Hypercalcemia

A 57-year-old woman underwent a combined skeletal and metabolic survey of her total body bone mass to establish the extent of osteoporosis. During this survey, she was found to have mild hypercalcemia, which prompted additional hormonal studies. These studies revealed that the serum concentration of the parathyroid hormone (PTH) was suppressed and that the serum concentration of the parathyroid hormone-related polypeptide (PTHrP) was elevated. The serum concentration of calcitonin was also high. A computed tomographic examination revealed a mass in the tail of the pancreas. A partial pancreatectomy, coupled with a splenectomy, was performed to remove the tumor. During surgery, the liver was examined for metastases, but none were found, and a random biopsy of the liver was performed. Postoperative laboratory findings were within normal limits.

The specimen received from the operating room included the spleen and part of the body and the tail of the pancreas containing a tumor. The tumor was bosselated, firm, and sharply demarcated from the spleen and the rest of the pancreas; it measured 8 x 6.5 x 6 cm. On cross section, the tumor appeared lobulated and yellow (Figure 1). Microscopically, it was predominantly composed of clear cells. Some of these cells appeared rounded and had their cytoplasm filled with large vacuoles, displacing the nuclei to the periphery (Figure 2). The other clear cells were cuboidal and arranged in acini or cords. The cytoplasm of these cells contained smaller dear vacuoles (Figure 3). The latter cells were often admixed with cuboidal cells of the same shape, which had more eosinophilic cytoplasm (Figure 3). These eosinophilic cells predominated in some parts of the tumor and were also found invading the blood vessels and forming a metastatic nest in a peripancreatic lymph node. The spleen and the liver contained no tumor cells.

An electron microscopic examination was performed, and it revealed cytoplasmic, 150- to 200-nm, membrane-bound, dense-cored neuroendocrine granules in essentially all tumor cells (Figure 4). The clear cells were of 2 kinds: some contained numerous fat droplets, whereas others showed cystic dilation of the endoplasmic reticulum. Immunohistochemically, tumor cells stained with antibodies to synaptophysin and chromogranin A and focally with antibodies to glucagon and calcitonin. We had no reliable antibodies to PTHrP, but the staining with the antibodies to PTH gave negative results. Staining with antibodies to vimentin gave positive results, whereas keratin could not be demonstrated.

What is your diagnosis?

Pathologic Diagnosis: Endocrine Pancreatic Tumor, Predominantly Clear Cell Type, Malignant, Associated With Hypercalcemia

This endocrine pancreatic tumor (EPT) was chosen for presentation because it had the following unusual features. It contained large amounts of lipid, imparting it with unique gross, microscopic, and ultrastructural features. Histologically, it was composed of clear cells and had to be distinguished from other clear cell tumors that could arise in the pancreas or metastasize to this organ. Clinically, it was associated with hypercalcemia, which in itself is rarely caused by pancreatic tumors.

As shown in Figure 1, the tumor appeared strikingly yellow on cross-sectioning. Lipid accumulation is most often seen in renal carcinomas and steroid-secreting tumors of the adrenal, ovary, and testis, but lipidosis of neuroendocrine cells of pancreatic tumors is distinctly rare.1 We could find only 2 detailed published descriptions of EPTs characterized by such extensive accumulation of cytoplasmic lipid.2,3 Like the present case, these cases had histologic features of clear cell tumors. Like our tumor, one previous case also contained more conventional neuroendocrine cells, whereas the second case was exclusively composed of clear cells.3 Proper sampling of these tumors is essential to show whether they consist of 1 or more cell types. If sections are taken only from one part of the tumor, the histologic data may be misleading. Inadequate sampling may even cause diagnostic problems, especially if all the sections are taken from heavily lipidized parts of the tumor, which will show histologic features similar to those illustrated in Figure 2.

Clear cell tumors of the pancreas must be distinguished from other lipid or glycogen- or mucin-rich tumors of pancreas, such as low-grade mucinous adenocarcinomas or serous microcystic adenoma. Clear cell endocrine pancreatic tumor associated with von Hippel-Lindau disease is yet another tumor that should be included in the differential diagnosis.4 These EPTs also contain cytoplasmic lipid globules and dense-core neurosecretory granules visible by electron microscopy. Immunohistochemically, these tumors are reactive with antibodies to chromogranin and synaptophysin, but are clinically nonfunctioning. In addition to the clear cell EPT, which is more specific for von Hippel-Lindau disease, some patients with this familiar disease have, however, conventional EPTs.4 These clear EPTs resemble clear cell carcinoids of the gall bladder, which also occur in von Hippel-Lindau disease. Gallbladder tumors stain often with antibodies to inhibin.5

All clear cell EPTs must be distinguished from malignant metastatic tumors, such as renal cell carcinomas, adrenal tumors, steroid-secreting tumors of the ovary and testis, and clear cell hepatocellular carcinomas. A series of metastatic tumors to the pancreas that illustrate this diagnostic dilemma showed that renal cell carcinomas might pose the greatest difficulty in this respect.6 As in our case, immunohistochemical analysis and electron microscopy are most useful in unequivocally demonstrating the neuroendocrine nature of the clear cell pancreatic tumors. It should be noted that both renal cell carcinomas and EPTs might be positive for vimentin and keratin.

Most EPTs secrete 1 or more of the hormones produced normally by the pancreatic endocrine cells, such as insulin, glucagon, somatostatin, or pancreatic polypeptide.7 Occasionally, as in this case, pancreatic tumors secrete hormones that are not produced by normal pancreatic islet cells. The present tumor was found to secrete PTHrP and calcitonin.

The true incidence of EPTs that cause hypercalcemia cannot be determined because most of such cases are individually reported.8,9 As in the most recently studied case from France, hypercalcemia in our case was related to elevated serum concentration of PTHrP, which caused depression of serum PTH. In either of these 2 cases, there was no explanation for the paradoxical elevation of serum calcium levels in the presence of high serum calcitonin levels. Thus, one is left speculating that PTHrP somehow may exert a much stronger effect on raising calcium levels in blood than calcitonin in lowering them.

References

1. Solcia E, Capella C, Kloppel G. Tumors of the Pancreas. Washington, DC: Armed Forces Institute of Pathology; 1995. Atlas of Tumor Pathology; 3rd series, fascicle 20.

2. Guarda LA, Silva EG, Ordonez NG, Mackay B, Ibanez ML. Clear cell islet cell tumor. Am J Clin Pathol. 1983;79:512-517.

3. Ord6fiez NG, Silva EG. Islet cell tumour with vacuolated lipid-rich cytoplasm: a new histological variant of islet cell tumour. Histopathology. 1997;31: 157-160.

4. Hoang MP, Hruban RH, Albores-Saavedra J. Clear cell endocrine pancreatic tumor mimicking renal cell carcinoma: a distinctive neoplasm of von HippelLindau disease. Am J Surg Pathol. 2001;25:602-609.

5. Sinkre PA, Murakata L, Rabin L, Hoang MP, Albores-Saavedra J. Clear cell carcinoid tumor of the gall bladder: another distinctive manifestation of von Hippel-Lindau disease. Am I Pathol. 2001;25:1334-1339.

6. Thompson LDR, Heffess CS. Renal cell carcinoma metastatic to the pancreas in surgical pathology material. Cancer. 2000;89:1076-1088.

7. Delcore R, Friesen S. Gastrointestinal neuroendocrine tumors. J Am Coll Surg. 1994;178:187-211.

8. Kaassis M, Duquenne M, Croue A, Ronceray J, Rohmer V, Bigorgne JC. Calcitonin-secreting neuroendocrine carcinoma of the pancreas with splenic invasion and paraneoplastic hypercalcemia [in French]. Presse Med. 2001;13:30.

9. Delcore R, Friesen SR. Other rare tumors of the endocrine pancreas. In: Howard J, Idezuki Y, Ihse I, Prinz R, eds. Surgical Diseases of the Pancreas. 3rd ed. Baltimore, Md: Williams & Wilkins; 1998:789-815.

Accepted for publication March 20, 2002.

From the Departments of Pathology (Drs Namiq and Damjanov) and Surgery (Dr Delcore), University of Kansas School of Medicine, Kansas City, Kan.

Corresponding author: Asraa L. Namiq, MD, Department of Pathology, University of Kansas Medical Center, 2017 Wahl Hall W, 3901 Rainbow Blvd, Kansas City, KS 66160-7410 (e-mail: anamiq@kumc.edu).

Reprints not available from the author.

Copyright College of American Pathologists Feb 2003
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