Zollinger-Ellison syndrome

A 49-year-old woman with a past medical history significant for hypertension, insulin-dependent diabetes mellitus, Hashimoto thyroiditis, mild chronic renal failure, and renal stones underwent abdominal computed tomography, which revealed an incidental left adrenal mass. Magnetic resonance imaging showed a 2.5-cm, smoothly marginated, ovoid mass that did not have the signal characteristics typical for benign adenoma or myelolipoma. On physical examination, the patient had a somewhat cushingoid appearance; height and weight were 163 cm and 98 kg, respectively. A laboratory workup showed normal 24-hour urinary, morning serum cortisol levels, and normal serum aldosterone level. Serum calcium was at the upper limit of normal, and serum triglyceride and glucose levels were elevated. Follow-up of this nonfunctional adrenal mass was recommended; however, surgical intervention was requested by the patient. A left laparoscopic adrenalectomy was scheduled. A retroperitoneal lesion was dissected that appeared to be an abnormally large tail of the pancreas. Frozen section of this mass showed pancreatic tissue with atrophy and focal mucinous change of ductal epithelium. Left adrenalectomy was subsequently performed after conversion of the procedure to an open operation. Postoperatively, the patient reported resolution of many of her preoperative constitutional symptoms, and she also lost more than 13.6 kg in 6 months.

On gross examination, the first specimen was a 5 × 3 × 1.5-cm piece of pink-brown rubbery tissue that weighed 8.6 g. The second specimen was a 25-g adrenal gland that measured 6 × 4 × 4 cm and contained a 3.1 × 2 × 1.6-cm, tan, well-circumscribed cortical nodule that grossly did not invade the adrenal capsule or the adrenal medulla. sections from the first specimen showed pancreatic tissue with focal mucinous change and an increased number of islets that were variable in size and shape. Two well-demarcated nodules composed of irregular islets, as well as nests of islet cells associated with small ductules were identified. Fibrous stroma surrounded these ductuloinsular complexes, giving the nodules an adenoma-like appearance (Figure 1; hematoxylin-eosin, original magnification ×100). Immunohistochemical stains showed a normal component of insulin-containing cells, but an increased number and abnormal distribution of somatostatin (Figure 2, A; somatostatin immunostain; original magnification ×200), glucagon, and pancreatic polypeptide-containing cells (Figure 2, B; pancreatic polypeptide immunostain, original magnification ×200).

Sections from the second specimen showed an adrenal cortical neoplasm composed of clear and eosinophilic cells, which in many areas had a diffuse growth pattern. Broad fibrous bands and areas of scarring with calcifications were seen. There was mild nuclear pleomorphism; mitoses were rare. No atypical mitoses; foci of necrosis; or capsular, sinusoidal, or vascular invasion were identified. In the nontumoral cortex, predominantly in a subcapsular location, there were wedge-shaped nodules composed of nests of oval and spindle cells with slightly basophilic cytoplasm and bland nuclei, surrounded by eosinophilic hyalinized stroma (Figure 3; hematoxylin-eosin, ×100). These cells stained positively for progesterone receptor protein (Figure 3, inset; progesterone receptor protein, original magnification ×200), focally positive for inhibin, and were negative for S100 and CD34. Reticulin stain showed the individual cells in the nodules to be surrounded by reticulin fibers (Figure 4; van Gieson, original magnification ×400); in contrast, the reticulin fibers surrounded the nests of entrapped normal cortical cells (Figure 4, arrows; van Gieson, original magnification ×400).

What are your diagnoses?

Pathologic Diagnoses: Pancreatic Tissue With Nesiclioclysplasia, Adrenocortical Adenoma, and Ovarian Thecal Metaplasia in the Adrenal Gland

The term nesidioblastosis (from Greek nesidion, islet; and blastos, sprout) was first used in 1938 to describe a persistence of fetal development of the endocrine cells of the pancreas. Morphologic features characteristic of nesidioblastosis, such as diffuse and disseminated proliferation of endocrine cells budding off from the pancreatic ductal epithelium to form new islets, and formation of ductuloinsular complexes are normally seen in the pancreata of neonates and are exaggerated in the pancreata of infants and children with persistent neonatal hyperinsulinemic hypoglycemia. It was suggested that nesidioblastosis could actually represent the pathomorphologic basis of persistent neonatal hyperinsulinemic hypoglycemia. Later it was found that morphologic features of nesidioblastosis could be seen not only in cases of persistent neonatal hyperinsulinemic hypoglycemia, but also in the pancreata of agematched controls and adult patients with and without endocrine abnormalities. Gould et al1 suggested that the term nesidiodysplasia may more accurately define the structural-functional abnormalities of the endocrine pancreas to designate increased, maldistributed, or malprogrammed pancreatic endocrine cells associated with clinical endocrine abnormality. The term reflects abnormalities in the formation of the normal islet, as well as deviations in normal distribution and quantitative relationships between 4 main islet cell types. Nesidiodysplasia is seen in 34% of the cases of persistent neonatal hyperinsulinemic hypoglycemia, but is extremely rare in adults. Adult nesidiodysplasia is most commonly associated with hyperinsulinemic hypoglycemia, but has also been associated with Zollinger-Ellison syndrome, Verner-Morrison syndrome, cystic fibrosis, and chronic pancreatitis. To our knowledge, there are no reports on adult nesidiodysplasia associated with insulin-dependent diabetes mellitus. It has been stated that nesidiodysplasia can be observed in pancreata of patients with MEN-1 in 30% of cases, and that it is rare in non-MEN pancreata.2

In our patient, in addition to the adrenal cortical tumor, there were foci of ovarian thecal metaplasia present in nontumoral adrenal cortex. Adrenal gland and gonadal anlage are embryologically very close, both arising in the region of the urogenital ridge. The presence of ectopic adrenal tissue in the periovarian region has been observed frequently. In contrast, the presence of ovarian tissue in the adrenal gland is an extremely rare finding.3 In 1967, Reed and Patrick first reported 11 cases of "fibroblastic adrenal nodules" that resembled ovarian stroma.3 In 1971, Wong and Warner3 reported 8 additional cases of ectopic ovarian stroma in the adrenals. They coined the term ovarian tliecal metaplasia for these nodules. The foci of wedgeshaped, ovarian-like stroma resembled thecal elements and were mainly found attached to the adrenal capsule in the adrenal glands of postmenopausal women and in women who underwent bilateral adrenalectomy for breast cancer treatment. The incidence was found to be 2.4% to 4.3% in surgical specimens and 0.35% in autopsy material.3,4 The pathogenesis of ovarian thecal metaplasia is not fully understood. It was suggested that foci of thecalike stroma in the adrenal gland may represent metaplasia from undifferentiated but embryologically competent mesenchymal cells of the adrenal capsule in response to an unopposed pituitary gonadotropin during menopause. The menopause can be spontaneous, due to oophorectomy, or radiologie sterilization, as in breast cancer patients.3 Support for this theory was found in studies on human embryogenesis, in animal experiments, and in reports on development of certain adrenal gland tumors, such as granulosa-theca cell tumors.3 A distinctive cell type that contributes to the formation of both the adrenal gland capsule and the gonads has been described.4 Experimental studies have shown that mice castrated at birth can recover from the castrated state, develop their vaginas, uteri, and breasts, although ovarian regeneration is absent. The adrenal glands of these mice developed functional subcapsular nodules, which morphologically "strikingly resemble the cells of ovarian stroma."4 Similarly, the loss of ovarian stroma due to menopause in women could lead to the metaplasia of the cells in the adrenal capsule. The inhibin and hormone receptor reactivity in these lesions has not been reported previously. The significance of the ovarian thecal metaplasia is unknown, but these nodules undoubtedly can be functional and can also undergo neoplastic transformation.3 In our patient, according to the criteria of Weiss,5 the adrenal cortical tumor was best characterized as an adenoma. Both pancreatic nesidiodysplasia and ovarian thecal metaplasia were incidental findings, and their significance was unclear.

References

1. Gould VE, Chejfec C, Shan K, Paloyan E, Lawrence AM. Adult nesidiodysplasia. Semin Diagn Pathol. 1984;1:43-53.

2. Le Bodic MF, Heymann MF, Lecornte M, et al. Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type I. Am J Surg Pathol. 1996:20:1378-1384.

3. Wong TW, Warner NE. Ovarian thecal metaplasia in the adrenal gland. Arch Pathol. 1971:92:319-328.

4. Fidler WJ. Ovarian thecal metaplasia in adrenal glands. Am J Clin Pathol. 1977:67:318-323.

5. Weiss LM. Comparative histologie study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol. 1984;8:163-169.

Tamar A. Giorgadze, MD, PhD; Subhojit Roy, MD, PhD; Douglas L. Fraker, MD; John S. I. Brooks, MD; Virginia A. LiVolsi, MD

Accepted for publication June 4, 2004.

From the Departments of Pathology and Laboratory Medicine (Drs Giorgadze, Roy, Brooks, and LiVolsi) and Surgery (Dr Fraker), University of Pennsylvania Medical Center, Philadelphia.

The authors have no relevant financial interest in the products or companies described in this article.

Corresponding author: Virginia A. LiVolsi, MD, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, 3400 Spruce St, 6 Founders Pavilion, Philadelphia, PA 19104 (e-mail: linus@mail.med.upenn.edu).

Reprints not available from the authors.

Copyright College of American Pathologists Nov 2004
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