approach to adrenal incidentalomas

Approach to Adrenal Incidentalomas

Moayad Assiri

Urology R4

KAUH

Definition. Prevalence. Causes led to it discovery. DDx. Diagnostic approach -Hormonally. -Imaging. -? FNA. Management approach. F\U. Summary. References.

(Clinically inapparent adrenal masses.)

adrenal tumor not suspected prior to radiological studies led to it discovery.

A disease of modern technology. J Endocrinal Metab

Clin North Am 1997

Except: -Pt w known non adrenal malignant tumor. -pt known HTN.

Definition

Incidence of adrenal masses is 9 - 12% in autopsies.

Incidence of AI is 2- 5 %.

>

Rt > lt . Bil 2 – 10 %. NATIONAL INSTITUTES OF HEALTH

Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). Final Statement. July 16, 2002

0

4850

0

2

0204060

RT

LT

BIL

LT RT BIL

Adrenal Incidentalomas Study - Chi Mei Medical Center

1998 Jan – 2002 Dec Abdominal CT scan 70,101 in 5 years 127 cases of AI in 256 cases of adrenal

tumors Incidence of AI: 0.18% Hormonally active: 4%

Mayo clinic 1985-1990 61,054 CT scans performed . Adrenal mass in 2066 pts ( 3.4%). 16.5% were present incidental ( <1 cm ). Overall, AI 259 pts ( 0.4% ) 50% metastatic ca. 25% other known lesions. 7.5% symptomatic tumors.

Prevalence of Adrenal Incidentalomas on CT Imaging

Study Year Number of Scans Number with Mass Frequency)%(

Abecassis et al, Toronto, Canada

1985 1,459 19 1.3

Belldegrun et al,Boston, MA

1986 12,000 88 0.7

Caplan et al,LaCrosse, WI

1994 1,779 33 1.9

Glazer et al,St. Louis, MO

1982 2,200 16 0.7

Herrera et al,Rochester, MN

1991 61,054 259 0.4

Prinz et al,Chicago,IL

1982 1,423 4 0.3

TOTAL)average( 79,915 419 (0.9)

Cheng & Shen 2003 70101 127 0.18

Causes led to discover IA

342 cases, 136 men and 206 women

Reasons for CT scan: nonspecific abdominal pain, 60% known abdominal or thoracic disease, renal problems, musculoskeletal pain

Acta Endocrine (copenh)1989

Age-dependent occurrence of adrenal adenomas

1% in age < 30 y. 3 -7 % in age > 50 y. Compensatory growth in response to local

ischemic damage of arteriosclerotic disease Higher number of diagnostic procedures performed

in aged patients N Engl J

Med, 1990

Increases with Age

Age-dependent occurrence of adrenal cortical adenomas autopsy studies with total of 57,262 subjects

0

2

4

6

8

0~9 10~19 20~29 30~39 40~49 50~59 60~69 >70

Age(y)

Endocrine and Metabolism Clinics of North America 2000; 29)1(:159-185

Clinical characteristics

Per definition ,NO clinical symptoms or signs of adrenal disease should be present at the time of Dx.

More detailed Q and careful PE might reveal evidence of subtle hormonal excess;

-recent w.t gain -skin atrophy. -episodic of headaches.

Àdrenal incidentaloma

Majority are neither function nor malignant 70-90%. The malignant tumors may and may not

secrete hormonal. The 3 mains hormone-producing tumors:1. Cortisone producing adenoma SCCS 11%.2. Pheochromocytoma 7%.3. Aldoestrone producing adenoma 2%.

PREVALENCE OF ADRENAL INCIDENTALOMAS IN DIFFERENT SERIES

_______________________________

Type of Tumor Mantero et al Al-SIE Othorst _______________________________________________ Nonhypersecretory tumors 76.0 74.0 70-94Hypersecretory tumors Cortisol-secreting adenomas 14.0 9.2 0-14 Aldosteronomas 1.0 1.4 0-7 Pheochromocytomas 3.4 4.2 0-11Adrenal carcinomas 1.0 4.0 0-25Myelolipomas 2.0 3.0 7-15Cysts 1.0 1.9 4-22Ganglioneuromas 1.0 1.5 0-6Metastases Unselected patients 1.0 0.7 0-21 Oncological patients 32-73 ________________________________________AI-SIE: Adrenal Incidentaloma Study Group of the Italian Society of Endocrinology

Prevalence (%)

Endocrine and Metabolism Clinics of North America 2000; 29)1(:107-126

Adrenal cancer

Benign Adenoma 50%

Cyst 10%

Myelolipoma 10%

Pheochromocytoma 10%

Metastases 6-30%

Adrenal Cancer 0.01%

The incidental adrenal mass. Am J Med 1996

Benign nonfunctioning

Adenoma Adrenolipoma Amyloidosis Cyst / Pseudocyst

Ganglioneuroma Granuloma

Infection Hamartoma

HemangiomaLeiomyoma

Lipoma Myelolipoma

Malignant nonfunctioning

Angiosarcoma

Ganglioneuroblastoma Leiomyosarcoma Malignant schwannoma Metastatic carcinoma Malignant melanoma

Malignant lymphoma Adrenocortical

carcinoma

Endocrine and Metabolism Clinics of North America 2000; 29)1(:159-185

Differential Diagnosis of Adreanl Incidentalomas

Hyperfunctioning mass

- Pheochromocytoma - Preclinical Cushing’s syndrome - Primary aldosteronism - Nodular hyperplasia - Congenital adrenal hyperplasia - Masculinizing or feminizing tumor - Primary malignancy (Adrenocortical carcinoma)

Pseudoadrenal mass

- Mistaken vasculature - Liver

- Lymph nodes - Pancreatic mass - Spleen - Renal mass - Stomach mass - Technical artifact

Differential Diagnosis of Adreanl Incidentalomas

Endocrine and Metabolism Clinics of North America 2000; 29)1(:159-185

After incidental discovery of an adrenal mass, 2 questions should be addressed

Functional status hormonally active even in the absence of a classic clinical presentation

Malignant potential any chance that the mass is malignant

Important consideration

Trying not to miss important pathology.

Trying no to subject the pt to unnecessary procedure or surgery.

Cost effect.

1-Endocrinology investigation

significant endocrine activity increase with increase tumor size

12

28

25

86

14

18

27

40

0204060

<2cm

2-2.9cm

3-3.9cm

4-5.9cm

>6cm

hormonally inactive hormonally active

Subclinical Cushing’s Syndrome

Most frequent hormonal abnormality (5 – 20%)

Autonomous cortisol secretion without stigmata of Cushing’s syndrome

Diagnostic criteria not yet clearly defined

• 10-20 mg/day

• Controlled Primarily By ACTH

• Negative and Positive Feedback Between Cortisol and ACTH at Pituitary and Hypothalamic Levels

Dx

Increased Urinary Free Cortisol (UFC)

Unsuppressed Serum Cortisol Levels After 1-mg Overnight

Dexamethasone Low ACTH Levels No Clinical Signs Of Cushing

Syndrome

Mantero F, Masini AM, Opocher G, Giovagnetti M, Arnaldi G.

Horm Res 47:284–289, 1997

Dexamethasone Suppression Test

Low-dose: 1mg dexamethasone at 2300, followed by assay of cortisol at 0800 the following day– Cortisol > 3 mcg/dl suggests autonomous secretion

High-dose: 8 mg dexamethasone at 2300 with assay of cortisol at 0800 the next day– Cortisol > 1 mcg/dl indicates autonomous secretion– Reduces false positives

“Intermediate-dose”: 2 – 3 mg dexamethasone at 2300, followed by cortisol at 0800– Cortisol > 3 mcg/dl reportedly suggestive of autonomy

Easier to perform overnight suppression rather than 2-day oral load

Association with Metabolic Syndrome?

1990’s Italian multiinstitutional study collection 1004 patients with adrenal incidentaloma– 41% prevalence HTN– 10% prevalence DM– 28% prevalence obesity

May contribute to, and worsen, hypertension, obesity , diabetes, dyslipidemia and osteoporosis

Pheochromocytoma

Approximately 5-7 % of adrenal incidentalomas.

0.5% among screened hypertensive pt’s

Can be clinically silent and not suggested by history

Mixed recommendations on diagnostic testing

Dx

24-h Urinary fractionated catecholamine excretion or free metanephrines.

• 24 hour urine fractionated metanephrines recommended by some as first diagnostic test

• Especially in incidentalomas without radiographic features suggestive of pheochromocytoma

• Sensitivity and specificity between 91 – 98% • Increased even further when fractionated

catecholamines added

Plasma Free Metanephrines

Plasma free metanephrines

– Used when imaging characteristics and other pre-test probability of pheochromocytoma are high, but 24 hr urine normal

– Due to high sensitivity (97 – 100%) but low specificity (85 – 89%, ) of test

– Negative result quite effective at ruling out

Which Is Better?

Catecholamine-Secreting Tumors Histologically Proven In 31 of 340 Patients:

Sensitivity Of Plasma Free Metanephrine 97% Specificity 98%

Sensitivity Of Urinary Total Metanephrine And Catecholamines 90%; Specificity

85%

Sawka et al. JCEM 88(2): 553-558. 2003.

Aldosteronism (Conns Sx)

Quite rare cause <1%– Most have already been diagnosed before

become large enough to be detected by CT/MRI

Should be evaluated in all hypertensive patients with incidentaloma

Serum potassium not sufficient, but should be included– Common to have normokalemia with

aldosterone producting adrenal tumor 7 – 38%.

Hypertension Headache Weakness And/Or Fatigue Paresthesias Muscle Cramps Polyuria, Polydipsia, Nocturia Arrhythmias

Signs and Symptomsin Primary Hyperaldosteronism

Aldosterone Production

100-150 ug/day

Stimulated by the Renin-Angiotensin System Decreased Perfusion Pressure

Hyperkalemia Stimulates and Hypokalemia Inhibits Aldosterone Secretion

ACTH Acutely May Stimulate Aldosterone Secretion

Dx

Plasma aldosterone/plasma renin activity ratio greater than 30 highly suggestive– Especially with plasma aldosterone >15 ng/dl

Confirm with aldosterone suppression test– IV 0.9 NS infusion – 2L over 2 hrs, with supine

aldosterone >10 suggestive– Can also do 24 hour urinary aldosterone while

patient orally ingests 5000 mg sodium/day x 3 days

Urinary aldosterone >14 mcg/24º

Appropriate screening tests should be performed if the patient has clinical features that are suggestive of increased adrenal function

Diagnosis Suggestive Clinical Features Laboratory Tests

Pheochromocytoma Hypertension, Paroxysmal Symptoms (eg, palpitation, diaphoresis, headache, pallor, tremor)

24-hr urine:fractionated metanephrines fractionated catecholaminesBlood:fractionated metanephrines

SC Cushing's syndrome (SCCS)

Central obesity, proximal muscle weakness, thin skin, supraclavicular fat pad, facial plethora

For patients lacking symptoms of CS:1-mg overnight dexamethasone suppression test

Diagnosis Suggestive Clinical Features

Laboratory Tests

Primary aldosteronism

Hypertension, hypokalemia

Plasma aldosterone concentration Plasma renin activity

Adrenocortical carcinoma

Mass effect symptoms, symptoms related to excess glucocorticoid, mineralocorticoid, androgen, or estrogen secretion

Serum dehydroepiandrosterone sulfateMeasures of clinically indicated steroid

Stepwise diagnostic approach

Step I :

1- 24-h Urinary catecholamine excretion or free metanephrines.

2- Serum cortisol after dexamethasone suppression 1mg at 11 pm PO.

3-HTN , Serum K and – PAC\PRA ratio.

Stepwise diagnostic approach

Step II : confirmatory test.

1- MRI . CT scan or 123-I-MIBG scintigraphy or 131 I-MIBG.

2- high-dose dexamethasone 8mg suppression test. If +ve

.CRH test analysis of diurnal cortisol secretion , and 24-h urine free cortisol.

3- confirm with aldosterone suppression test.And 24-h urine aldosterone .

Step III. Revaluation

-repeat screening tests after 2 years in patient with a tumor size of > 3 cm.

Stepwise diagnostic approach

2 -Imaging

Imaging Characteristics

CT Scan– Hounsfield Scale

Measures xray attenuation

Each number represents a shade of grey, with air and bone

Water as zero Air = -1000 Bone = +1000

Hounsfield Units for Relative Densities of Various SubstancesSubstance Hounsfield units(H)

-1,000 Air

-50 Fat

0 Water

+40 Soft tissue )i.e., muscle(

+100 to +400 Calculus

+1,000 Bone

Hounsfield units = units of x-ray attenuation used in CT. each pixel is assigned a value on a scale from -1,000 to +1,000.

CT scan

Attenuation On CT Scan Is Measured In Hounsfield Units (HU)

Lipid-Rich Masses Are Usually Benign

Lipid-Rich Lesions Have Low Attenuation

Low Attenuation Lesions Have Low HU Values

Computed Tomographic Scans

Unenhanced CT: Adenomas: < 10 HUMalignancies: > 18 HU

Sensitivity: 73% Specificity: 96%

Delayed Enhanced CT: Adenomas: < 30 HU Malignancies: > 30 HU

Sensitivity 95% And Specificity: 100%

Adrenocortical carcinoma

Size large, typically > 4 cmShape irregular with unclear marginsTexture inhomogenous with mixed densities compared with liverLaterality usually solitary and unilateralCT > 10 HU without contrast and >30-40 HU 30 min after contrast administrationMRI hyperintense to liver on T2-weighted imagePresence of necrosis, hemorrhage, or calcifications-- commonGrowth usually rapid

Adrenal cancer CT

Contrast-enhanced CT scan through the abdomen of a 56-year-old man reveals a complex solid and cystic, calcified mass (arrow) in the right suprarenal fossa extending into the adjacent liver. The tumor proved at surgery to be a carcinoma of the adrenal cortex. .

Malignant Potential

Imaging phenotype and mass size are two major predictors of malignancy

Additional test that may be preformed to predict malignancy include image-guided needle biopsy and iodocholesterol scintigraphy

Hormonal evaluation is not predictive of malignancy

Approximately 41% of 1,891 published cases of adrenocortical carcinoma, was not hormone-secreting

size

The probability that an AI is ACC is increases with increasing size of the lesion.

90% of all ACC is > 6 cm in size.

The prevalence of ACC related to size of tumor 2% in tumors < 4 cm. 6% in tumors 4-6 cm. 25% in tumor > 6 cm.

Resection all tumor > 4 cm- 8 benign tumors removed for each cancer resected.

Imaging Phenotypes of Adrenal Incidentalomas

Adrenal cortical adenomas

Size small, typically < 3 cmShape round to oval with smooth marginsTexture homogenous and low density compared with liverLaterality usually solitary and unilateralCT < 10 HU without contrast and <37 HU 30 min after contrast administrationMRI isointense to liver on T2-weighted imagePresence of necrosis, hemorrhage, or calcifications-- rareGrowth usually stable size over time or very slow growth

Adrenal adenoma hypodense

Abdominal CT showing a 1.5-cm round hypodense left adrenal cortical adenoma (arrow).

PheochromocytomaSize large, typically > 3 cmShape round to oval with smooth marginsTexture inhomogenous with cystic texture Laterality usually solitary and unilateralCT >10 HU without contrast and >40 HU 30 min after contrast administration, usually vascular, marked enhancement MRI marked hyperintense compared with liver on T2-weighted imagePresence of necrosis, hemorrhage, or calcifications-- hemorrhage and cystic necrotic areas commonGrowth very slow

Pheochromocytoma silent Abdominal CT showing an 8-cm left adrenal mass (arrow) discovered incidentally. Note the vascular and inhomogenous imaging characteristics of this mass. Biochemical evaluation was consistent with a clinically silent pheochromocytoma, which was confirmed at surgery..

MRI of the abdomen shows a 4.5-cm right adrenal pheochromocytoma (arrows). Upper panel: T1-weighted image. Lower panel: T2-weighted image shows increased signal intensity typical of a pheochromocytoma.

Metastasis

Size variable, frequently < 3 cmShape round to irregular with unclear marginsTexture inhomogenousLaterality often bilateralCT > 10 HU without contrast and >40 HU 30 min after contrast administration, usually vascular, enhancement on tumor rim MRI hyperintense compared with liver on T2-weighted imagePresence of necrosis, hemorrhage, or calcifications-- hemorrhage and cystic necrotic areas commonGrowth usually slow

Imaging CharacteristicsAdenoma Adrenocortical

CarcinomaPheochromocytoma

Metastasis

Size < 3 cm diameter >4 cm diameter >3 cm diameter Usually <3 cm

Shape Round, smoothMargins

Irregular, no clear margins

Round/oval, clear margins

Oval/irregular, unclear margins

Texture Homogenous Heterogenous, mixed densities

Heterogenous, cystic

Heterogenous, mixed densities

Lateralize Solitary, unilateral

Solitary, unilateral

Solitary, unilateraly Bilateral

CT Attenuation

<10 HU >25 HU >25 HU >25 HU

CT Washout at 10 minutes

>50% <50% <50% <50%

T2 MRI Appearance )compare to liver(

= + +++ +

Necrosis, Ca, hemorrhage

Rare Common Common Occasional

Growth rate Slow Rapid Slow Variable

Nuclear Imaging PET – most useful in

patients with oncologic history and incidentaloma– 100% sensitive

determining both metastasis and benign adenomas based on adrenalectomy studies

Radionuclide Scintigraphy

Schlamp A et al. )2007( Recurrent adrenocortical carcinoma after laparoscopic resectionNat Clin Pract Endocrinol Metab 3: 191–195 doi:10.1038/ncpendmet0391

CT and fluorodeoxyglucose(FDG)-PET scans of the tumor before and after primary surgery

MIBG – used to confirm suspicion of pheochromocytoma, little utility in eval of incidentalomas in general

NP-59 – radiolabeled cholesterol derivative, preferentially taken up by adrenal adenomas– Unilateral uptake suggests

functional adenomas, and may be useful in screening for subclinical cushing’s syndrome

3 -Fine-needle aspiration biopsy

(FNA) cannot distinguish a benign adrenal mass from the rare adrenal carcinoma.

It can distinguish between an adrenal tumor and a metastatic tumor.

FNA may be indicated : when there is a suspicion of cancer outside the adrenal

gland, or in the patient undergoing a staging evaluation for a

known cancer. ? Infection. NATIONAL INSTITUTES OF HEALTH

Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). Final Statement. July 16, 2002

Tumors that most commonly metastasize to adrenals are carcinomas of lung, breast, kidney and gastrointestinal tract, melanoma or lymphoma

FNA is not free of S.E .

• FNA is not useful in the routine evaluation.

• Pheochromocytoma should always be excluded before attempting FNA biopsy of an adrenal mass

NATIONAL INSTITUTES OF HEALTHManagement of the Clinically Inapparent Adrenal Mass (Incidentaloma).

Final Statement. July 16, 2002

Bilateral masses

Analyses from two large adrenal incidentaloma studies with 887 and 202 patients showed that bilateral masses were found in 10 to 15 percent of cases.

Bilateral adrenal masses can be seen with – metastatic disease, – congenital adrenal hyperplasia, – cortical adenomas, lymphoma, – infection (eg, tuberculosis, fungal), – hemorrhage, – ACTH-dependent Cushing's, – pheochromocytoma, – amyloidosis, – infiltrative disease of the adrenal glands, and – ACTH-independent bilateral macronodular adrenal

hyperplasia

Adrenalectomy?

Individualized approach

The decision to operate on pt should be based on :

Suspicious of the presence of malignancy. Evidence of function of the tumor. Pt age . Pt preference .

Adrenalectomy?

Recommended for: all patients with mass size > 6 cm, pheochromocytoma, aldosteronism, and Cushing’s syndrome

Aldosteronism and CS can be treated medically, but surgical approach favored

MedicalSpironolactone

Inhibits sodium-postassium exchange in the distal tubule, normalizes serum K and may lower blood pressure.

4 – 6 cm masses– Either surgical approach or close follow-up

considered reasonable

*Strongly consider adrenalectomy:– if imaging phenotype suspicious,– increase in size > 1 cm during f/u, – or development of hormonal hyperfunction during

f/u.

Considered in SCS, especially in pt’s < 40 or 50 y/o, and those with disorders attributable to hypercortisolism

- Caution for postoperative adrenal insufficiency in SCS patients taken to adrenalectomy.

No difference between open and laparoscopic approaches

Complication rate of ~3%Special consideration : -Poor surgical patient – FU. -Not possible or difficult FU – Sx.

Izaki H et al. Indications for laparoscopic adrenalectomy for non-functional adrenal tumor with hypertension: usefulness of

adrenocortical scintigraphy. Int J Urol 2006:13(6):677-81.

342 pts AI. 52 patients underwent adrenalectomy 5 patients had malignancy: 4 adrenocortical carcinomas and one

metastasis 1.2% of 342 had cancer No malignancy < 5 cm in diameter 287 of 342 had follow-up; 90% at one year None had extension of tumor or hormonal

excess Herrera et al, Surgery

Conclusions: (1) Hormonal screening on patients with an

AI > 1 cm, (2) any patient with a hyper-secretory state

should undergo adrenalectomy, (3) advise adrenalectomy on AIs > 4 cm and (4) comparison CT scans at 3 month intervals

for those choosing observation only of their AI < 4 cm

Herrera et al, Surgery

National survey on AI Purpose: To evaluate AI based on imaging

size alone Strict exclusion criteria 1004 enrolled; 584 women and 420 men All patients underwent CT scan or MRI

Montero, JCEM

85% underwent hormonal evaluation Results: 9.2% had SCS, 1.6% had an aldosteronoma

and 4.2% had pheochromocytomas All these patients underwent adrenalectomy A total of 380 patients underwent

adrenalectomy.

Montero, JCEM

Table 4 Histological picture in relation with gender, age, and mass size )CT measurement(. Mantero, JCEM

Conclusions: (1) An AI > 4 cm is 93% sensitive for

detecting all malignancies and (2) Pain at presentation may be

associated with a malignant outcome

Mantero, JCEM

The Mayo Clinic Study

432 Patients With Adrenal Incidentaloma Retrospectively Evaluated

Tumor Diameter Averaged 2.5 cm. Most Malignant Tumors Measured > 5 cm. Removing All Tumors > 4 cm Would Have

Removed Eight Benign Tumors For Every Carcinoma

Incidentally discovered adrenal tumors: an institutional perspective. Herrera MF; Grant CS; van Heerden JA; Sheedy PF; Ilstrup DM. Surgery 1991 Dec;110(6):1014-21

Incidentaloma Follow-Up

No single approach is proof yet.

1st Follow up 3 - 6 m with another FU at 12 m.

Repeat hormone screening after 12m.

Then annually. 2 -3 y

IA Mass Risk of progression

Adrenal Hyperfunction: Unlikely If Lesion < 3 cm Cortisol Hypersecretion Most Likely Disorder 4% After 1 Year 9.5% Within 3 Years None ThereafterMass Enlargement: 8% After 1 Year 18% After 5 Years Most Enlargement Occurred Within 3 Years

Barzon et al J Clin Endocrinol Metab 1999

Summary

Relatively common – prevalence ~ 2 – 5 %.– Increases with age, so expected to increase further in

future. 1 in every 4000-1.6 million adrenal tumors are malignant Up to 20% are hyperfunction.

All patients with incidentaloma need hormonal eval-24º urinary metanephrines-Midnight dexamethasone suppression test-PAC\PRA ratio in pt’s with underlying HTN or

hpokalemia.No optimal radiologic test to distinguish between benign and

malignant tumors

Summary

FNA of little value.

Sx indicated for hyperfunction masses , size >6cm and possibility of malignancy .

Malignant tumors more likely to be > 4 cm Nearly all masses <4 cm are benign

No consensus on follow-up

References

AI-SIE: Adrenal Incidentaloma Study Group of the Italian Society of Endocrinology

Acta Endocrine (copenh)1989

N Engl J Med, 1990

Endocrine and Metabolism Clinics of North America 2000; 29(1):159-185

NATIONAL INSTITUTES OF HEALTHManagement of the Clinically Inapparent Adrenal Mass(Incidentaloma).Final Statement. July 16, 2002

Endocrine and Metabolism Clinics of North America 1997

Barzon et al J Clin Endocrinol Metab 1999

References

Endocrine and Metabolism Clinics of North America 2000; 29(1):107-126

Mantero F, Masini AM, Opocher G, Giovagnetti M, Arnaldi G. Horm Res 47:284–289, 1997

Sawka et al. JCEM 88(2): 553-558. 2003.

Izaki H et al. Indications for laparoscopic adrenalectomy for non-functional adrenal tumor with hypertension: usefulness of adrenocortical scintigraphy. Int J Urol 2006:13(6):677-81.

Incidentally discovered adrenal tumors: an institutional perspective. Herrera MF; Grant CS; van Heerden JA; Sheedy PF; Ilstrup DM. Surgery 1991 Dec;110(6):1014-21