroblastomata and eight ganglioneuromata.

Of the twenty-seven tumors of the abdominal sympathetic chain, sevenwere neuroblastomata; sixteen ganglioneuromata; and four paragangliomata.

Of the twenty-one miscellaneous tumors listed in the chart, there are fiveneuroblastomata: one in the retina, one in the nasal cavity, one in the uterusand two in the coccygeal gland; twelve ganglioneuromata-one in the spheno-maxillary fossa, one in the eye-lid, one in the nares, one in the mesentery,three in the pelvis, one in the sacral region, two in the subcutaneous tissue,one in the chin and one in the knee-joint; and four paragangliomata-onein the aortic ganglion, one in the retroperitoneal tissue and two in the upperpole of the kidney (possibly in the suprarenal gland).

Very little has been written about neuromata of the autonomic nervoussystem. Consequently our statistics do not convey any accurate idea as to theincidence of this condition.

TUMORS OF THE SUPRARENAL MEDULLA

Classified According to Type, and the Authors Reporting Them.Neuroblastomata

Dalton, I885 ........................Marchand, I89I .....................Orr, i9oo ..........................

Amberg, I904 .......................Richards, I905 ......................Kuster, I905 ........................

Lapointe and Lacene, 1907 ..........Tileston and Wolbach, I908.Wright, I91O ........................Landau, 19I2 .......................Herxheimer, 1913 ..................Wahl, I914 .........................Dunn, 1915 .........................

Glosmet, I9I5 ......................Harbitz, 1915 .......................Lehman, 1917 ......................

II

I

I

I

I

II

2IIII2I

Hertz and Secher, I9I8 .............Wolbach and Morse, I9I8 ............Gunby, 1920'........................Carter, 192I ........................

Van Dam, 1924......................Boyd, 1926 .........................

Lederer, I926 .......................Bendixes and Lamb, I926 ...........Meltzer, I926 .......................Kawatin and Twiss, I927 ...........Saphis, I927 ........................

Gibson, I927 ........................Sturtevant and Heller, I927 ..........

Total cases ......................

Ganglioneuromata

Weichselbaum, i88i .......... ....... IBusse and Kredel, I898 ....... ....... ISchmidt, I899 ........ IBruchanow, I899 ............ ......... IBeneke, I9OI . ....................... IFabris, 1903 ........... IRibbert, I904 ....................... 2

Oberndorfer, I907 ...................Miller, 1908 ........................Hook, I9II .........................Dunn, 19I5 .........................Berner, I922........................

Total cases .......................

I

3I

32

I

2

3I2

I.

40

I

I

III

'352934

Berdez, I892 ..................Manasse, I896 .................Marchetti, I904 ...........-

Laignel Lavastine, i908 ........Alezais et Peyron, I9II ........Suzuki, I9IO ...................Hedinger, I9II ................Kawashima, I9II ..............Herde, I9I2 ...................

MONT R. REID

Paragangliomata

I Wegelin, I9I2 .

I Thomas, 1913 .I -wing, I922 .

I Zweiker, I925 .

I Bonnamour et al, I927 .

3 Oberling et Jung, 1927.I

I

I

Total cases ... ..... I7Grand total .... .... 70 Cases

DISTRIBUTION OF TUMORS OF THE AUTONOMIC NERVOUS SYSTEM

Classified According to Type, and the Authors Reportinig Them.

NeuroblastomataNumber of

Location Author CasesCentral nervous system.................... Marchand, I9o7... .................. I

Central nervous system ................... Bailey and Cushing, I926 3

Central nervous system ................... Silverberg, I926 I

Retina .... ................. Boyd, I926 ....................... ICavity of nose .......... ........... Wolbach, 19II .................... I

Cervical sympathetic chain ............... Martius, I9I3 ............. I

Cervical sympathetic chain ............... Capaldi, I927 ............. IThoracic sympathetic chain ...............Anderson and Sheenan, I923 I

Thoracic sympathetic chain ............... Cabot, 1927 .............. IThoracic sympathetic chain ............... Capaldi, I927 .................... I

Abdominal sympathetic chain ............. Hecht, I909................. I

Abdominal sympathetic chain ............. Schilder, I909 .................... I

Abdominal sympathetic chain ............. Wright, I9IO .................... I

Abdominal sympathetic chain .............Landau, I9I2 ..................... I

Abdominal sympathetic chain .............Anitschkow, I913 I

Abdominal sympathetic chain ............. Boyd, I926 ........................

Abdominal sympathetic chain ............. Karelitz, I927. ................... I

Uterus ..................... Pick, I912 ........................ ICoccygeal (gland) region ................. Alezais and Imbert, I907 I

Coccygeal (gland) region ................. Harbitz, I9I5 ............. I

Total cases .. .... 22

GanglioneuromataCentral nervous system (cerebrum) ......Worcester, I9OICentral nervous system (cerebrum) ......Dumas, I904Central nervous system (cerebrum) ...... Schmincke, 190. .

Central nervous system (cerebellum) ......Achucarro, I9I3Central nervous system (cerebellum) ....... Lhermitte, I920Central nervous system (tuber cinerium) Robertson, I9I5Central nervous system (tuber cinerium) Greenfield,

Central nervous system (medulla) ......... Pick and Bielschowsky, igiiCentral nervous system (gasserian ganglion) Risel and Zwickaw, I909 ...........

Central nervous system (pineal body) .... Cushing and Wolbach, I927Central nervous system (duraandependyma)..Haenel, a899.....................Central nervous system (dura and ependyma) Bielschowsky, I925 ................

530

I

I

I

I

I

I

I

I

I

I

I

I

II

I

I

. . .. .


Ganglionteuromata-Continued

Central nervous system (spinal canal).....Cushing and Wolbach, I927 .. ISpheno-maxillary fossa ................ Dunn, 19I5 . ...........; IEye-lid .... ........................ Krauss, I9II .................. INares ... Axel Key, I879 ........ ICervical sympathetic chain ................ Benda, I904 . . ICervical sympathetic chain ................ Glinski, I9o6 ........ I

Cervical sympathetic chain ................ Woods, I906 ........ I

Cervical sympathetic chain ................ Freund, 19I3 . ....... ICervical synmpathetic chain ................ Sommerfelt, I920 .. ICervical sympathetic chain ................ Stout, 1924. ..................... IThoracic sympathetic chain ............... Loretz, I870. ..................... IThoracic sympathetic chain ............... Tschistowitsch, i9o8 ............... I

Thoracic sympathetic chain ............... Friedrich, I9II . ............ I

Thoracic sympathetic chain ............... Rosenson, I923. ................... IThoracic sympathetic chain ............... Brunner, I924. ................... IThoracic sympathetic chain ............... Stout, 1924. ..................... IAbdominal sympathetic chain ............. Busse, I897. ..................... IAbdominal sympathetic chain ............. Cripps and Williamson, i899 ....... I

Abdominal sympathetic chain ............. Beneke, I9OI . ............. I

Abdominal sympathetic chain ............. Rosenbach, I90I. ................. IAbdominal sympathetic chain ............. Glockner, I902. ................... IAbdominal sympathetic chain ............. Ohse, I906 . .............. I

Abdominal sympathetic chain ............. Falk, 1907. ..................... IAbdominal sympathetic chain ............. Braun, I.8.. IAbdominal sympathetic chain ............. Oelsner, I908. ................... IAbdominal sympathetic chain ............. Miller, I908 .................... I

Abdominal sympathetic chain ............. Sato, I9I2 .................... IAbdominal sympathetic chain .............McNaughton-Jones, I9I2 .. IAbdominal sympathetic chain ............. Jacobsthal, io9 0................... IAbdominal sympathetic chain ............. Peters, 1913.................... IAbdominal sympathetic chain ............. Adams, I914. ................... IAbdominal sympathetic chain ............. Berner, 1922. ................... IMesentery ..... ..Peterson, 1913 .. IPelvis .................... Beneke, I9OI01. . IPelvis .............. Schorr, I9IO . .IPelvis . .............. Stoeckel,- 1923 . . ISacralregion .......McNaughton-Jones, I9I2. ISubcutaneous tissues ...... ........Knauss, I898 .. ISubcutaneous tissues ..... .........Kredel and Beneke, 2...I IChin ...... Chiari, I898 ........ I

Knee-joint ...... Hagenbach, I9IO ..... I

Total cases .55

Paragangliomata

Aortic ganglion ........................... Stangl, I902 ...... IRetroperitoneal .............'. -. Vecchi, I905 ...... IUpper pole kidney (suprarenal?) ......... Weisel, 1902 ........ I

Upper pole'kidney (suprarenal?) ......... Stoerk. ........ I

Total cases ..........' 4(Grand total). 8i Cases

531

MONT R. REID

BIBLIOGRAPHY

TUMORS OF THE SUPRARENAL MEDULLA

Pepper, W.: Am. J. Med. SC., vol. Cxxi, p. 287, I90I.Tileston, W., and Wolbach, S. B.: Am. J. Med. Sc., vol. cxxxv, p. 871, I908.Wright, J. H.: Jour. Exp. Med., vol. xii, p. 556, i9io.Pick, L.: Berliner Klin. Wchnschrf., vol. xlix, p. i6, I9I2.Wahl, R. A.: Jour. Med. Research, vol. xxx, p. 205, 19I4.Dunn, J. S.: Jour. of Path. and Bact., vol. xix, p. 456, I914-I915.Glomset, D. J.: Arch. Int. Med., vol. xv, p. 341, I915.Harbitz, F.: Arch. Int. Med., vol. xvi, p. 312, 1915.Lehman, E. P.: Jour. Med. Research, vol. xxxvi, p. 309, I9I7.Hertz, P., and Secher, K.: Jour. A. M. A., vol. lxx, p. 278, I9I8.Wolbach, S. B., and Morse, J. L.: Am. Jour. Dis. Child., vol. xvi, p. 63, I9I8.-Carter, W. E.: Am. Jour. Dis. Child., vol. xxii, p. 244, 192I.Van Dam, C.: J. A. M. A., vol. lxxxiii, p. I630, I924. (Abstract.)Zeckwer, I. T.: Boston Med. and Surg. J., vol. cxciii, p. 254, I925.Brunner, A.: Arch. f. Klin. Chir., vol. cxxix, p. 364, 1924.Boyd, Wm.: Arch. of Surg., vol. xii, p. I031, I926.Meltzer, S.: Canadian Med. Assn. Jour., vol. xvi, p. 647, 1926.Bonnamour, S., Doubrow, et Montegue: Ann. de Anatomie Pathologique, vol. iv, p.

141, I927-Kwartin, B., and Twiss, J. R.: Am. J. Dis. Child., vol. xvi, pp. 279, 34-61, I927.Gibson, T. E.: Jour. of Urol., vol. xviii, p. 33, 1927.Hutchinson, R.: Quarterly Med. Jour., vol. i, p. 33, I907-I908.

TUMORS OF THE CAROTID BODY

Keen, W. W., and Funke, J.: Jour. A. M. A., vol. xlvii, p. 469, I906.Douglas, J.: Med. Rec., vol. lxxv, p. 397, I909.Stendel, H.: Deutsche Zeitschrift f. Chir., vol. cxxxii, p. I, I9I4.Winslow, R.: ANNALS OF SURGERY, vol. lxiv, p. 257, I9I6.Schley, W. S.: ANNALS OF SURGERY, vol. Ixvi, p. 252, 19I7.Lund, F. B.: Boston Med. and Surg. Jour., vol. clxxvi, p. 62I, I917.Reenstierna: Arkiv. f. Inre. Medicin, vol. li, p. 215, 1919.Reid, M. R.: Bulletin J. Hopkins Hosp., vol. xxxi, p. 177, 1920.Anquez, E. E. P.: International Clinics, vol: iii, p. 208, 1920.Klose, H.: Arch. f. Klin. Chir., vol. cxxi, p. 689, I922.Fedeli, F.: Arch. Ital. d. Chir., Bologna, vol. vi, p. 217, I922-1923.Birman, A.: Deutsche Zeitschr. f. Chir., vol. clxxxvi, p. 384, I924.Miller, R. H., and Garland, F. E.: Boston Med. and Surg. Jour., vol. cxci, p. 659, I924.Sheehan, J. E., and Rabimer, M.: Laryngoscope, vol. xxxvii, p. 433, 1927.Sullivan, R. P., and Fraser, A.: Surg., Gyne. and Obst. Jour., vol. xlv, p. 209, 1927.

TUMORS OF THE SYMPATHETIC NERVOUS SYSTEM

Wright, J. H.: Jour. Exp. Med., vol. xii, p. 556, I9I0.Pick, L.: Berliner Klin. Wchnschrf., xlix, p. i6, 1912.Wahl, H. R.: Jour. Med. Research, Vol. xxx, p. 205, 1914.Dunn, J. S.: Jour. Path. and Bact., vol. xix, p. 456, I9I5.Lehman, E. P.: Jour. Med. Research,- vol. xxxvi, p. 309, 1917.Wolbach, S. B., and Morse, J. L.: Am. J. Dis. Child., vol. xvi, p. 63, I9I8.Stout, A. T.: Jour. A. M. A., vol. lxxxii, p. 1770, I924.Ritter, S. A.: Am. Jour. Path., vol. i, p. 5I9, 1925.Boyd, Wm.: Archiv. of Surg., vol. xii, p. 1031, 1926.

532


Bailey, P., and Cushing, H.: Tumors of Glioma Group, p. 128, I926, Lippincott, Phila.Silberberg, E.: Virchows Arch. Path. Anat., vol. cclx, p. 25I, I926.Capaldi, B.: Frankf. Ztschr. f. Path., vol. xxxv, p. 83, I927.Karelitz, S.: Am. Jour. Dis. Child., vol. xxxiii, p. 394, I927.Cushing, H., and Wolbach, S. B.: Am. J. of Path., vol. iii, p. 203, I927.

INTRATHORACIC TUMORS OF THE SYMPATHETIC NERVOUS SYSTEM

Wahl, H. R.: Jour. Med. Research, vol. xxx, p. 205, 19I4.Dunn, J. S.: Jour. Path. and Bact., vol. xix, p. 456, 1915.Rosenson, Wm.; Am. Jour. Dis. Child., vol. xxvi, p. 4II, I923.Brunner, Alfred: Arch. f. Klin. Chir., vol. cxxix, p. 364, I924.Stout, A. P.: Jour. A. M. A., vol. lxxxii, p. 1770, I924.Anderson, J. S., and Shennan, T.: Jour. Path. and Bact., vol. xxvi, p. 545, I923.Capaldi, B.: Frankf. Ztschr. f. Path., vol. xxxv, p. 83, I927.

CARCINOID TUMORS OF THE APPENDIX

Elting, A. W.: ANNALS OF SURGERY, vol. xxxvii, p. 548, I903.Rolleston, H. D., and Jones, L.: Trans. Med. Chir. Soc., London, vol. xxxix, p. I25, I906.McWilliams, C. A.: Jour. Am. Jour. Med. Sc., vol. cxxxv, p. 822, I908.Graham, J. M.: Edinburgh Med. Jour., vol. x, p. 30, W9U3.Meyer, L. B.: Surgery, Gyn. and Obst., vol. xxi, p. 354, I915.Jackson, A. S.: Archives of Surgery, vol. vi, p. 653, I923.Shafer, R. J.: Boston Med. and Surg. Jour., vol. clxxxix, p. 206, 1923.Forbus, W. D.: Bulletin Johns Hopkins Hosp., vol. xxxvii, p. 130, 1925.Shaw, E. H.: Brit. Jour. of Surg., vol. xiii, p. I30, 1925.Stewart, M. J., and Taylor, A. L.: Jour. Path. and Bact., vol. xxix, p. 136, I926.McGlannahan, A., and McCleary, S.: Jour. A. M. A., vol. lxxxix, p. 850, 1927.Walker, G. B. W.: Brit. J. Surg., vol. xiv, p. 665, I927.

PARAGANGLIOMATA OF THE SMALL INTESTINE AND STOMACH

Bunting, C. H.: Bull. of J. H. Hosp., vol. xv, p. 389, I904.Massary, de J., and Walser, J.: Bull. et mem. Soc. d. Hop. de Paris, vol. xlvii, p.

284, I923.Dupuy, M.: International Clinics, vol. iv, p. I64, I925.Forbus, W. D.: Bull. of J. H. Hosp., vol. xxxvii, p. 130, I925.Ritter, S. A.: Am. Jour. of Pathology, vol. i, p. 5I9, I925.Wolfer, J. A.: Surg., Gyn. and Obst., vol. xliii, p. 443, I926.Stewart, M. J., and Taylor, A. L.: Jour. of Path. and Bact., vol. xxix, p. 136, I926.Dukes, C., and Mummery, L.: Jour. of Path. and Bact., vol. xxix, p. 308, I926.McGlannahan, A., and McCleary, S.: Jour. of A. M. A., vol. lxxxix, p. 850, I927.

533

led me to present to this society a brief report on the tumors ofthis

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