t~AYO PATHOLOGY ALUMNI

SUDE SEMINAR

NOV EMBER 22, 1980

Di scussion: ~I.A. Meissner, l.B. Woolner , F.~l. £nzinger, and E.H . Soule

CASE 1 :

CASE 2:

. CASE 3:

CASE 4:

CASE 5:

A man, age 19, noticed an il l -defined s11el1 i ng of his right neck for five months. At this time a lymph node was biopsied and reported as nodular hyperplasia. The swellin9 slowly increased over the next tl~o months . A surgical exploration revealed a lar9e soft tan colored invasive tumor in the right paraspinal muscles . There was bone i nvo 1 vement.

A man, age 70, had noticed an asymptomatic mass in his ri~ht axilla for one year. Four months a9o it began to enlarge and he devel oped clinical evidence of brachia l plexus involvement. During th i s period he had temperature elevation up to 102 degrees Fahrenheit. His 14.B.C. was 8,400 with 13.5% eosinophils. A 6 x 5 x 4 em invasive tumor was excised .

A man, age 63, had experienced episodes of pain and S~1ellin9 of his right foot for 15 years. A diagnosis of gout had been suspecte~ but not established by his home physician. Hhen examined at the ~~ayo Clinic there was a firm mass on t he lateral aspect of his foot. An a~putation through the mi d- leg was done .

A man, age 53, was found to have a mass on his right shoulder when he presented himself for a routine examination. The lesion was asymptomatic, has been present for 3-4 years but ha d enlarged during the past three months. A circumscribed tumor 5 x 5 x 4 em ~1as exci sed from the subcutaneous tissue.

A woman, age 51, was seen because of an enlarging mass deep in the left buttock. In 1969 a chordoma had been excised from her sacrum. The chordoma recurred in 1971 and it ~1as treated by surgical excision and radiation (5250 rads). In June of 1975 the patient was seen at the Mayo Cli nic because of a 1 a rge recurrence of the sacra 1 mass and t1~o pulmonary nodules. The patient was given chemotherapy (vincristine , Cytoxan, dactinomycin, Cis-Platinum). By January 1976 there 1~as complete remission of the sacral and pulmonary masses. In October of 1979 a mass in the left buttock was found and exc ised. The slides are froM this tumor.

CASE 6:

CASE 7:

CASE 8:

(~~>)

CASE 8: (B)

CASE 9:

CASE 10:

This 66-year-old ~10man noted a sudden throbbin9 pain in the anterior neck associated with a f eeling of obstruction in her throat. Her physician noted a mass in the left lobe of the thyroid. R.i,IR v1as reported as +2 and the P.B.I. 5 ug%. At the time of thyroi~ suroery, a 2 em circumscri bed nodule 1~as noted in the 1 eft 1 obe, represented by this section.

This 54-year-old asymptomatic .v10man durin(l duri n(l a routine examinati on was noted to have an enlarged thyroid gland and a firm noclul e in the left lobe, 2 em in diameter. Secti ons are from the nodule.

Mal e, 55, developed asymptomatic l ump in right mid neck lY, to 2 year s prior to admission. The mass ~?rew very slowly durino this perioci of time . Two 1·1eeks prior to admission, ri f!ht cervical lymph node was removed and the patient referred to the ~1ayo Clinic ~lith a rlia~nosis of metastatic carcinoma. There were no symptoms referabl e to chest or urinary tract. Admission chest x-ray: Pathologic process in right base, probably bronchiectasis . Examination: Mass in right neck 1·1hich does not move with swallowi n9. Thyroid primary versus metastatic cancer to neck. Surgery: Total right thyroid lobectomy with removal of isthmus . Sections are of right thyroid mass.

~1a 1 e, 70, came to the Mayo Clinic in ()ctober, 19.54, because of a l ump in the 1 eft side of the neck said to have been present for ~0 year s. Patient other1~i se asymptomatic. Surgery: Tota 1 r i 9ht thyroid 1 obectorny 1qith remova 1 of isthmus. Sections are of left thyroid mass.

Female, age 69, admitted on April 3, 1957, v1ith l ong history of ren111 calculi, mu l tiple fractures, tumor of ulna and mass in neck. Prior surgery: 1936 - Right total lobect omy of thyroi d; 1954 - Resection proximal thi·rd of ulna. Physical examination: Large nodular mass, left neck, extendinp beneath sternum. Tumorous enlargement of ri~ht lov1er ribs. Laboratory data: Serum calcium, 12.G mgms; phosphorus, 3 . ~ mprns per lOOcc serum; alkaline phosphorus, 2~7 units. Surgery: February 25, 1957: subtotal resection of the l eft lobe of the thyroid (right lobe resected prior). Hu~h cystic mass on the left displacing trachea markedly to the ri9ht extending beneath sternum. r·,lass resected ~1eighed 132 grams. Sections are from mass adjacent to thyroid.

Female , age 24, presented with asymptomatic nodule in thyroirl oland. Sections are from thyroid nodule.

DIAGNOSES

CASE 1: Extra-osseous Ewing's sarcoma.

CASE 2: Angioblastic lymphoid hyper plasia ~lith bl ood eosinophilia (Kimura's disease).

CASE 3: Synovial sarcoma.

CASE 4: Pleomorphic l ipoma.

CASE 5: Malignant fibrous histiocytoma, inflammatory variant .

CASE 6: Nedullary carcinoma ,,•ith ca1:cinoid syndrome. Reported by Hoertel , et al, New England Journal of Medicine, 273:244, 1965 .

•

CASE 7 : ?Hedullary carcinoma vs. spindled trabecular adenoma . Patient is 13 years postoperative '"ith no recurrence.

CASE 8: Clear cell tollicular carcinoma: primary in thyroid. (a)

CASE 8: Hetastatic renal cell carcinoma (hypernephroma) . (b)

CASE 9: P.rimary ~<aterclear hyperplasia of parat hyroid glands.

CASElO : Chemodectoma (cellular with mitoses) in thyroid gland . 4 years later.

Patient is '~ell

'

THE NEW E~GL-\.l'ID JOUR.I.~AL OF ~1 EDICIXE_ Jul>· 29, 1965 .

wo!!ld not be devastati."lg; this proved to be correct. .\!though the "blowout" on the artery suggested th a : the subacute infection remained confined to a stnaller area of the wall inspection of these aneu­rysms show~d that the necks had a broad origin from at least half the circumference. A clip or ligature would surely have occluded the vesseL

applied only to aneurysms on major vessels and should be based on the improbability of safe sur­gical treatment <1;t an earlier stage. In cases in which ligation or .excision is not possible, or would produce a serious infarct, it might be wise to wrap the lesion in a plastic jacket and relr on :1nti. biotics to destroy the infe.ction within.

St:..-~L\fARY .\."'<"D CoNCLUSIONS

The urgency of craniotomy depends on the site of the aneurysm and whether a significant clot is pres­ent In 3 cases a large intracerebral clot prompted i:nmedia te operation. These p atients fared poorly; Rupture of a cerebra l aneurysm caused by mycotic Case 2 died, and Cases I and 3 were left with pet=-- organisms i:; a rare cause of spontaneous intracranial manent severe deficits. It is unfortunate that the bleeding. Of 191 cases 5 (2.6 per cent) were oi in­r.ature o£ the first aneurysm in Case 3 was notl fectious origin ( 1 patient had 2 such aneurysms) . recognized, for treatme~ght have prevented the ' These cerebral aneurysms should be suspected i[

se,:ere hemorrhage fro e second three months· there is an ob\-ious infec tion, murmur, splenomegaly, later. • petechiae, microscopical hematuria, fe\·er o:- elc:v:ued

In the absence of significant clot or repeated sedimentation rate, an aneurysm in a peculiar si:e hemorrhages the location of the aneurysm will de- or a second aneurysm. termine the priority of medical or surgical treat- -_ Each aneurysm was treated surgically. T wo pa­ment. The more peripheral aneurysms should be ex- tients are well; 1 is dead, and 2 h::t\·e serious neuro­cised or obliterated promptly since the ensuing logic deficit. :'\one have clinically significant he:lrt neurologic deficit is likely to be negligible. If the disease. aneurysm arises from a major vessel a delay of oper- Peripheral aneurysms should be excised or lig:ued ation must be considered. :\Iassive appropriate anti- immediately. Aneurysms im·oh·ing major ves;e!~

biotic therapy should destroy the organism and allow · should probably be treated with antibiotics initi:t:iy wme reparative fibrosis to take place in the wall of unless a significant clot is present. Although tlill the aneUiysm and parent artery. A dip or ligature delay carries the J;sk of recurrent bleeding, the re...<o­

can then more safely be applied, and the unfortu- lution of the arterial infection should ma!.;e the nate consequences of an operation on a fragile, an eurysm less fragile for surgical treatment. acutely inflamed aneurysm, as in Case 2, thus avoid-ed. Such a delay is undoubtedly dangerous because of the possibility of repeated bleeding. In addition the aneurysm may enlarge, as shown angiographical­

REFERE!'OCES

I. O sler, W. Guluonian lectures on m;ilignu t endoc;,rtliis. L:-.nt I :415-418, 459-46-1 a nd 503·508, L885.

ly in Case 4 during the four-·week period of anti- z. biotic treatment. T he decision for delay should be 3.

McDonald, C. .-\. , nnd Korb, ~(. Introer:tnial >••euqsclS. -~ttl. N eurol. & Psychittt. 42:298-328, 1939. Barker, W. F. ~)·corie :.neurysms. A nn. S urz . 1 39 :~-89. 1~-

"MALIGNAl'J'T CARCINOID SYNDROME" ASSOCIATED WITH NONCARCINOID WMORS*

CHARLES G. MOERTEL, M.D.,t OLIVER H. BEAHRS, M.D.,:j: L E \VIS B. \VOOLNER, }.f.D.,§ ANO

G ERTRUDE M. TYeE, PH.D.1f

ROCHESTER, l\ll NNESOTA

DURING the past decade the "malignant carci-noid syndrome" has been a fa ,·ored subject in

the medical literatu re because of the dramatic na­ture of its acute and chronic clinical manifestations and of its as yet unresolved challenges to the physiol-

• Frorn the -ections of ~fedicine, Su<3cry. Su rgie:.l Pathology and Bio-ch<:!>:itry, ~fa~o Clinic a nd :\!;,yo Found3tion.

+)[ember, Sec-:ion of ~lcdicin~, ).f;.yo Clinic and 1\fayo Foundation. ! :'-!e mbe r, Section of Surgery. :\layo Clinic :1nd llh~·o Found:>tion. i~Je:n?er, See tiun of Surgie3.1 P:1thology, ~fayo Clinic 31\d ~byo

f ound:tt:on. • :.!ember, Section d Biochemi•tcy, M:1yo Clini.: and 1>-hyo Foundation.

ogist and thera pist. Still more fascinating are recent reports that the syndrome has been produced b~· noncarcinoid t umors. T o date, 7 such unusl:::d c:1>t!S

have been adequately documen~ed and recordectt·r: in 3, the primary carcinoma had .its origin in the! pancreas1•3 ; in 3, the primary lesion was an oat-cc:U carcinoma of the lung; and in 1, it was a highly anaplastic carcinoma with the site of origin unde­teJminecV T he pertirient data in these case5 ~ summ.arized in T able I. This report adds an eighili case to this elite circle - a "malignant carcinoid

273 Xo. 5 :-L-\LIGX.-'L'\T CARCTXOID S't-:-.'"DRO:-H: - ~10ERTEL ET AL. 245

,_!!!LT. J. Summar)' of R tported Cases of "Malignan: Ccrc:Z·:'lid S>·ndromc" Cc-existent u:ith Jo:oncarcinoid J.falignant Neo­pla!m.!.

Mullen & H anson' Carcinorn:~. in p an­creas

Carcinoma in pan· creas

Islet-cell carcinoma in pancreas

Oat-<ell Pj carci­noma m ung

~ & Azzopardi' Oat-cell carcinoma in lung

•tnlock et aJ.• Oat-cell carcinolDJ\ in lung

p et al. 1 Anaplastic carci-noma of u n­known origin

~ydroxyindoleaatic acid. :11: i\.i.rdro:cyt:r)-pto.miue. fbl-droJ<Ttryptophan.

CuxtC\L ~1.-..."""tt"l.~· TAT!O~S

.3-HL~-\.•

rng./dcy .

F lushing; asthnt:l. ustrongh· positive.,

Flushing 460~90

Flushing; diarrhea; asthma.

53-88

Flu!hing : diarrhea; "Greater (?) asthma. than nor-

mal" F!usbing; diarrhea. 55#..1

( ?) F!uslllng; diar-r hea.

130-230

Flushiog 113-160

drome" coexistent with and presumably produced primary solid thyroid carcinoma " ; th metas-

CASE REPoRT

! 66-year-old woman was first admitred to the Mayo ~k on April 13, 1962, because of a mass in the neck that had noted accidentally 2 rnomhs pre,·iously. She had no s.ignifi~t symptoms, a11d physical examination re­

,ttJ only a solitary, firm, 2-cm. nodule in the left lobe of thrroid gland. Results of basic laboratory studies a nd

~mlent of thyroid fu nction were with in nonnal Umits. April 20 a total lobectomy on the left and subtotal ~omy on the right, ,,-jth remo,·al of the thyroid istht:lu.s, 1 perfonned. At operation the left inferior parathyroid d ,,·as noted to be enlarged and " ·as also excised, as

• the tracheoesophageal lymph nodes. Adenopathy was ooted atong the jugular vein. Pathological examination ~ed a circumscribed, infiluati,·e carcinoma, 2 em. in ptter, in the left lobe of the thyToid gland. I n acdition, ::1 was a single H iirthle-cell adenoma, 1.5 em. in diam­r, within the loue. The right lobe sho,,·ed normal thyroid ~ch:-ma, "ith slight focal fibrosis. ptologically, the carcinon1a was moderately acri,·e ( Grade ):cording to Broders' s classification) and had a solid pat­

(fig. 1 a ) . Some · central hyaline fibrosis ,,·as present. .ough solid ( nonglandular), the tumor appeared some­<1 more active than the subtype of thyroid carcinoma tha t l:tsently referred to as "solid (medullary) carcinoma with

tid stroma." :Mitotic acti\; t). seemed somewhat less that seen in the anaplastic fonn of thyroid cancer. ossl)•, the parathyroid adenoma was 8 mm. in diameter •'cighed 350 mg. Microscopically, it consisted of mixed

!II. o>.:yphil and transitional water-clear cells. · ~use of the parathyroid adenoma the serum calcium rletermined at the time of operacion and " ·as found to 13.3 mg. per 100 ml. (nonnal, 8.9 to JO.l mg. ) . Twent)·­hours after operation the value "·as 8. 7 tng.; at 6 days,

8.9 mg., and on the lith postoperative day, it had to 9.6 mg. Although data were incomplete, it was 25·

that this patient had had prima ry hyperparath~·roidism. Februarr, 1963, she noted enlarged lymph nodes in the

tde of the neck. She rerumed to the Clinic on :\Ia'· 3. a radical neck d issection was performed . Pathological nation shO\,·ed metastatic, Grade 3, solid carcinoma · g multiple lymph nodes of the lfliddle· and the lower jugular regions. The histologic architecture was iden­•ith tl1at of the tumor in the corresponding lobe pre-

'1l resected l fig. lb) .

t:';;.rs..a .... q,·, '£.~"':::"-r..:.-riOX Tt:>-lOR Coxn:---r

5·=+ j.HTr! HlST .. ·UrT!'ol"'E 5-Jtr+ 5·HTT':

mg./dey n-:;z./day mg./day microgn ./ miCTotm./ g m. gm.

0.330-0.49.5 4

:"onnal ::-.-onn.al None

20

12-21 12·1i 0.022-1 .260 < 0.04 <0.05

4000.0

The patient remained asymptomatic during 1963 and early 196-4. She returned again on .-\ugust 25, 1964, ,,·hen she stated that ior 6 months she had had recurrent attacks of intense flushing invoh-ing the face and chest. The attacks occasionally c=e on after the ingestion of a large meal but were in,-ar'.ably precipita ted by the use of alcohol. YeT)~ small quantities of alcohol were required to precipitate an attack. and she became flushed after taking a sip of her nu.s3and·s beer or a single teaspoonful of eliw oi terpin hydrate and codeine, " ·hich she took for a cold. T"·o and a half months before this a dmission, she had noted the sudden orl.set of diarrhea, which had pe~isted. She had from 15 to 20 ,,·atery stools daily, 5 or 6 of them awakening her from sleep at night. Because profuse diarrhea occurred after meais, she ,,·as afraid to eat, "ith a resultant 13.6-kg. i 30-pound j loss in weight. She had had no respiratory S)-mptoms or skin rash. For the pre,; ous 5 months she had no<ed a progressively enlarging nodule in the skin of the left-temple area. Physical examination re,·ealed a hard node, deep in the left side of the neck, and a raised, tender cutaneous le5io:I of the left temple, 1 by 1.2 em. She had no hea!"t ml.!ImUIS. A t)-pical carcinoid flush wo.s reproduced by the ingestion of a lcohol. Normal results were obtained from routine henl2;tologic studies and tests of blood sugar a~d urea, seru:n electrolytes, serum carotene, liver function, in~:luding alkaline phosphatase, proth rombin ~e a nd brom­sulfalein r etention. and from tests of thyroid function, in­c!uonlr basal me1:2bolism a nd protein-bound iodine. Chemi­ca! analyses of fecal fat sho,,·td that daily excretion ,,·as 3.2 gm. and that fat constituted 16 per cent of the total fecal solids. A u.ri::alysis for catechol amines ''o.s negath·e. A Ji,·er scan ,..;th !"''-labeled rose bengal ,,·as ,,-jthin normal limits. A proctoscopic e."':amination showed sacculation of the sig­moid and se,·era! di,·er.icula. A roentgenogram of the colon demonstrateC. d.h·enic-uJosis; roentgenograms of the stomach and small btMei were normal. X-ray study of the chest dis­closed fibrosis ar.d calcification in both apexes that had been present a:;d unchanged for at least 1 i yea.'>, ,,·h.ich was consistent with a pre,·iously known ruberculous infec­tion in 1920. Srudies pertinent to the patient's carcinoid syndrome are !ist.ec :n Table 2. On September 9, 1964, the skin ies.ion ,..:z.s excised, and h istologic sections r7(.ealed metastatic, Grade 3, solid carcinoma identical in structure ,,;:h the th)Toid tumor (Fig. lc ). Se,·en days late1 abdom­inal exploration re,·ealed multip le metastatic nodules, mt.a­suring up to I em. in diameter, in the right andlleft lobes of the Ji,·er. Tnere ,,-as a superficial, solitary 2-Cm. nodule in the oody of the pancreas. Both liver (Fig. ld) and pancreatic nodules ,,·ere similar in histologic stnfcture to chat seen in the thyToid gla:1d. A careful search/of the entire g-c..Strointestinal t:racet ga,·e no evidence of o/cinoid tumor,

I

246 rr..E ~EW E~GLA1'ID JOL"Rl~AL OF ~L~DTC~E July 29, 196

FtCt!RE I. Thyroid Carcinoma with Metastatic Spread (Hematoxylin and Eosin Stain X155) . a = the thyroid carcinoma. Note the regular nests of cells in a solid pattern. b = a metastatic deposit of similar tumor

in regional lymph nodu. c = a metastasis to the skin u/ the face. d = a metastatic deposit i11 the liuer.

and there was no involvement of the mesenteric lymph nodes. The appendix had been removed for acute appendi­citis in 1925. The concentrations of 5-hydroxytrypt::tmine (serotonin, 5-HT) in the metastatic lesions of the skin and liver are gi,·en in Table 2. Sero tonin was not detected in a specimen of nor.nal skin. After operation, the diarrhea and flushing continut.d, and the patient com;>la.ined of pain

in the right hip, A roentgenogram of the pelvis showed a metastatic lytic lesion involving the righ t innominate bone.

D rscussiO:-i

The '·malignant carcinoid syndrome" m this pa-

Xo. 5 }.fALIG!\:\.'\T C.·\RCJXOID S1"")."'DROME - ~10ERTEL ET AL. 24i

Am:)'s of 5-HydroxyindoZ.es and Histamine in G

"MG!ignant Carcinoid Syndrome" Associated u.:ith Noncarcir.vid Tumors.

per 24 hr.

j3.2, 41._; 42 .7, '">.7 ms. (nor­mal, <9 mg.)

:\one detect­able

:\ouc d<tect­able

10 Ulicrogm. (norrna.l, <<lO mi­crogm.)

Sot:acr.

BLOODt Ct."'TA..""1!.· OUS M.ttAS-

TASlSt

p~r mi. per gm.

0.6, 0.4 miao- 31.1 mi-gm. (nor- crogm. mal, <0.3 microgm.)

0.013 IWc:ro­gm. (nor­mal, <0.03 IDicrogm.)

Rt..P,TIC ~:;!':I!'-

Y.rl"AS• ''OL\-""0 TASJS! sru_...,._:

ptr fm.

63.3 mi- :\ O<>e crogm.. d!:-=­abl.e

5-HlAA measured by m elltod of Macfarlane et al.•; paper phic uudics of 5-bydrox)i.ndoles in ur~~ accor1iing to Smi1b,• revealed presenc.o or absence of 5-.H.J & 3-HTP. =>tioo of 5-HT in -.·hole blood ma.sured by melhod of Udto­t" t-.tion of 5-HT in lis$ue bom~enates determined ~ter pre­o! prutein.s as described b)· \\ ~h2ch et al. u foUo"'Cd br ietioo.u

definitely established. The attacks of arid the diarrhea ~,·ere both typical. Lab­results were like" -ise diagnostic, "ith con­high levels of 5-hydrox)-i.ndoleacetic aciC:

A.) in the urine and high Je,·eis of blood The onset of ·the carcinoid syndrome

to have been delayed until there were ex­hepatic metastases. ce· that this syndrome was not produced · ary carcinoid tumor is also strong, for observations, including abdominal explora­onstrated no such tumor. The most con-

ncling, however, was the very high serotonin of tumor regions that, histologically, ,,·ere e carcinoid type.

xact pathological classification of the tumor cult. Intestinal or bronchial carcinoid was

because the cells were con..c;jderably hu-ger tic figures were more numerous than would ted in a carcinoid. The time sequence in-

la prin1ary thyroidal neoplasm, with metas­regional lymph nodes one year later and spread to the lh·er, pancreas, skin of the d bone, sixteert months after the original :n. As a primary . th)TOidal lesion, the rumor resembled the subtype designated as "solid

:na with amyloid su·oma." Although zones of fibrosis were present, . classic amyloid char..ge king, and the degree of mitotic acti,-ity was at greater than in the usual carcinoma of !, but the histologic changes and the delayed netastasis did not favor a cliagnosis of ana­carcinoma of the thyroid gland. Metastasis hyroid gland from a small primary lesion in creas m ust be considered a· strong alterna-

tiYe possibility, espec:ally in ':ew of the fact that 2 of the other pre, ·iou:;l:- cited ca.<.es had a primary pancreatic adenocarcinoma. In our opinion, hO\,·­e,·er, the histology, the time Sb:!:.:ence and the pat­tern of metastatic ~pread tip?ed t.~c ~ca !es in fa,·or of a primary lesion in the thyroid g!and.

Some common denominator among the cases of noncarcinoid. tumors associated with the "malignant carcinoid syndrome" may be pre&nt. All the cases reported with known primary sources ha\·e origi­nated in ~sues deri,·ed from the entoderm of pouches of the primitive foregut - that is: pancreas, lung and th}Toid gland. T he possibility of a stem cell common to all these tumors, therefore, can be con­sidered.

Of inte...rest is the faet that 3 of the 8 patients had had other e' -idence of endocriJle hyperfunction. The p<!tient of Harrison and his associates~ had Cushing's :;:ndrorne, apparently related to an oat­cell carcinoma of the lung since the adrenal glands were normal at autopsy; the S2.Ille tumor presumably was responsible for the patient's '·malignant car­cinoid syndrome." The patient of '\-an der Veer and his co-workers! had an insulin-producing, malignant islet-cell twnor and had well documented hypogly­cemic attacks, the sa.rne rumor seemingly producing a carcinoid :;:-ndrome. The patient described abO'\·e had a parath~TOid adenoma "-ith hypercalcemia and was assumed to ha,·e hyperparath~Toidism. Al­though the possibility of coincidence cannot be de­nied, the odds against 3 such examples of endocrine hyperfunction oc~.ng by chance among 8 patients chosen at nmdom seem tO be a_~onomically high. Furthermore, a similar association of hyperfunction­ing end~rine tumors has been noted " itb bron­chial carcinoid rumors, 13 also derived from the prim­itive foregut.

As more cases of this kind are s:udied, these prob­lems mar be clarified.

A case im·oh-ing a metastatic 50lid carcinoma that was assumed to ha,-e its origin in the th)TOid gland and was associated ,,;th high rumor serotonin con­tent, hyperserotonemia and a "malignant carcinoid syndrome" is reported. In this ca.....;e a parath~Toid adenoma and byperparathyroidis::n were also noted.

Of the 8 cases (including the present case) of ·'malignant carcinoid syndrome" associated "ith noncarcinoid tumors no"· reported, 7 in ,,·hich the , pr.mary rumor " ·as kno,,-n rook origin in tissues/ ¥>-ith a common embn·ologic anlage. Three of these 8 patients also had ~ther condicioru of endocrin~ hyperfunction. ; '

R:r:rr:ru:..~cES

I. Mdfuilen.' F. F., Jr . . :wd H.aruoo, a H. Excessi-"t uru.J 5-h~dro.~·-3-iodoJt! a~tic acid i:l a.bseoce <i_ me-wtatic carcino:cl

c;,...,.... " '"""'· ''"'· I .

2-i-8

2 Dencer, H. Ar:o;>;.6~ Ca--cinoidsrndrom mir v~!!nn -~.,._ schetdung von 5-H!C:-ox-;ioeoles!i!!S"\!tt bei P=l._~inom. K lrn. W ch lt.Ich r. 37 :12-+5-12.;3, !959.

3. \~ Ce-r V~r-.. f. 5 . . "!t a!. ~le!:1SusisinJ ~lct-<e-11 ruroour c-i p3ttcre::u a.ssoci:ued •-.-ith h~~ and c:::Lrcinoid ~"Tldro~- 1A1tc1t I : H i"-1+19. !9';+.

4. Fbrri.«>n. ~- T ., ~Ionqomay, D. :\. D., R:>..ll:lky, A. S . . Robert­son , J. H .. and \ ' e!b-OOLrn . iL B. Cu~h.in!<"s S)-ndrome -.,; u, carci­noma. of brooci:n!$: and wit:b ieal'll.N!S suggesting carcinoid tumour. l..cnu t 1:23-25, 1357. -

5. ,,~illi3ms. .E. D~ and .-\z:zooudi. J. G. Tumours of l=g and car­cinoid sy:xlrome. T lwr= IS :3:l-36, 1960.

6. Qo,.·enlock.. A. H., Platt. D. 5 .. CunpOdl, -~- C. P .. and Worms!~. K . G . O:u<eD c::>.rO>oma of bronchus S«nting 5-l>;d;oX')'tl'"fptc>­plwl.. Lmtut 1 :3M-Sf..6, 1~-

7. S mit!>. A. ~ •• a al. Further obseJ-,..,.cioJ:IS 0 11 endoa'..ne ~ of argu t:lffinom:;o.. S=t:Wt: M . ]. 2 :2+--33, ~i.

July 29, 196)

3. ~be_£7!an.e. P - S., er al. E nd_ocn ne ~ o_l ~ntaffinoma • 'P~i"' =rr.:::~ce <() us.. of . ~na..ry >-ny~o~_ndolt<lcetic •cid -:;t "'-"!'oM .:1 c t:.gnostS. Scotttsn .\f. / . I : , -13- IJJ , 1956.

9. Smtth. I. C Ju ,Jmtttotraphic t:!'l d lltt!Mphf,die T , cJ111iquu Vtl,. 1.. 51i }'? - ~~w \_'~rk: lnterscit nce. 1~_.. • ·

10. {;d<nlnend, :> •• II etssbach. H., and BI"'<!tc. B. B. Assay of ...-.,. n in 3nd : tl.:ttetl metabolic.,;. enl}'"l'nc> and dnn<S. In Glici, Ll .\fttirods oi Biochemical d nalyris. Vol. 6 . "•w York · Inte~ 1953. P. 95. - •

I I. Weissba0. H., W~alkes. T. r: .. an~ vdeofnend. S. SimpliSo.! rot·t ht:-d tor .mf'3Su.nn$ set:o torHn 1n. t"s$$Ud: Simultaneous a.ss.t• d both serotom:o and h<S!o.rnmc. ] •. Brol_. Cht m. 230 :805-871 , 1954.

! ~ . Bogd•n>ki. D. F., Pler.scher, :\ .. Broclie. B. B., and l,;denfriend, S. fdtntifia;:'on and as;"Y of ~erotonin in brain. ] . Pltar-ol. ;,' E.xper. Tur~p- 117:8- -88. !9J6. •

13. WiUb.ms. E. D., and Cd ostin, L. R. Association o£ bronC;.; c:>rc-i!loid = d plurig'.andul:tr adenoma1osiJ. Thotaz 17 :1~127.. 1962.

V ASCUIAR LESIONS CAUSING HYPERTENSION IN NEUROFIBROMATOSIS*

MoRDECAI R .u.PERN, -~LD.,t Al'o""D Gumo CuRRARINO, M.D.t

NEW YORK CITY

NE'l'"ROFIBRO~B.TOSIS is a congenital and heredita-ry cfuorder involving ectodermal, neu­

roectodermal and mesodermal ti.s:.--ue. Cafe-au-lait spots, cutaneous neurofibromas, tumors of the cen­tral and peripheral ner\"ous systems, skeletal cilanges of scoliosis, orbital-h·all defects, pseudarthrosis and gigantism are ~well known manifestations.

The occurrence of vascular lesions is less well known but has been described by a number of authors.~-+ These va_-<.eular changes are said to pre­dominate in the kidne~-s, endocrine glands, heart and gastrointestinal rrac:, and ma~- lead to arterial stenosis or obliteration of the ar.erial lumen. Wh en these "·ascular lesions oi neurofibromatosis involve the abdominal aor ..a or the renal arteries systemic arterial hy;:>ertelliion rna~- result.

Two recent cases of neurofi bromatosis, hyperten­sion and renal-artery srenosis ba,·e been studied a t the Xew York H o:.--pital. We have also obtained additional information by re'l.i e,ying the case report­ed from thi5 w.stirurion by Gl.enn et a J.S in 1932. We ha,·e been able to find only 7 similar cases in the literature, the details of which are gi'l.·en in Table 1.

C -\.SE REPoRTS

C ... SE; 1.~ A 19-year-old woma n presented ger:eralized neurofibroma tosis maniiested by caie-au-!ait spoLS, m ulcipl!' neurofibromas a nd m ocerat.e scoliosis. ~!u lriple facial he­mangiomas present a t bir.b !a ter coalesced to crea te dis­figuration requiring~ r epe:it:r:e !acial surgery. Se,·ere sys temic hrpertension i.'1 the ra:-:ge oi 230/120 in th e upper ex­tremi ties and 150/ 120 in ±e !o" ·er extremirie;; had been recognized for 10 yea:-;;. I mra·.·enous and rerro~ace aortog­raphy re,·ealed a fu.; iiorm narro,,-ing oi the lowe!' moracir a nd pro:--.. imal a bcion ina l :u:.:-;a ir.·:ohing L~e ceEac ?-xi->, ,,; th extension do,,·:l o:o ~e re::~l a.."teries. .-\ large a.TJeurysm <l f the proxlica! portion of t::e right renal artery ,_..;.~ p re;em.

Operation co mi..,-.:ed of a ~:--pass of the coarcted segment

•From the Departmen t of RX:o!ogy, " • "· York Ho,7it21--Cornell ~fccii...a.l C<m er. ~c!•d by a ~t irom the ' ' rut•ha!l Fou.ndatioo.

t .\l$ocl.'1te p:o[d>C,r oi n>diology, Cornell l:ni,·ersk~- ~!e-dical Coll•ge. !P....eviously rr~on-e-d by Glenn rot ar.s

of the aorta utilizing the splenic artery. A tuft of den.sd. adherent fibroric tissue surrounded a nd constricted the aom at the le•·el oi the 11 th and 12th thoracic segment5. IE. tologically, thi.s was composed of fibrous and nerve tissur diagnosed as neurofibroma. Xo a ttempt was made to li.J> preach the renal-artery a neurysm. After operarion the blood pressure '~as recorded as H0/ 90 in th~ arms a nd 1+0/ 100 in the legs. O ne year later the patient died of cardiac arrest after plastic surgery for: a facial neurofibroma.

CASE 2 . .-\n 18-year-old boy has had 19 admissioru ro the Xe"· York H ospital for con·eccion of disfiguring fl::i.lll neurofibromas. Facial "hemangiomas·· present at birth tn­larged and coalesced during infancy. and biopsy at -! )"CW

of age revealed ·a plexiform nturom.:l.. Xumerous cafe-w­lait ;pots were present over the bod:·. T he patient's mother also had neurofibromatosi; . Hypertension was first notrti a< the age of 3 Yz years, and in recent }"ears the Olvod pressure had ranged from H S/ 56 to 193/ 130. T he systc:nUc arterial hypertension had been rel:nh·eiy unaffected oy anli­hn>ertensi,-e therapy during the last 5 yea rs.

Pertinent studies performed during the repeated hospiol admissioDS re,·ealed no1mal excretory urograms at the <1!"< of -! and at the age of 12. Fractional intravenous and ~m> grade pyelosrrams a t 13 a nd H years of age were normal .-\t that ~e a radioisotope renogram ,,·as interpreted lla

gi,·ing no e..-idence of unilatt ral reno,·ascular dysfu."lctoc:. Differential renal-function studies "·~re normal at LI-te ~ga of 1-! and ! 8. .-\.11 biochemical and bbrorarory studies, iD­cluding an a ngiotensin assay. were within nonnal limiD:

O n percu:aneous tramfemoral renal aortography iDtl selecti,·e renal arteriography performed in 1963 (Fig. l l the proximal half of the r ight main renal artery was ~ sent. R enal o!ood flow on this side ,,as provided br ~ lateral char.nels from the 12th intercostal artery, the m­temal spermatic artery and the retroperitoneal renal arte~ plexus. Stenosis of the left maio rena l artery, witil ! aneurysms distal to rhe stenotic segment. was ob;e!\tli Operat ion "a; contraindicated by rr.e complexity of U:< rer.al arterial lesions.

c .... s::: 3. :\. 3~ -year-o !d girl \\"l'.S admitted to the ;-;.-. York Hospi:al in 196+, when systemic arter ial h~·peneniia:> { IJ!ood prem ue of !50/ 11 0 ) ,,·as detected during the coun< of rout in~ ioJ.:-_.-.,·-up observation of a kuo" n srstol ic munu111

of no defi:U;e significance. Birth and ce,·ebpmeut haJ !:«-> nor:na l. Caic-au-iait spots were pr.-sent o\·er the trunk ;u;G

extremirie~, ·,,·irhout as3ociated skin ::odulcs. .-\ comp:c~r radio;: raphic s~eleta ! exai'T'inat ion rc\ ealed mild sc."\Uup~ of the ante:ic·r margins of rhc -!:.b through 9th th.J~ segments. Tn~ patient's father a !3o showed caie-au-b>: spots but no other m anifestation oi neurofibromatOsis.

Routine !?.hora tory swdie$, blood chemical findings ~...! c:ucchol amine de termina tions " ·ere ,,·1thin nonnal li!tu~ Fractional intravenous pyelography showed normal anc