MATURATION OF SYMPATHICOBLASTOMA I N T O GANGLIONEUROMA

Report of2 Patients with 20- and 46-Year Suruivals Respectively FREDERICK Fox, M.D., JOHN DAVIDSON, M.D.,* AND LOUIS B. THOMAS, M.D.

HE PURPOSE of this paper is to report on 2 T patients who had sympathicoblastoma or neuroblastoma in early childhood and have survived for 20 and 46 years respectively. In each case, the tumor exhibited the phenome- non of maturation into a ganglioneuroma. The first of these cases-that of P.W., a 20- year-old man-has not previously been fully reported. The patient has been mentioned in reports describing the treatment of malignant tumors with Coley’s toxin, in a report by Stewart’ on his experiences with spontaneous regression of tumors, and in Phillip’s report6 on neuroblastoma. The second case-that of W.W., a 48-year-old man-was previously re- ported by Cushing and Wolbach in 1927.2 This is the most frequently quoted reference to spontaneous maturation of a neuroblastoma into a benign ganglioneuroma. This patient had been followed for 16 years when first re- ported on; more recent examination and study of the patient adds an additional 30 years of follow-up.

CASE REPORTS

Case 1. P.W. (NIH 01-36-53). The patient had been a normal healthy infant until the age of 4 months when he developed multiple subcutaneous tumors varying from 0.3 to 3.0 cm. in diameter. In the initial history i t was stated that “the mother thinks some of the le- sions have disappeared or shrunken. She also thinks that slight ecchymosis frequently ac- companied the appearance of new nodules.” The 3 largest tumors were located on the fore- head, the medial aspect of the right thigh, and the right flank res ectively. At the age of

was excised and a diagnosis of “metastatic 7 months, a tumor no c f ule from the left axilla

From the Surgical Pathology and Postmortem Serv- ice, Department of PathologIc Anatomy, the clinical Cmter, and the National Heart Institute, of the Na- tional Institutes of Health, Public Health Service, Be- thesda. Md.

*Present address: Department of Preventive Medi- cine, Washington University School of Medicine, St. Louis, Mo.

Received for publication May 6. 1958.

neurocytoma of adrenal gland” was made by James Ewing. Through the courtesy of Frank W. Foote, Jr., we have recently had an oppor- tunity to examine a histological section of this tumor (Fig. 1A; slide H2645, Memorial Hospital, New York, N.Y.).

This highly cellular tumor was composed of loosely arranged, uniform small cells with hy- perchromatic nuclei and scant cytoplasm. I n some areas, the tumor cells were arranged around fibrillar strands (Fig. 1A and B). Ves- sels and fibrous connective tissue were exceed- ingly scant. Because of the atient’s long sur-

numerous slide seminars and examined by many pathologists. No differentiated ganglion cells have been observed.

The patient was treated with Coley’s toxin, and radium plaques were applied to the skin overlying the 3 largest lesions. Within 2 months, the radium-treated lesions regressed in size and many of the untreated lesions dis- appeared. Five months after the start of ther- apy, 2 additional subcutaneous nodules ap- peared and then disappeared spontaneously. At the age of 15 months, the patient was clini- cally free of tumor. No further treatment was given.

The patient had several e isodes of bron- chopneumonia in early child rl ood, but other- wise he was in good health until the age of 15 years when a routine physical examination at school revealed a blood pressure of 185 mm. of mercury. During the next 2 years, he re- ceived 2 short courses of antihypertensive therapy without benefit.

In December, 1955, at the age of 19, he was hospitalized because of severe headaches that had occurred intermittently for approximately 3 years. The headaches were bitemporal and apparently related to periods of emotional stress and excitement. His systolic blood pres- sure varied from 140 to 180 mm. of mercury, and his diastolic pressure from 80 to 110 mm. of mercury. A roentgenogram of the chest showed slight left ventricular enlargement and a partially calcified mass in the right suprare- nal area. Intravenous pyelograms revealed downward displacement of the right kidney but normal excretory function. Histamine tests with an 0.025 mg. of histamine base re-

vival, sections of the tumor K ave been used in

108

No. 1 MATURATION OF SYMPATHICOBLASTOMA INTO GANGLIONEUROMA. - Fox et al. 109

Frc. 1. Case 1. P.W. A, Section of a subcutaneous tumor removed from the axilla 20 years previously when the patient was 7 months old. The diagnosis was neuroblastoma. The tumor was composed of small uniform cells with hyperchromatic nuclei. The cytoplasm was irregular and stained faintly. Delicate fibrils could be noted be- tween cells and in a few areas poorly formed rosettes were seen. No ganglion cells were seen in multiple sections of this tumor. (H. & E. x105.) B, Higher ma$lfication of the neuroblastoma seen in Fig. 1A. Note loosely ar- ranged cells forming rosettes around masses o fibrillar material. (H. & E. x205.)

sulted in a rise in blood pressure from 150 over 90 to 160 over 100 mm. of mercury. There was an increase in blood pressure from 160 over 100 to 170 over 100 mm. of mercury with an 0.050 mg. of histamine base. The patient was transferred to the Clinical Center of the National Institutes of Health for further study.

Physical examination on admission revealed a well nourished, well developed man in no acute distress, His blood pressure was 160 over 100 mm. of mercury and labile. Blood cate- chols at a time of elevated blood pressure and after insulin stimulation showed both the epi- nephrine and the norepinephrine fractions to be within normal range. These determina- tions were performed by Albert Sjoersdma of the National Heart Institute. Roentgenograms of the chest, skeleton, and gastrointestinal tract were negative. Roentgenograms of the a b domen showed a partially calcified mass that caused downward displacement of the right kidney (Fig. 4A). This mass could be palpated in the right upper quadrant of the abdomen. Slightly depressed scars measuring 2 to 3 an. in diameter were noted in the skin of the forehead, the right thigh, and the right flank -the sites of the radium plaque applications 19 years previously. No tumor could be pal- pated beneath or in the region of these super- ficial cutaneous scars. Careful palpation of the skin did, however, reveal 2 subcutaneous nodules. One of these nodules measured 3 cm.

in diameter and was located in the right flank. The second nodule was to the right of the xiphoid process. The patient was not aware of either of these subcutaneous nodules.

On Aug. 6, 1956, the nodule in the right flank was excised. It was a firm, sharply cir- cumscribed, spherical mass covered by a thin shiny capsule to which were attached several strands of gray-white tissue. The cut surface was homogeneous tan with small focal areas of yellow mottling. Close inspection of the surface revealed a wavy attern resulting from inter-

sections revealed the tumor to be a ganglio- neuroma with numerous nests of gan lion

ture: however, some immature ganglion cells having smaller nuclei with a coarse chromatin pattern and only a small amount of cytoplasm were also seen. Many of the ganglion cells ex- hibited degenerative changes as evidenced by multiple nuclei, karyolysis, and vacuolization of the nuclei and cytoplasm ( Fig. 3A and B). Cap cells were present around many of the ganglion cells. On Aug. 23, 1956, the retroperitoneal tu-

mor above the right kidney was resected. The tumor measured 14 cm. in diameter, and its outer surface was smooth except for adhe- sions to adjacent structures (Fig. 4B). Medi- ally, a tongue-shaped portion of the tumor partially encircled and was firmly attached to a 4-cm. segment of the vena cava above the

lacing bundles o B tissue (Fig. 2). Histological

cells. Most of the ganglion cells appeare c f ma-

110 CANCER January-February 1959 Vol. 12

FIG. 2. Case I . P.W. Cut surface of encapsulated, sub- cutaneous ganglioneuroma that was 3 crn. in diameter. This tumor was removed from the patient’s right flank in 1956, nearly 20 years after he had first de- veloped subcutaneous nodules of neuroblastoma. This particular nodule had not been treated with a radium mold as were some of the other subcutaneous tumors when the patient was an infant.

renal veins. The tumor was completely re- moved except for that small portion firmly at- tached to the inferior vena cava. The thin capsule of the tumor ruptured, and a large amount of thick red-brown fluid and partially necrotic debris was spilled into the surgical wound.

Gross examination of the tumor revealed multiple cystic spaces filled with thick red- brown fluid and lined by an irregular layer of partially necrotic, friable tissue. Between the

thin fibrous capsule and the necrotic central portion, there was a zone of firm granular brown tissue measuring 1 to 2 cm. in thick- ness. On the medial aspect of the tumor, there was a localized thickening of the wall that was was composed of well preserved homogeneous- tan tissue containing foci of calcification. Aris- ing from this area was the tongue-shaped mass of similar tissue that partially encircled the inferior vena cava.

Histological sections of the capsule and the walls of many of the cystic spaces revealed only hyalinized connective tissue with focal areas of calcification and small collections of lymphocytes. Sections of the well preserved portions of the tumor showed numerous nests of ganglion cells having the same degenerative changes and variation in maturity as were seen in the subcutaneous ganglioneuroma (Fig 5A). Around many of the ganglion cells were small deeply staining cap cells. The in- tervening stroma showed considerable varia- tion in pattern. In some areas, the palisading of nuclei produced a neurofibromatous ap- pearance; in other areas, more tightly coiled fibers produced a pattern much like that of an amputation neuroma. In the zone of granu- lar tissue immediately surrounding the central necrotic portion, the tumor had the appear- ance of a ganglioneuroblastoma. In this area, the ganglion cells showed all stages of devel- opment, from small hyperchromatic cells hav- ing the appearance of neuroblasts to mature

FIG. 3. Case 1. P.W. A, Photomicrograph of the ganglioneuroma shown in Fig. 2. Note that there was marked variation in the size of the ganglion cells and that several of the cells had 2 or more nuclei. Cap cells can be seen around some of the ganglion cells. H. 8e E. ~295.) B, Higher magnification of the ganglioneuroma shown in Fig.

and nuclei, multiple nuclei, and karyolysis. Cap cells can be easily seen around some of the ganglion cells. (H. E. XSOS.)

2 and 3A. Many of the larger gang I ion cells exhibited dqenerative changes. Note vacuolization of the cytoplasm

No. 1 MATURATION OF SYMPATHICOBLASTOMA INTO GANGLIONEUROMA Fox et al. 111

FIG. 4. Case 1. P.W. A, Intravenous pyelogram. Note the calcified mass that produced downward displacement of the kidney and angulation of the ureter. B, Tumor removed from the retroperitoneal area above the right kidney. It measured 14 m. in diameter and was covered by a thin capsule that was easily ruptured. A portion of the tumor could not be removed because of its attachment to the inferior vena cava.

ganglion cells and bizarre giant ganglion cells (Fig. 5B). In 2 sections, there were nest of tu- mor cells resembling the more immature forms within endothelial-lined spaces. The portion of tumor that extended to the inferior vena cava contained nests of mature ganglion cells in a dense connective tissue stroma.

The ri ht adrenal gland was found on the

not involved by the tumor. It measured 5 . 0 ~ 3 . 0 ~ 0 . 1 cm., and on cut section the cor- tices were noted to be remarkably thin. The adrenal medulla could not be seen grossly, and microscopically the medulla consisted of only a few strands of fibrous connective tissue and a few mature ganglion cells. The adrenal cortex was atrophic.

The surgical incision through the right flank made at the time of resection of the retroperitoneal tumor passed near 1 of the 3 cutaneous scars that had resulted from the a p plication of the radium plaques. This scarred area of skin and adjacent subcutaneous tissue were resected. No tumor had been palpated in t h i s region, but pathological examination of the excised tissue revealed an 0.3-an. circum- scribed nodule in the subcutaneous tissue di- rectly below the slightly scarred dermis. Mi- croscopically, this nodule proved to be a sparsely cellular ganglioneuroma (Fig. 6) simi- lar in appearance to the other subcutaneous ganglioneuroma excised 2 weeks earlier. The

surface o B the retroperitoneal tumor, but it was

skin overlying this small ganglioneuroma showed radiation changes, which consisted of moderate dermal fibrosis, loss of dermal ap- pendages, atrophy of the epithelium, and hy- perpigmentation of the basal layer. Because of the superficial scar in the skin produced by the radium pla ue, it seems uite justifiable

in fact a residual portion of the subcutaneous tumor observed and treated when the patient had been 7 months old. As noted previously, histological sections of 1 of the subcutaneous tumors that was present at that time showed undifferentiated neuroblastoma. It should be

ointed out that this particular flank nodule gad not previously been biopsied.

Postoperatively, the -patient had an un- eventful recovery, and he was clinically well 1 year later.

Case 2. W.W. (NIH 01-61-36). The case his- tory to be given includes a brief synopsis of the report by Cushing and Wolbach in 19272 and a more detailed report of the subsequent 30-year follow-up.

Patient W.W. was born in 1909. At 18 months of age, he developed progressive weak- ness of the legs concomitant with paraverte bral swelling opposite the middle of the right scapula. The weakness progressed to include the arms, and the child developed ptosis, in- ability to coordinate eye movements, and loss

to believe that t 1 is small gang ? ioneuroma was

112 CANCER January-February 1959 VOl. 12

FIG. 5. Case 1. P.W. A, Ganglioneuromatous portion of the retroperitoneal tumor, showing mature ganglion cells of variable size and interlacing bundles of stromal fibers. Note fanglion cells with multiple nuclei and cap cells around many of the ganglion cells. (H. & E. X295.) B, Area o the retroperitoneal tumor that shows all stages of development, from small cells resembling neuroblasts to mature ganglion cells and bizarre giant gang lion cells. Many of the largest ganglion cells had multiple nuclei and exhibited degenerative changes similar to those seen in the subcutaneous tumor illustrated in Fig. 3B. (H. & E. X295.)

of sphincter control. The paravertebral mass was biopsied and a diagnosis of malignant tu- mor, possibly neurocytoma, was made by James Ewing. Subsequently a section of the tumor was examined by Wolbach whose interpreta- tion was that the tumor was a “sympathetic neuroblastoma.” Shortly after the biopsy, the patient was started on Coley’s toxin, 3 to 4 minims per week, and this therapy was given for the next 2 years. A year after the onset of symptoms, the patient showed signs predomi- nantly of cerebellar involvement. There had been improvement in the degree of paraplegia related to the paravertebral mass. During the ensuing years the cerebellar signs gradually abated, and the patient developed consider- able sphincter control and was able to get around on crutches; he attended school, al- though he was definitely of less than average intelligence.

In 1921, at the age of 12, he was seen by Harvey Cushing who noted that the nystag- mus, ptosis of the eyelids, and cerebellar involvement of the upper extremities as de- scribed previously were no longer evident. Be- low the level of the sixth thoracic dermatome, there was marked spasticity with sustained clonus of the ankles and knees. Even a light touch would evoke spontaneous reflex flexions of both legs. A laminectomy performed at the level of the previous biopsy site revealed a sharply defined extradural mass of dense non-

infiltrating tissue that on histological exami- nation proved to be a benign ganglioneuroma. After removal of the tumor, the compressed dura filled out to normal dimensions and resumed its pulsations. Through the courtesy of George Curtis of Peter Bent Brigham Hos- pital, Boston, Mass., we have had the oppor- tunity of reviewing a section of the tumor re- moved in 1921. This section has faded some- what during the past 36 years but is still clearly recognizable as a ganglioneuroma (Fig. 7). During the 5 years after the removal of the tumor, the patient’s father wrote to Cushing several times and described his son’s unex- pected and gratifying improvement. By Au- gust, 1926, his urinary incontinence had so improved that he had not wet his bed in more than 2 years. He was able to dress himself, walk around a room without crutches, hitch his pony to a carriage, and drive around town whenever he pleased. In 1927, when the pa- tient was 18 years old, the case was reported by Cushing and Wolbach.2

Because of our interest in the prognosis in our first case (patient P.W. in case l), we were anxious to know the eventual outcome in Gushing’s case. Accordingly the patient was traced with the aid of records at the Peter Bent Brigham Hospital and was found to be living in Virginia. He was admitted to the Clinical Center of the National Institutes of Health for follow-up study.

No. 1 MATURATION OF SYMPATHICOBLASTOMA INTO GANGLIONEUROMA - Fox et al. 113

In the SO-year period from 1927 to 1957, this patient had continued to be remarkably active. He managed a confectionery and drug store adequately under his father’s supervi- sion. He continued to have spastic paraplegia but was able to walk with the aid of crutches, and he had driven an automobile for many years without mishap. His most bothersome symptom was occasional urinary or stool in- continence. Except for these residua of his neurological disease, he remained in excellent general health until 1951.

In 1951 he exhibited weight loss, nervous- ness, and exophthalamus for which he was treated with iodides and propylthiouracil. The symptoms gradually abated during the administration of these medications and did not return after their discontinuance. For several months preceding his admission to the Clinical Center, the atient noted increasing

an stool incontinence. Fre uently he would have a bowel movement whi 4 e trying to void.

At the time of his admission to the Clinical Center, the patient was noted to have normal muscular development of the upper half of his body. He walked with the aid of crutches. The right leg was approximately 3 inches shorter than the left, and it was also smaller. The remainder of the physical examination

uency, nocturia, c r ysuria, and both urinary 9

was not remarkable. Neurological examination revealed the following positive findings: the patient was unable to stand or ambulate without his crutches; biceps, trice s, radial,

hyperactive; bilateral flexor finger reflexes were present as were Babinski reflexes, and one observer found slight dysdiadochokinesia in the upper extremities.

Laboratory studies (including a hemogram, determinations of blood urea nitrogen, blood sugar, serology, and blood electrolytes, thyroid function studies, electrocardiograms, and chest roentgenograms) were normal or noncontrib- utory. Cranial roentgenograms revealed mul- tiple calcific dural plaques. Spinal roentgen- ograms revealed moderate kyphosis of the dorsal spine and spondylolisthesis of L-5 on S-1. Myelograms revealed no evidence of a block at the site of the original tumor, and the size of the subdural space was essentially normal. On intravenous pyelography a golf ball-sized stone was noted in the urinary blad- der. Urine analysis revealed many red and white blood cells and 1+ albuminuria. Proteus vulgaris was cultured from the urine.

A biopsy of the cicatrix resulting from the laminectomy performed in 1921 revealed only dense fibrous connective tissue. No tumor was found. The bladder stone was removed

patellar, and ankle reflexes were a g normally

FIG. 6. Case 1. P.W. Photomicrograph of an 0.3-an. ganglioneuroma in the subcutaneous tissue underlyin a depressed. scarred area in the skin of the right flanlr. This wan the site of one of the subcutaneous nodule b a t had developed 20 years previously when the patient was 4 months old. A radium plaque had been applied to the overlying skin when the atieat was 7 months of age. Thk Eglioneumma wad not palpable but was found b careful examination of su&utaneous time removed at the t e of resection of the retroperitoneal tumor in &. The tumor exhibited more compact fibrous connective tissue and fewer gan@on c d g than the other subcutaneom FIG. 7. Case%.W. Photomicrograph of a histological section prepared in 19el from an extradual spinal

removed by Cushing. Note the variability in size of the ganglion cells, the p-ae aE multinudeated &, and the karyolysis of nudet. These degenerative changes are similar to those seen in the ganglioneuromas re- moved from patient P.W. in case 1 (Figs. 3A and B, 5A and B, and 6). (XSSO.)

lioneunnna (Fig. 3A and B), which had not been treated with a rad~um plaque (~295.)

114 CANCER January-February 1959 Vol. 12

through a suprapubic cystotomy, and the pa- tient was fitted with appropriate shoes, crutches, and a bladder prosthesis. He later developed Proteus vulgaris septicemia with profound vascular collapse and oliguria. He was treated with large doses of norepine h-

a prolonged convalescence, he returned home. Osteomyelitis of the fifth and sixth cervical vertebrae became evident, and he was again treated at the Clinical Center with massive antibiotic therapy for 6 weeks. When last ex- amined, in August, 1957, he was feeling well and had returned to his former activities. His clinical condition was unchanged in Decem- ber, 1957.

DISCUSSION

Well documented instances of spontaneous maturation of neuroblastoma or sympathico- blastoma are even more uncommon than are those of spontaneous regression. The patient reported by Cushing and Wolbach2 is the most frequently quoted example of spon- taneous maturation. Phillips6 briefly described a case very similar to that of Cushing and Wolbach. In Phillips’ case, a biopsy when the patient was 2 weeks old revealed a neuroblas- toma, while a second biopsy at the age of 18 months revealed a ganglioneuroma. A lami- nectomy performed at the age of 2 years dis- closed an extradural tumor that was partially removed and interpreted pathologically as a ganglioneuroblastoma. The patient was given postoperative irradiation and was well 4 years later.

O b d in a discussion of a paper by Chand- ler and Norcross mentioned 2 patients with neuroblastoma that underwent maturation into benign ganglioneuroma but he gave no further details, Uhlmann and von Essen8 described a patient who had neuroblastoma with liver metastases diagnosed in infancy and survived 20 years after receiving irradiation therapy with persistent liver nodules. The authors speculated that this may represent a case of maturation into ganglioneuroma; how- ever, the liver nodules were not examined histologically. The authors suggested that one of the effects of irradiation may be the in- duction or promotion of maturation of the more primitive tumor cells.

The 2 patients presented in this report have many features that are remarkable in their similarity. In brief, at an early age each pa- tient developed a tumor that was histologically interpreted as a neuroblastoma or sympathico-

rine, antibiotics, and hydrocortisone. A P ter

blastoma, and many years later each patient was found to have residual tumor that ex- hibited differentiation into ganglioneuroma.

The first patient (P.W.) has been followed for 20 years since developing multiple sub- cutaneous nodules of tumor, some of which were treated with the application of radium plaques. The second patient (W.W.) had been followed for approximately 16 years when re- ported by Cushing and Wolbach in 1927.2 , Our study of this patient, 30 years after Cush- ing and Wolbach’s report, revealed no evi- dence of residual or recurrent tumor. This was approximately 46 years after partial re- section of a tumor diagnosed as a “sympathetic neuroblastoma.” He still had loss of function as a result of spinal cord compression and the complications arising from a cord bladder. He also had slurred speech and other signs that apparently date back to the cerebellar lesion he manifested in 1911.

In their report in 1927, Cushing and Wol- bach2 stressed the fact that the initial tumor had a histological structure typical of a sym- pathicoblastoma (sympathetic neuroblastoma) and that no differentiated ganglion cells were seen. Ten years later, the residual tumor was found to be composed of ganglion, capsular, and sheath of Schwann cells. The potentiality of differentiating into several cell types led them to believe that the initial tumor cells were of a more primitive type, sympathico- blast, than the sympathetic neuroblast, and this supported their use of the term sympathi- coblastoma for the initial tumor. Sections of the initial tumor, partially removed in 1911, are not available for study at this time, but sections of the extradural mass removed in 192 1 have been reexamined histologically and reveal a well differentiated ganglioneuroma. It is interesting to note that many of the ganglion cells exhibit degenerative changes consisting of vacuolization of cytoplasm, mul- tiple nuclei, and pyknosis with fragmentation of nuclei. Similar degenerative changes are seen in the ganglioneuromas of the other pa- tient in this report.

Sections of subcutaneous tumors recently removed from patient P.W. showed ganglio- neuromas composed of ganglion cells, cap cells, and cells of the sheath of Schwann. One of these subcutaneous tumors is known to have been present when the patient was only a few months old because the overlying skin was slightly scarred as a result of the application of a radium mold at that time. Thus, it ap-

No. 1 MATURATION OF SYMPATHICOBLASTOMA INTO GANGLIONEUROMA - Fox et al. 115

pears certain that the subcutaneous tumors that had the appearance of sympathicoblas- toma or neuroblastoma when the patient was an infant regressed in size and differentiated into the cellular and tissue elements of gan- glioneuromas. In fact, the histological appear- ance of the ganglion cells suggested that there was continuing differentiation from small im- mature cells into larger ganglion cells. In ad- dition, there was degeneration and necrosis of the larger and more mature ganglion cells. Both of these changes-maturation and de- generation of ganglion cells-were prominent in the histological sections of the ganglioneu- romas from both of the patients. These two processes occurring together could explain the apparent paradox of reduction in size of the subcutaneous tumors concomitant with matu- ration of the original tumor cells. One of the principal arguments against the interpretation of cases of this sort as instances of spontaneous maturation of a sympathicoblastoma is that this should result in enlargement of the tu- mor.’

These two patients are similar in another respect, namely, that each received Coley’s toxin. The relationship between regression and maturation of the tumors and the use of Coley’s toxin is not clear. The first patient (P.W.) also had radium plaques applied to 3 subcutaneous tumors. The treated tumors re- gressed in size, and at about the same time un- treated subcutaneous tumors also decreased in size. It should be recalled that the parent be- lieved that some of the lesions had disappeared or shrunk prior to the institution of any treat- ment whatsoever. One of the radium-treated subcutaneous tumors and 1 of the untreated tumors have now, nearly 20 years later, been excised and examined histologically. The 2 tumors are histologically similar. How Coley’s toxin and the application of radium plaques may have caused or stimulated the transfor- mation of the undifferentiated tumor cells into more mature, differentiated cells remains a matter for speculation.

I t was thought during the study of the first patient that the retroperitoneal tumor was primary and the multiple subcutaneous nod- ules were metastases. However, the duration

,

of the retroperitoneal tumor is not known, and the relationship between it and the sub- cutaneous nodules has not been proved. Sev- eral patients with multiple cutaneous gan- glioneuromas have been reported, and it has been suggested that primitive neurocytes or sympathagonia may be widespread in the body.4 Thus, it is possible that the subcutane- ous tumors and the retroperitoneal tumor may have been independent primary lesions. His- tologically, the initial subcutaneous tumors were indistinguishable from metastatic de- posits of a neuroblastoma.

The absence of medullary tissue in the right adrenal gland suggests an anomalous develop- ment characterized by failure of the medul- lary precursor cells to invade the cortical anlage. This supports the belief that the retro- peritoneal tumor may have been present dur- ing all of the patient’s life. Halpert et a1.a have reported absence of the adrenal medulla in a case of neuroblastoma that apparently arose in a suprarenal medullary anlage in a 53-year-old man.

SUMMARY

Two patients in whom there was transfor- mation of a neuroblastoma or sympathico- blastoma into a ganglioneuroma with long term survival are reported. One of the pa- tients was previously reported by Cushing and Wolbach in 19272 as showing transformation of a malignant sympathicoblastoma into a benign ganglioneuroma after the patient had been followed for approximately 16 years. This patient was re-examined in 1957, and at that time, nearly 46 years after the initial diagnosis, he was apparently free of residual or recurrent tumor.

The other patient was first diagnosed as having multiple subcutaneous nodules of metastatic neuroblastoma nearly 20 years ago, at the age of 7 months. The patient when re- cently studied had multiple subcutaneous ganglioneuromas and a retroperitoneal gan- glioneumblastoma. The latter tumor was in part composed of immature ganglion cells and was incompletely removed because of its attachment to the inferior vena cava.

(For references see following page.)

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REFERENCES

1. ANON.: Preliminary observations on treatment of ential diagnosis from reticulohistiocytic granuloma, neuroma, xanthoma and Recklinghausen’s disease of skin. Arch. Dermat. dr Syfih. 2 9 26-52, 1934.

5. O m , F. R.: Abstract of discussion of CHANDLER, F. A., and NORCROSS, J. R.: Sympathicoblastoma. 1. A . M . A . 114: 112-117; pp. 116-117.

6. PHILLIPS, R.: Neuroblastoma; Hunterian lecture. Ann. Roy. COIL Surgeons England 12: 29-48, 1953.

7. STEWART, F. W.: Experiences in spontaneous re- yes ion of neoplastic disease in man. per tner lecture.]

exac Rep. Biol. dr Med. 1 0 239.253. 1952. 8. UHLMANN, E. M., and VON ESSEN, C.: Neuroblas-

toma (neumblastoma sympatheticum). Pediatrics 15: 402-411, 1955.

neuroblastoma with vitamin B12. In Ocnvne, H., Ed.: British Empire Cancer Campaign; Thirty-First Annual

British Empire Cancer Campaign. [1954]: p. 177. 2. CUSHINC, H., and WOLBACH, S. B.: Transformation

of malignant paravertebral sympathimblastoma into benign ganglioneuroma. Am. 1. Path. 3: 203-216, PI. 62-65, 1927.

3. HALPERT, B.: POLLARD, C., JR., and M c ~ u ~ , T. H.: Neuroblastoma of suprarenal medullary anlage with metastases to brain. Cancer 6 512-515, 1953.

4. MONTGOMERY, H.. and O’LEARY, P. A.: Multi le ganglioneuromas of skin: report of case with di&-

Covering the Year 1953. London*

CANCER AND NEOPLASTIC GROWTH The Thirteenth Annual Symposium on Fundamental Cancer Research is

scheduled to be held at the University of Texas M. D. Anderson Hospital and Tumor Institute, Houston, Texas, Feb. 26, 27, and 28, 1959. The topic for the discussion is Genetics and Neoplastic Growth. The sessions will deal with (1) fundamental aspects of genetics in carcinogenesis, (2) gene interaction in neo- plastic growth, (3) the genetic basis of cell resistance, and (4) heredity and human cancer. Further information on the symposium may be obtained from Felix L. Haas, Ph.D., Department of Biology, University of Texas M. D. Anderson Hos- pital and Tumor Institute, Houston 25, Texas.