Diagnostic and surgical aspects of insulinoma

Diagnostic and surgical aspects of insulinoma

Diagnostic and Surgical Aspects of lnsulinoma A Review of Twenty-Seven Cases Clayton H. Shatney, MD, Minneapolis, Minnesota Theodor B. Grage, MD, Min...

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Diagnostic and Surgical Aspects of lnsulinoma A Review of Twenty-Seven Cases

Clayton H. Shatney, MD, Minneapolis, Minnesota Theodor B. Grage, MD, Minneapolis, Minnesota

Langerhans described the pancreatic islets in 1869, but it was not until 1902 that the first tumor involving these cells was reported by Nicholls [I]. In 1908 Lane [2] described the alpha and beta cells of the islets and suggested that each cell type had a separate secretory function. After the discovery of insulin in 1922 [3], Harris [4] in 1924 introduced the concept of hyperinsulinism. In 1927 Wilder et al [5] reported the association of hyperinsulinism and hypoglycemia in a patient with a metastatic islet cell tumor of the pancreas. The first surgical cure of an insulinoma is credited to Graham in 1929 [6]. More than 1,000 cases of functioning beta cell tumors have since been reported in the world literature [ 7J. This paper reviews twenty-seven cases of insulinoma seen at the University of Minnesota Hospitals and all other major hospitals in Minneapolis and St. Paul from 1934 to 1973. Both autopsy and case records in eighteen hospitals were examined for this study. From the Department of Surgery, University of Minnesota Hospital, Minneapolis, Minnesota. This work was supported by USPHS Grant CA-08832 and American Cancer Society Clinical Fellowship. Reprint requests should be addressed to Dr Shatney, University of Minnesota Hospital, 412 Union Street S.E., Box 273 Mayo, Minneapolis, Minnesota 55455. Presented at the Fourteenth Annual Meeting of the Society for Surgery of the Alimentary Tract, New York, New York, May 22 and 23, 1973.

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Incidence Functioning beta cell tumors are rare. They are found in only 0.08 per cent of routine postmortem examinations [8]. However, because most patients are successfully diagnosed and treated, autopsy figures do not represent the true incidence of this neoplasm. Of 549 cases collected by Moss and Rhoads [9], only seventy-four (13.5 per cent) were discovered at autopsy. None of the insulinomas in the present series was found at autopsy. Thus, the precise incidence of this entity is not known. Pathology This study uncovered sixty-seven patients with pancreatic islet cell neoplasms. (Table I.) Thirtyone persons (46 per cent) had nonfunctioning tumors and thirty-six (54 per cent) had functioning neoplasms. Twenty-seven patients (40 per cent) had insulinomas, all of which were discovered at surgery, and nine (13 per cent) had Zollinger-Ellison tumors. Insulinomas are small. The average diameter of the forty tumors in our twenty-seven patients was 1.75 cm. (Table II.) Twenty-five patients (93 per cent) had tumors less than 3 cm in diameter and thirty-eight (95 per cent) of the neoplasms were less than 3 cm in diameter. There was no correla-

The

American

Journal

of Surgery

tion hetweet\ tumor size and severity of symptoms. The largest neoplasm in this series was malignant, but there is no correlation between size and malignancy 191. The distribution of functioning beta cell tumors of the pancreas is shown in Table III. Of those lesions found in the gland, 66 per cent are situated in the body and tail and ‘i0 per cent occur distal to the mesentcric vessels. Two per cent of insulinomas are located outside the pancreas. the most frequent ectopic site being in or around the duodenum 191. None of our patients had ectopic tumors. Five patients had multiple adenomas, a rate slightly higher than the 14 per cent rate generally quoted [7,91. The number of tumors in four of these patients ranged from three to seven. The fifth patient (KW) had adenomatosis of the body and tail. Grossly. insulinomas are yellow or reddish brown in color. Although these neoplasms appear to be encapsulated and sharply demarcated from the surrounding pancreatic tissue, they can rarely be dissected along a clear plane of cleavage [8]. On cut section the tumor has a smooth, homogeneous texture. unlike the lobulated appearance of the normal pancreas. The consistency is somewhat firmer than that of the surrounding pancreas, but this difference is not great enough to be helpful in localizing small. deeply seated tumors during surgery. Microscopically, insulinomas consist of cells of similar size arranged in anastomosing strands one to a few cells thick. Between the cords of cells, capillaries and vascular sinusoids course in abundance \rO]. Associated with the capillaries is a thin fibrous framework, which ultimately condenses to form a capsule of variable thickness. The histologic characteristics are essentially the same in both benign and malignant insulinomas. Even with ultramicroscopy no difference is found [II]. Despite the efforts of some investigators [8,9] in the past t.o determine malignancy by histologic features alone, at present the sole criterion for malignancy is the demonstration of metastases [12]. Only one of our patients had a malignant insulinoma. In larger series a 10 per cent rate of malignancy has been reported [9,13]. Clinical

Data

Functioning beta cell tumors can occur in patients of any age, but they are uncommon in patients in the extreme age groups. TO date just over forty cases have been reported in children under age sixt,een. including nine neonates [14,25]. There

Volume 127, February 1974

TABLE I

Classification Category

of Patients with Islet Cell Tumors Benign

Mal!gnarlt

Found at surgery Found at autopsy Total

38 17 55(82%)

12 0 12(18%)

Nonfunctioning Functioning

21

10

26 8

I 1

lnsulinoma Zollinger-Ellison Total

tumor

TotalC; 56/74.60/,) 17 (25.4%) 67 31 36 !I 9 67

__ were three neonates and two children iamong our twenty-seven patients. The median age of the adult patients was fifty years. (Table II.) In larger studies the peak incidence has occurred in the fifth decade of life, followed by the fourth and sixth decades [9]. There is no correlation between the age of the patient and malignancy 19,131. Insulinomas occur with equal frequency in males and females. and there is no sex predotninance with malignant neoplasms [9,1X]. In our series there were fifteen male and twelve fetnale patients. Psychiatric and neurologic symptoms are the predominant and most dramatic manifestations of this entity [26], and many patients are initially evaluated by the psychiatric and neurologic services (I 71. The signs and symptoms may be priswea.ting, and autonomic (weakness, marily tachycardia) or cerebral (confusion, convulsion, and paralysis) in nature, or both. In our patients, the symptoms were as follows: syncope (unconsciousness), fourteen patients; mental confusion, fourteen; convulsions, ten; weakness, nine; bizarre behavior, seven; slurred speech, six: diaphoresis, six; lethargy, six; visual disturbances, four; ataxia, three; cyanosis (newborn patients), t‘hree; lightheadedness, three; tremulousness, three; incontinence, two; paresthesia, two; amnesia, two; uncontrollable behavior, one; headache, one; hemiplegia, one. Although most patients do not become sympt.omatic until the blood glucose concentration is less than 50 mg per 100 ml. it is the rate of full of the blood glucose, not the lowest level attained, that is the determinant, factor in the symptom pattern in each patient [9,18]. If the decrease in blood glucose is rapid, autonomic symptoms predominate. The mechanism of symptom production is thought to be compensatory hyperepinephrinemia. When the blood gluco:ie level f’alls slowly over a few hours, the manifestations are primarily cerebral in nature due to direct effects of hypoglycemia on the central nervcms syst.em. “If the decrease in blood glucose is rapid, profound, and persistent, the initial symptoms due to

175

Shatney

TABLE

and

II

Grage

Clinical

Data in twenty-seven

Duration of Symptoms

P%t Hospital* PH/UMH LW/UMH WB/UMH SR/UMH M K/NWH HA/UMH

1934 1934 1936 1940 1945 1947

28, 37, 11. 37. 48. 52,

M F M M F F

GSfUMH AS/UMH

1951 1953

20, F 52, M

IS/AH ND/UMH GS/UMH EL/MVAH RZfUMH

1957 1959 1960 1964 1964

73. 63, 10. 46, 18,

with Functioning

Beta Cell Tumors

tlz?

Whipple’s Triad

Glucose Level

Glucose Tolerance (mg/lOOml) Test

... ... ... ... ... ...

... ... ... . .. . .. ...

Palpable tumor in tail Tumor visible in body Palpable tumor in head Fullness in uncinate Tumor visible in body (1) No tumor

5 yr

..* Present

24 25

Positive ...

... ...

... ...

(2) 1955: no tumor Tumor in head Three tumors visible in tail

3 yr 10 yr 1 yr 3 yr 30 mo

Present Present Present Present Present

18 27 25 23 18

... Positive Positive Positive Positive

. . Positive . .. Positive Negative

. .. ... 0.404 . ..

32 mo

Present

25

Positive

Negative

0.326

(2) No tumor

Present Present Present Present Present Present

6 32 23 30 23 22

... Negative Positive Positive Positive Positive

Positive . .. Positive . .. ... ...

0.233 ... . .. . .. ... 0.170

No tumor Tumor in Tumor in Tumor in Tumor in No tumor

... ...

Positive . ..

0.260 . ..

Positive

2.153

Tumor in body Tumor in body and mesocolon Tumor in body and mass at gastroesophageal junction No tumor Tumor in body Tumor in tail Nodule in head (1) No tumor

SA/MH

5 wk 2 yr 6mo 4 yr 3mo 4mo

MS/UMH MP/UMH

1968 1968

51, F 64, F

4 yr 3 wk

... ...

25 18

H K/M’JAH

1970

62. M

18 yr

Present

37

Positive

KWfNMH AJ/MMC TS/UMH LS/UMH JA/UMH

1970 1970 1971 1971 1972

9 hr. F 71. M 46. M 64, M 3 days.

9 hr 8mo

Present Present Present Present

10 36 27 35 16

... Negative Positive Positive ...

M

Operative Findings

Negative . .. . .. Positive Positive ...

5wk.F 34, M 56, F 67, M 29, M 25, F

JJ/~~vAH

Lowest Glucose : Insulin Ratio

15 31 41 32 32 15

1964 1965 1966 1967 1967 1968

LG/UMH AS/FH MY/MH DL/CMH

Tolbutamide Test

Present Present Present Present Present Present

3 Y’ 1 Yr 17 mo 2 Yr 5 yr

F F M M M

Patients

1 Yr 40 mo 2 days

... ... ... . .. ...

. ..

0.124

... 0.622 0.551 0.633

Tumor Tumor Tumor Tumor (1) No

palpable in head palpable in uncinate palpable in uncinate palpable in body tumor

body tail tail tail

(2) No tumor * AH, Abbott Hospital; Minnesota Hospitals.

CMH. Charles Miller Hospital;

FH, Fairview Hospital; MH, Methodist

excessive circulating epinephrine merge with those of cerebral glucose deprivation” [18]. Virtually all of the attacks in our adult patients were associated with a blood glucose concentration of less than 50 mg per 100 ml. The lowest recorded blood glucose level ranged from 6 to 41 mg per 100 ml, with a mean of 26 mg per 100 ml. (Table II.) Not every patient was symptomatic at the time of the lowest blood glucose level and almost every patient experienced attacks at higher levels of blood glucose than the lowest recorded value. Despite the considerable variation in the blood glucose level during an attack, the symptom complex was quite consistent in each patient. As reported in other studies [13,19], our patients experienced recurrence of attacks with increasing frequency and severity the longer the tumors were present. All adult patients had at least monthly episodes, and twenty-one reported weekly episodes of hypoglycemic symptoms. Attacks usually occurred after either fasting or strenuous exercise.

176

Hospital;

MMC. Metropolitan

Medical Center;

During the daytime the symptoms appeared before breakfast or just prior to the next meal. Only one patient experienced nocturnal episodes, and these occurred around 3:00 am. Among the adults the duration of symptoms prior to diagnosis varied from three weeks to eighteen years, with a mean of forty-one months and a median of thirty-three months. (Table II.) Reasons for the delay in diagnosis included: (1) the initial infrequency of the attacks and discovery that symptoms could be aborted by the ingestion of food, which deterred patients from seeking help earlier; (2) failure of the initial examining physician to consider the diagnosis of insulinoma; and (3) faulty interpretation of laboratory data, poor selection of diagnostic tests, or both. Failure of the physician to consider the diagnosis of a functioning beta cell tumor is common. Breidahl, Priestly, and Rynearson [I7] reported that 51 per cent of their patients were initially misdiagnosed. In thirteen of our patients the ini-

The American Journal 01 Surgery

lnsulinonfa

Pabent and Hospital*

Operative

Location of Tumor

Procedure

PH/UMH LWjUMH

Resection

of tail

Tail

60%

pancreatectomy

Body

WB/UMH

Enucleation

SRfUMH

Blind

MK/NWH

Enucleation

HAjUMH

Blind

707*

Total

pancreatectomy

GS/UM

H

distal

and

distal

WhIppIe

of tail enucleation

of tail

Body Body

2

7mm

Head

1

Head

1

Tail

4

3 mm 1 cm 8 mm, 1 cm. 1.5 cm, 1.8cm 2.4~~ 1.8cm 2cm 1 cm

IS/AH

Enucleation

and

cholecystectomy

Head

1

ND/UMH

Enucleation

and

gastric

Unclnate

1

U ncinate

1

Body

1

GS/UMH

Enucleation,

EL/MV&H

80%

R7fUMH

Blind

dtstal

60%

distal

polypectomy pancreatectomy

pancreatectomy

65%

distal

Pathology

1.2 cm 1 cl”

Uncinate

procedure

Size of Tumors

1 1 1 1 1

Head

then

pancreatectomy

distaf

Resection

AS/UMH

resection

pancreatectomy.

Number of Tumors

Results

Adenoma

CUW

Adenoma

Cure

2 cm

Adenoma

Ctlre

8mm

Adenoma

Cure

Adenoma

CUE

Adenoma

Adenoma

Still has symptom:; &Ire Cure Cure

Adenoma

Cure

Adenoma

Cure

Adenoma

Cure

Adenoma

Cure

2.3

cm

Adenoma Adenoma

Still

pancreatectomy

Length of Fo~pu”dvup 3 yr, 9 mo 3 Y’ 19 mo 24 yr 9 Y’

3 Yr 14 yr 5 yr

10 yr 1 Yr 4 Yr 8yr has

sympton15 Blind

subtotal

pancreatectomy.

then

enuclea-

1

1.5 cm

Adenoma

Cure

Body

1

6mm

Adenoma

Cure

Body

1

1.4

cm

Adenoma

Cure

cm

Head

7 yr

t1on LGfUMH

Blind

AS/FH

Enucleation

MYIMH

Resection

of tail

Tail

1

5.5

Adenoma

Cure

DLfCMH

Resection

of tail

Tail

I

3 cm

Adenoma

Cure

JJ/MVAH

knucleation

Tail

1

1 cm

Adenoma

Cure

SAfMH

Blind

1

Microscopic,

Adenoma

Cure

80%

50%

distal

pancreaiectomy

distal

pancreatectomy

Body

and

tail

8 Y’ 1 ,110 I mo 7 mo 5 yr 1 mo

4mm MS/UMH

Enucleatlon

MP/UMH

80%

HKfMVAH

8O(r, distal

distal

pancreatectomy,

transverse total

and

descending

pancreatectomy

gastectomy 80%

splenectomy.

1

1.5cm

Adenoma

&Ire

1

13 cm

Carcinoma

Asymptomatic

4 Y’ 4Yr

Body

4

2-4mm.lcm

Adenoma

Cure

2 Yr 18mo lrTl0 14 mo 18 mo

colectomy and

distal

splenectomy;

esophagectomy and tail

Microscopic

Adenoma

Cure

2.2 cm

Adenoma

Cure

Tail

1

Cure

1

1.5cm 2cm

Adenoma

Head

Adenoma

Cure

Blind

Enucleation

Body

TS/UMH

Erlucleatlon

LS/UMH

Enucleation

JAfUMH

Blind

distal

pancreatectomy

1

KW/NMH AJ/MMC

80%

distal

and

Body Body

Body

Multiple

Still

pancreatectomy

has

symptoms Blind MVAH.

Minneapolis

subtotal Veterans

3mm

pancreatectomy ~ ~_ ..~ Administration

Hospital;

NMH.

North

tial impression was incorrect, the most common diagnosis being a psychiatric disorder (five patients). Other diagnoses included: functional hypoglycemia, two; seizure disorder, two; cerebrovascular accident, two; brain tumor, one; vertebral or basilar artery insufficiency, one; drunkenness, one. One patient was labeled a schizophrenic for eighteen years, until an insulinoma was discovered. Such a delay is hazardous, because the longer a functioning beta cell tumor is present, the greater the risk of permanent brain damage or death [9,13].

Diagnosis h Adults. Historically, the onset of hypoglycemic symptoms during the fasting state or with with relief by food ingestion, should exercise, arouse suspicion of an insulinoma. In addition to further inquiries about these symptoms the physician should attempt to illicit a history of familial

Volume

127.

February

1974

Memorial

Hospital;

NWH,

Adenoma Northwestern

lmo

Cure Hospital;

UMH,

UniversrtY

of

multiple endocrine adenomatosis (MEA), which has been associated with insulinoma [23,20]. None of our patients had MEA, but six (22 per cent) had a history of either a thyroid nodule (three patients) or diffuse glandular enlargement with hyperfunction (three patients). The physical examination is useful. primarily to help rule out other causes of hypoglycemia. (Table IV.) Obesity is a consistent finding with insulinomas, and it was present to some extent in most of our adult patients. Because of the effects of repeated hypoglycemia on the central nervous system, some patients will exhibit brain damage when initially seen [9, I
177

Shatney

and

Grage

TABLE IV

Location of lnsulinomas*

TABLE III

Number of lnsulinomas Filipi’s Site

Series

Head Neck Body Junction of body and tail Tail Ectopic Total * Including

Present Series

Total

Percentage of Total

300 42 263

9 1 14

309 43 277

29.2 4.1 26.2

61 332 20 1,018

3 13 0 40

64 345 20 1,058

6.0 32.6 1.9 100

data from the series of Filipi and Higgins

171.

>5.0 5.0

I. Inadequate glucose supply A. Starvation B. Excessive loss from body (urine, stool, milk) C. Excessive utilization (fever, exercise, neoplasm) II. Hepatic disorders A. General dysfunction (cirrhosis, hepatitis, circulatory deficiency)? B. Enzyme defects 1. Glycogen storage diseasesf 2. Fructose-l-phosphate aldolase deficiency (hereditary fructose intolerance) 3. Galactose-l-phosphate uridyl transferase deficiency (galactosemia) 4. Glycogen synthetase deficiency (aglycogenosis)f 5. Maple syrup urine disease (branched-chain ketonuria) 6. Familial fructose and galactose intolerance 7. Ketotic hypoglycemia of childhood-i III.

l?

4.0

.

.t 7 E 3.0 Z 2 8 (3 1 2.0

. 0 a.

1.0

P. . .

;”

:

-.

‘@ -

G.S. R.Z.LS S.A. M.S.K.W. H.K. IS. J.A.L.S. Potrent

Figure 1. Blood glucose:ptasma insulin ratios in ten pati&ts with insulinoma. 0 = preoperative; 0 = postoperative.

Causes of Hypoglycemia*

Increased secretion of insulin A. Beta cell tumor of the pancreas-f B. Epithelioid tumor derived from foregut anlagef 1. Pancreatic islet cell tumor producing insulin and other peptide hormones 2. Ectopic insulinoma 3. Carcinoid tumor producing insulin C. Alimentary hyperinsulinism D. Early diabetes mellitus (reactive hypoglycemia in early, mild cases) E. Leucine hypersensitivity of infancy and childhoodf F. Hypoglycemia in newborns of diabetic mothersf G. Erythroblastosis fetalisf

IV. Hormone deficiency A. Hypopituitarism (ACTH and growth hormone)? B. Adrenocortical dysfunctionf 1. Addison’s disease 2. Secondary to hypothalamic-pit&tary dysfunction 3. Enzymatic defects of glucocorticoid synthesis C. Catecholamine deficiency D. Hypothyroidism E. Glucagon deficiency V. Drug-induced A. Insulin administration (factitious B. Hypoglycemic sulfonylureasf C. Ethanolf D. Other agents

or iatrogenic)?

VI. Causes with undetermined mechanism of action A. “Functional” hypoglycemia B. Massive extrapancreatic neoplasmsf C. Transient hypoglycemia in newborns of low birth weight? D. Infantile gigantismf E. Idiopathic hypoglycemia of infancy and childhood (McQuarrie’s syndrome)f

Figure 2. Visualization of a functioning beta cell tumor by celiac and superior mesenteric arteriography (patient HK).

178

* Modified from Conn and Pek [78] and Williams, and Hume (23). t Indicates fasting hypoglycemia.

Bryson,

The American Journal of Surgery

Insullnoma

case concentration of less than 50 mg per 100 ml during an attack; (3) relief of symptoms by the administration of glucose [22]. Blood samples should be drawn early in an attack, since later samples are less likely to reveal the true level of hypoglycemia due to hepatic glycogenolysis [22]. Although most patients with insulinoma will manifest Whipple’s triad (Table II), it is not absolutely diagnostic of a functioning beta cell tumor [9]. Thus, in addition to further tests for insulinoma the appropriate laboratory and radiologic studies should be performed to rule out other causes of hypoglycemia. (Table IV.) The best test for establishing the diagnosis of insulinoma is a seventy-two hour fast with periods of exercise, during which multiple blood samples are analyzed for glucose and insulin [I3,23]. This test has a high degree of accuracy and is also safe for the patient. A positive response to fasting is the development of symptoms associated with a blood glucose concentration of under 50 mg per 100 ml. with relief by glucose administration. About 65 per cent of patients will become symptomatic within the first twenty-four hours, and 95 per cent will experience hypoglycemic symptoms within the first forty-eight hours [13]. Eight of our patients were subjected to a prolonged fast. Four experienced an attack during the first twenty-four hours, and seven became symptomatic during the first forty-eight hours. The eighth patient experienced symptoms at fifty-two hours. Diagnostic accuracy is enhanced by the concomitant measurement of fasting blood glucose and plasma insulin concentrations. Glucose:insulin ratios are calculated to determine if the plasma insulin level is inappropriately high for the blood glucose, that is, if hyperinsulinism is present. Multiple fasting blood samples should be drawn over at least three days to maximize the chances of demonstrating hyperinsulinism. Fasting glucose:insulin ratios were determined in ten of our patients. (Figure 1.) The mean of the lowest ratios (Table II) was 0.548, with a median value of 0.365. Fasting plasma insulin concentrations by themselves should not be used in evaluating a patient, since even with multiple samples an increased level can be found in only half the patients with insulinoma [24-261. If the fasting plasma insulin level is compared with the simultaneous blood glucose concentration, however, hyperinsulinism will be found in 90 per cent of patients with functioning beta cell tumors at some t.ime during their evaluation [24].

Volume

127, February

1974

Although the fasting glucose:insulin ratio is a valuable determination, there has not heen general agreement on which level is diagnosl:ic for insulinoma. Data from Floyd et al [2ri] and Grunt, Pallotta. and Soeldner [27] suggest that a ratio of 2.5 or less should be diagnostic. In the present study all ten patients had at least one ratio below 2.5, and in nine it was consistently below 1.5. Currently at the llniversity of Minneisota Hospitals a ratio of 1 or less is considered “absolutely diagnostic” for insulinoma, and a value of :! or less is considered “probably diagnostic.” Perhaps in the fut,ure the measurement of plasma proinsulinlike material will further simplify the diagnosis in these patients [28]. If a prolonged fast and mult.iple fasting glucose:insulin ratios are not conclusively diagnostic, it may be necessary to proceed to an intravenous tolbutamide tolerance test 129,301. Three of our adult patients had both pre- and postoperative tolbutamide tolerance tests. Three adNdit.ional patients had the test in the preoperative period only. Of the six patients studied preoperatively there was one false-negative result. Of a total of ten tests performed both pre- and postoperatively, there were two false-negative results and one false-positive result. It was necessary to stop the performance of the test prematurely in two patients because of severe hypoglycemic symptoms. Thus, in our experience and that of others [ 13,181, the intravenous tolbutamide tolerance test has an accuracy of 75 to 85 per cent with at least a 10 per cent incidence of false-negative results. Other stimulatory tests which have been advocated in the diagnosis of functioning beta cell tumors were not helpful in the present series. An overnight fast does not provide useful diagnostic information, because many patients with insulinoma will have normal blood glucose levl?ls [13]. The glucagon test and the leucine sensitivity test do not conclusively establish the diagnosis. since they give positive results in only 50 and 70 per cent, respectively, of adults with insulinoma [18,2.5]. A glucose tolerance test is also not useful, since patients with other disturbances in glucose metabolism may show responses similar to 1 hose seen in patients with functioning beta cell tumors [22,23,32]. In all patients suspected of having an insulinoma, celiac and superior mesenteric arteriography should be performed. Angiography can both confirm the diagnosis of a functioning beta cell tumor and localize the tumor for the surgeon. (Figure 2.)

179

Shatney and Grage

Arteriography has a reported diagnostic accuracy of about 70 per cent, with a 4 to 5 per cent rate of false-positive diagnoses [32,33]. Localization of the tumor depends on several factors including tumor vascularity, size, and location. The most important over-all factor is the degree of vascularity of the neoplasm [IO]. Tumors as small as 1 cm in diameter have been demonstrated, and the visualization of multiple adenomas has been reported [34]. Tumors at the extreme ends of the gland are the most difficult to localize, since the vasculature of the duodenum and spleen tends to mask either the tumor blush or displacement of normal pancreatic vessels by the neoplasm or both. Although to date tumors have been demonstrated in only two of six patients at our institutions, arteriography is strongly recommended in all patients suspected of having a functioning beta cell tumor. At its present stage of development pancreatic scanning is not helpful in localizing an insulinoma [22,23]. Scanning was employed in only one patient in this series and was unsuccessful in demonstrating the neoplasm. In Children. The diagnosis of insulinoma in infants and children is difficult, because these patients react inconsistently to stimulatory diagnostic tests. In addition, children with idiopathic, leucine-sensitive, or ketotic hypoglycemia may respond to intravenous tolbutamide in the same manner as may children and adults with insulinoma [14,24,35]. The leucine and glucagon tests are also not reliable diagnostic aids, because children with other forms of hypoglycemia may exhibit the same responses seen in children with functioning beta cell tumors [14,25]. Insulinoma in an infant is usually manifested by convulsions or cyanotic episodes. All three of our newborn patients exhibited these signs. Characteristically, the hypoglycemia is very resistant to the usual therapeutic measures, and the infant may rapidly progress to unconsciousness and even death during an episode [14]. In older children the history is frequently helpful, since hypoglycemia tends to occur in the fasting state. Such was the case in our two children. The presence of Whipple’s triad in children does not aid in establishing the diagnosis of insulinoma, since children with idiopathic hypoglycemia can also manifest the triad [14]. The age of the child is somewhat helpful. In general, hypoglycemia is a frequent occurrence during infancy and early childhood, and a functioning beta cell tumor is a rare cause. Prior to

180

this writing only eleven cases of insulinoma in children under four years of age had been reported [14,15]. In children over four years of age spontaneous hypoglycemia is uncommon, and insulinoma is a more likely cause when it occurs [23]. Although Mann, Rayner, and Gaurevitch [14] suggest that an increased fasting plasma insulin level (greater than 32 pU/ml) is the most useful diagnostic indication in children, we have found it more meaningful to evaluate the fasting plasma insulin concentration in the light of the simultaneous blood glucose level. Among our four pediatric patients in whom plasma insulin levels had been obtained, three had abnormal fasting plasma insulin concentrations, but all four had abnormal glucose:insulin ratios. The measurement of serum proinsulin-like material may eventually be useful in confirming the diagnosis of insulinoma in children [28]. At the present time, however, whenever an inappropriately high level of serum insulin is found in an infant or child with resistant spontaneous hypoglycemia, surgical exploration of the pancreas is indicated. Treatment

Surgical Treatment. Ninety per cent of patients with insulinoma have benign disease and are cured by the removal of all functioning neoplastic tissue. Surgery should not be delayed, since these patients run the risk of brain damage or death from repeated episodes of hypoglycemia [9]. In addition, obesity is progressive in these patients and not only makes the operation more difficult but also increases the chance of postoperative complications. After the diagnosis is established the patient should be maintained on frequent feedings of a high protein, high fat, low carbohydrate diet until surgery in order to reduce the occurrence of hypoglycemic attacks [22]. It is not practical to institute a weight-reducing program because of the prolonged time required for results in the presence of a potentially lethal disease. An intravenous infusion of a 10 per cent glucose solution is started prior to surgery and is maintained throughout the operation to protect the patient from hypoglycemia. During surgery the blood glucose level should be monitored continually. This practice not only provides insurance against severe hypoglycemia due to transient hyperinsulinemia (as a result of manipulating the tumor) [36], but also helps to assure the surgeon that all functioning tumor has been removed. With glucose infused intravenously at a constant

The American Journal of Surgery

insuiintima

rate the blood glucose concentration usually begins to rise ten to thirty minutes after excision of an insulincjma [.‘16.37]. (Figure 3.) The increase in blood glucose continues at an accelerated rate during the second half hour. and the peak level usually occurs during the first six to eight hours post resection. In most patients the blood glucose concentration gradually returns to normal limits over the first postoperative week. (Figure 3.) Occasionally, insulin must be administered to control the blood glucose, and some of these patients (patient KW, for example) may be difficult to manage initially. Most surgeons prefer either a bilateral subcostal or a high transverse abdominal incision. A thorough abdominal exploration is always undertaken in an effort not only to locate an insulinoma but also to rule out other causes of hypoglycemia. The pancreas is completely mobilized and explored. Special care should be taken to examine the head of the gland, where small adenomas are difficult to locate. and the periduodenal, peripancreatic, and perisplenic areas, where ectopic adenomas are usually found. The surgical procedure undertaken is dictated by the operative findings. In general. enucleation is the procedure of choice for a localized adenoma. Partial pancreatectomy is used under the following circumstances: (I 1 if multiple tumors are present: (2) if the adenoma is very large; (3) if the procedure would facilitate the the removal of the tumor (that is, if it is located deep in the gland); (4) if “blind” resection is necessary [9]. Total pancreatectomy is advised only in the patient who has previously undergone resection of a major portion of the gland with no tumor found or with multiple adenomas present and who has continued to have symptoms [38]. Enucleation is a very effective form of therapy for insulinoma, with a low operative mortality and morbidity [7l. Eleven of our patients underwent only simple excision of the adenomas with no mortality. (Table V.) All patients were cured by this procedure. The follow-up time has ranged from one month to ten years, with a median time of nineteen months. Sixteen patients underwent eighteen partial pancreatectomies, including one Whipple procedure. (Table V.) Fifteen patients were rendered asymptomatic. The follow-up time has ranged from one month to twenty-four years, with a median time of forty-five months. In nine patients the tumor(s) was either visible or palpable on exploration of the pancreas. All of

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1

~~~~~

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i_

Iiours

Figure 3. functioning

Blood glucose response beta cell tumors.

Y

----

[hyr

after

removal

of

these patients ha,ve been asymptomatic *after partial pancreatectomy. There was no operative mortality. In seven patients a thorough exploration of the abdomen did not reveal an insulinoma, and “blind” distal pancreatectomy was performed. (Tables II and V.) This procedure wa.s successful in removing the lesion(s) in four patients at the first operation. Two of the remaining patients later underwent a second blind distal pancreatectomy, with recovery of adenomas in the head of the gland in each instance. In the third patient two adenomas were recovered from the body of the pancreas at the first operation. Because this patient was still symptomatic and had a history of multiple tumors, total pancreatectomy was performed at the second operation. A third adenoma was found in the head of the gland. ln summary, six of the seven .patients with occult insulinomas were ultimately cured by blind distal pancreatectomy. There was no operative mortality. The locations omfthe occult insulinomal; in six of the seven patients were as follows: head, four; body, seven; tail, three. The seventh patient had adenomatosis of the body and tail. The neoplastic TABLE V

Procedures for Tumor Removal in TwentySeven Patients with lnsulinoma _~ Number of Patients Procedure

Enucleation Partial pancreatectomy Tumor visible or palpable “Blind” procedure Total pancrea-tectomy Total

-13* 18

-

9 9t 1 32

* Two patients also had prophylactic resection of tail. t In two patients an adenoma was palpated at the line of transection and ellucleated.

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tissue was confined exclusively to the head of the pancreas in three patients. In two of these patients it was possible to palpate a small adenoma in the pancreatic stump after distal pancreatectomy, and the tumors were then enucleated. The operative morbidity and mortality for total pancreatectomy in patients with insulinomas have been low. ReMine et al [38] reported one death in ten patients. The surviving nine patients were cured; eight lived five to twenty-seven years after surgery. Only one patient encountered difficulty with insulin regulation, and unlike patients undergoing total pancreatectomy for adenocarcinoma or chronic pancreatitis, none of this group experienced symptoms of pancreatic insufficiency. Our only patient with total pancreatectomy had an uncomplicated postoperative course and had no difficulty managing the diabetes or pancreatic insufficiency. In summary, functioning beta cell tumors can be removed with a low operative mortality and a high rate of cure. The twenty-seven patients in this study underwent thirty-two pancreatic procedures in thirty operations with no mortality. All patients were rendered asymptomatic. The followup time has ranged from one month to twentyfour years, with a mean of fifty-four months and a median of thirty-six months. In larger series 92 to 96 per cent of those patients with benign disease who survived the operation have been cured ]9,131. Consequences of surgery: No precise figures are available in the literature regarding the incidence of complications after surgery for insulinoma, but pancreatitis, wound infection, and pulmonary problems have frequently been mentioned [19,39]. In the present study there were postoperative complications in fifteen patients (55.5 per cent). Five of these patients underwent enucleation and ten had partial pancreatectomy. The most common problems were pancreatitis, pneumonia, and wound infection. (Table VI.) Ten patients experiencing postoperative difficulties had had drainage with Penrose drains. Although not all of the complications in these patients were intra-abdominal, a sump drain is preferable after pancreatic resection, since it effects more adequate evacuation of peripancreatic collections [ZZ,401. Diabetes is a long-term complication of surgery for insulinoma which has received little attention in the past. Moss and Rhoads [9] mentioned its occurrence in five patients, and Clarke et al [31] noted the appearance of diabetes in two of thirteen patients. Recently, Dunn [41] reported that in a long-term postoperative study of eight pa-

182

tients with insulinoma, five had subnormal insulin production in response to oral glucose and three had impaired glucose tolerance. All patients with low insulin responses had had either major pancreatic resection or severe postoperative intraabdominal sepsis. Diabetes occurred in four of our twenty-seven patients, including the patient who had total pancreatectomy. The other three patients had undergone pancreatic resection ranging from excision of the tail to 95 per cent pancreatectomy. Of a total of thirteen patients undergoing partial pancreatic resection who have been followed up for at least eighteen months, diabetes has developed in three. It is apparent, therefore, that this complication is not uncommon after surgery for insulinoma, especially in patients undergoing partial pancreatectomy. Medical Treatment. Although surgery is the treatment of choice for insulinoma, there are times when medical management is indicated, as follows: (1) the patient may refuse to have surgery; (2) the surgical risk may be too great; (3) the patient has a malignant beta cell tumor in which case medical treatment is the only recourse. The various regimens tried in the past have included frequent feedings with a high protein, high fat, low carbohydrate diet; alloxan; preprandial insulin; ACTH; cortisone; diazoxide; growth hormone; glucagon; 5-fluorouracil; and nitrogen mustard [9,42,43]. None of these methods has been successful in effecting a permanent remission of symptoms, and little success has been achieved in even controlling the symptoms in severe cases (9,421. We have seen no sustained symptomatic relief using ACTH, cortisone, glucagon, epinephrine, growth hormone, and diazoxide preoperatively in three patients. In 1968 Murray-Lyon et al [42] reported the first successful use of streptozotocin in a patient with a metastatic insulin-producing tumor of the pancreas. Since this report, a number of patients have had remission of symptoms with this agent [44,45]. Streptozotocin, an antibiotic derived from Streptomyces acromogenes, is toxic to pancreatic beta cells in experimental animals and presumably in man [42]. The drug is also slightly hepatotoxic and strongly nephrotoxic [44,45]. Despite these side effects, streptozotocin is capable of reversing the biochemical abnormalities in patients with malignant insulinoma and thereby rendering them asymptomatic and able to resume gainful employment. Theoretically it should also be helpful in patients with benign lesions who are not candidates for surgery.

The American Journal of Surgery

TABLE VI

Complications

after Surgery for lnsulinoma

Complication Pancreatitis Diabetes Wound infection Pneumonia Pancreatic insufficiency Incisional hernia Peritonitis Small bowel obstruction Pancreatic fistula Subphrenic abscess Pleural effusion Septicemia Cellulitis Appendicitis Transient ischemic attacks Prolonged ileus Pulmonary embolus Myocardial infarction Atelectasis Intra-abdominal abscess Upper gastrointestinal bleeding *

Transient

in one

Number of Patients 4 4 3 3 2* 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

The advent of plasma insulin determination by immunoassay has markedly decreased the difficulty and increased the accuracy of diagnosing patients with functioning beta cell tumors. Although multiple glucose:insulin ratios will establish the diagnosis in the majority of cases, it may be necessary in some patients to employ other stimulatory tests. Similarly, intraoperative blood glucose monitoring has eased the surgeon’s burden, since a hyperglycemic response after resection is evidence that all functioning neoplastic tissue has been removed. If multiple adenomas are present, for example, the lack of a hyperglycemic rebound after removal of an obvious adenoma indicates the need for more thorough exploration of the pancreas and surrounding tissues and, if necessary, “blind” pancreatic resection. Intraoperative blood glucose monitoring is invaluable when no tumor can be found and “blind” partial pancreatectomy is undertaken. Again, a hyperglycemic rebound is evidence that the offending lesion(s) has been removed. Although some authors [19,46] have advocated “blind” pancreaticoduodenectomy when abdominal exploration reveals no tumor, in the experience of most surgeons the morbidity and mortality from this procedure are too high compared with a

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chance of cure of 50 per cent at most. If the injection of toluidine blue 0 into the splenic and gastroduodenal arteries [47] fails to demonstrate an adenoma, the most reasonable approach in both children and adults is “blind” distal pancreatectomy, starting at the level of the mesenteric vein, and splenectomy. A hyperglycemic rebound is an indication for terminating the operation, whether or not a tumor is immediately found in the specimen. If no rebound occurs, subtotal pancreatectomy, leaving about 10 per cent of the gland adjacent to the duodenum, is indicated. Regardless of the subsequent blood glucose response, further pancreatic resection is not warranted at the first operation because: ( 1) a small adenoma may later be found on closer examination of the specimen: (2) the risk of pancreaticoduodenectomy is too high when weighed against the slim chance for cure; (3) a small lesion in the pancreat:lc remnant may increase in size and be easily found at subsequent exploration [ 2.‘?,38]. With this approach, one should be able to remove virtually all pancreatic insulinomas at the first operation with a ltow mortality. Summary

The clinical features of twenty-seven patients with insulinoma ;are discussed. The best diagnostic test is a seventy-two hour fast with multiple determinations of blood glucose a!nd insulin.

Shatney and Grage

arteriography and intraoperative Preoperative blood glucose monitoring are recommended in all patients. In the present series there was no operative mortality, and all patients were rendered asymptomatic.

26. 27.

References 28. 1. Nicholls AG: Simple adenoma of the pancreas arising from an island of Langerhans. J Med Res 8: 385, 1902. Lane MA: The cytological characters of the areas of Langerhans. Am J Anat 7: 409, 1908. Banting FG, Best CH: The internal secretion of the pancreas. J Lab C/in Med 7: 251, 1922. Harris S: Hyperinsulinism and dysinsulinism. JAMA 83: 729.1924. Wilder RM, Allan FN, Power MH, Robertson HE: Carcinoma of the islands of the pancreas. Hyperinsulinism and hypoglycemia. JAMA 89:.348, 1927. -Howland G. Camobell WR. Maltbv EJ. Robinson WL: Dysinsulinism. JAMA 93: 674, 1929. Filipi CJ, Higgins GA: Diagnosis and management of insulinoma. Am J Surg 125: 231, 1973. Lopez-Kruger R, Dockerty MB: Tumors of the islets of Langerhans. Surg Gynecol Obstet 85: 495, 1947. Moss NH, Rhoads JE: Hyperinsulinism and islet cell tumors of the pancreas. Surgical Diseases of the Pancreas (Howland JM, Jordan GL, ed). Philadelphia, Lippincott, 1960, p 321. 10. Alfidi RJ, Bhyun DS, Crile G Jr, Hawk W: Arteriography and hypoglycemia. Surg Gynecol Obstet 133: 447, 1971. 11. Suzuki H, Matsuyama M: Ultrastructure of functioning beta cell tumors of the pancreatic islets. Cancer 28: 1302.1971. 12. Robins SL: The pancreas, p 963. Pathology. Philadelphia, Saunders, 1967. 13. Laroche GP, Ferris DO, Priestley JT, Scholz DA, Dockerty MB: Hyperinsulinism. Arch Surg 96: 763, 1968. A: lnsulinoma in 14. Mann JR, Rayner PHW, Gaurevitch childhood. Arch Dis Child 44: 435, 1969. 15. Robinson MJ, Clarke AM, Gold H, Connelly JF: Islet cell adenoma in the newborn. Report of two patients. Pediatrics 48: 232, 1971. 16. Crain EL Jr, Thorn GW: Functioning pancreatic islet cell adenomas. Medicine 28: 427, 1949. 17. Breidahl HD. Priestlev JT. Rvnearson EH: Hvoerinsulinism: surgical aspects and results. Ann Sur9.142: 698, 1955. 18. Conn JW, Pek S: On spontaneous hypoglycemia. Current Concepts. The Upjohn Company, Kalamazoo, Michigan, 1970. 19. Miller DR: Functioning adenomas of pancreas with hyperinsulinism. Arch Surg 90: 509, 1965. 20. Ballard HS, Frame B, Hartsock RJ: Familial endocrine adenoma-peptic ulcer complex. Medicine 43: 481, 1964. 21. Whipple AO: Hyperinsulinism in relation to pancreatic tumors. Surgery 16: 289, 1944. 22. dePeyster FA: Planning the appropriate operations for islet cell tumors of the pancreas. Surg C/in North Am 50: 133,197o. 23. Williams C Jr, Bryson GH, Hume DM: Islet cell tumors and hypoglycemia. Ann Surg 169: 757, 1969. 24. Yalow RS, Berson SA: Dynamics of insulin secretion. Diabetes 14: 341, 1965. 25. Floyd JD Jr, Fajans SS, Knopf RF, Conn JW: Plasma insulin in organic hyperinsulinism: comparative effects

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of tolbutamide, leucine, and glucose. J C/in Endocrinot 24: 747, 1964. Samols E, Marks V: Insulin assay in insulinomas. Br MedJ 1: 507, 1963. Grunt JA, Pallotta JA, Soeldner JS: Blood sugar, serum insulin, and free fatty acid interrelationships during intravenous tolbutamide testing in normal young adults and in patients with insulinoma. Diabetes 19: 122, 1970. Gutman RA, Lazarus NR, Penhos JC, Fajans S, Recant L: Circulating proinsulin-like material in patients with functioning insulinomas. N Engl J Med 284: 1003, 1971. Fajans SS, Conn JW: An intravenous tolbutamide test as an adjunct in the diagnosis of functioning pancreatic islet cell adenomas. J C/in Med 54: 811, 1959. Fajans SS, Schneider JM, Schteingart DE, Conn JW: The diagnostic value of sodium tolbutamide in hypoglycemic states. J C/in Endocrinol21: 371, 1961. Clarke M, Crofford OB. Graves HA Jr, Scott HW Jr: Functioning beta cell tumors (insulinomas) of the pancreas. Ann Surg 175: 956, 1972. Epstein HY, Abrams RM, Beranbaum ER, Localio SA: Angiographic localization of insulinomas: high reported success rate and two additional cases. Ann Surg 169: 349, 1969. Boijsen E, Samuelsson L: Angiographic diagnosis of tumors arising from the pancreatic islets Acta Radio/ [Diagn] (Stockh) 10: 161,197O. Gray RK, Rosch J, Grollman JH: Arteriography in the diagnosis of islet-cell tumors. Radiology 97: 39, 1970. Schotland MG, Kaplan SL, Grumback MM: The tolbutamide tolerance test in the evaluation of childhood hypoglycemia. Pediatrics 39: 838, 1967. Schnelle N, Molnar GD, Ferris DO, Rosevear JW, Moffitt EA: Circulating glucose and insulin in surgery for insulinomas. JAMA 217: 1072, 1971. Landor JH, Klachko DM, Lie TH: Continuous monitoring of blood glucose during operation for islet cell adenoma. Ann Surg 171: 394,197O. ReMine WH, Priestley JT, Judd ES, King JN: Total pancreatectomy. Ann Surg 172: 595, 1970. Freeark RJ, dePeyster FA: Progress in the diagnosis and surgical treatment of insulin-secreting tumors of the pancreas. Surg C/in North Am 43: 79, 1963. Northrup WF III, Simmons RL: Pancreatic trauma: a review. Surgery 71: 27, 1972. Dunn CC: Diabetes after removal of insulin tumors of pancreas: a long-term follow-up survey of 11 patients. Br Med J 2: 84,197l. Murray-Lyon IM, Eddleston ALWF, Williams R, Brown M, Hogbin BM, Bennett A, Edwards JC, Taylor KW: Treatment of multiple-hormone-producing malignant islet-cell tumor with streptozotocin. Lancet 2: 895, 1968. Steinke J, Soeldner JS: Metabolic effects of diazoxide in normal subjects, patients with diabetes mellitus and patients with organic hypoglycemia. Ann NY Acad Sci 150: 326,1968. Taylor SG, Schwartz TB, Zannini JJ, Ryan WG: Streptozotocin therapy for metastatic insulinoma. Arch intern Med 126: 654,197O. Smith CK, Stall RW, Vance J, Ricketts H, Williams RH: Treatment of malignant insulinoma with streptozotocin. Diabetologia 7: 118, 1971. Fonkalsrud EW, Dilley RB, Longmire WP Jr: Insulin secreting tumors of the pancreas. Ann Surg 159: 730, 1964. Keaveny TV, Tawes R, Belzer FO: A new method for intra-operative identification of insulinomas. Br J Surg 58: 233, 1971.

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