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Islet cell tumors arise from the islets of Langerhans, the endocrine-hormone producing portion of the pancreas. Tumors arising from the beta cells which normally produce insulin are called insulinomas. Tumors producing gastrin, a hormone that promotes acid secretion in the stomach, are called gastrinomas. There are additional rarer tumors producing a variety of hormones ranging from glucagon, somatostatin, and vasoactive intestinal polypeptide. The pathologist can correlate the laboratory findings of the elevated hormone levels with immunohistochemical studies using monoclonal antibodies to these hormones applied to tissue sections.


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SYNONYMS Pancreatic endocrine tumors
INCIDENCE 1/100,000 in USA
AGE RANGE-MEDIAN Mean 58 years
Range 12-78 years
Northern Ireland 1-5/1,000,000


DIABETES MELLITUS Family history in 20-30% of insulinomas
MEN syndromes  

Malignant pancreatic endocrine tumor in a child with tuberous sclerosis.

Francalanci P, Diomedi-Camassei F, Purificato C, Santorelli FM, Giannotti A, Dominici C, Inserra A, Boldrini R.
Am J Surg Pathol. 2003 Oct;27(10):1386-9. Abstract quote  

SUMMARY: Tuberous sclerosis complex (TSC) is an autosomal dominant condition whose signs and symptoms may vary from a few hypopigmented skin spots to epilepsy, severe mental retardation, and renal failure. The disease is caused by mutations in either TSC1 or TSC2 gene, at chromosome 9q34 and 16p13.3. Inactivation of both alleles at TSC1 or TSC2 loci is associated with the development of hamartomas in different organs, and only rarely with malignant neoplasms.

In this study we present a 6-year-old boy with TSC and with a malignant islet cell tumor of the pancreas. Mutation analysis of DNA extracted from peripheral blood cells of the patient identified an R1459X de novo mutation in exon 33 of the TSC2 gene.

Immunohistochemical analysis with anti-tuberin antibodies on paraffin-embedded tissue sections showed loss of tuberin immunostaining in tumor cells but normal expression in residual normal pancreas. DNA analysis of tumor and normal cells showed chromosome 16p13 loss of heterozygosity in malignant pancreatic islet cell tumor but not in normal pancreas. These findings suggest a role for tuberin, the TSC2 gene product, in the pathogenesis of malignant pancreatic endocrine tumor.


von Hippel-Lindau gene Possible role with loss of this tumor suppressor gene

p27: A potential main inhibitor of cell proliferation in digestive endocrine tumors but not a marker of benign behavior

Gabriella Canavese, MD
Cinzia Azzoni, PhD
Silvia Pizzi, PhD, etal.


Hum Pathol 2001;32:1094-1101. Abstract quote

The immunohistochemical expression of the inhibitors of cyclin-dependent kinases p21 and p27 was investigated in 109 endocrine tumors of the pancreas and gastrointestinal tract and compared with that of Ki67 and p53.

p21 was found to be scarcely expressed without significant differences between benign and malignant or between differentiated and undifferentiated tumors. This suggests no relationship between changes in p21 levels and clinical behavior in these endocrine tumors.

p27 was found to be highly expressed in differentiated neoplasms and proved to be inversely related to Ki67 labeling (P = .02), which was usually low. These data indicate that p27 may have an important inhibiting role on the low proliferation rate of the tumors. Moreover, the protein may have a role in the resistance of differentiated endocrine tumors to chemotherapeutic agents. p27 high-expressor neoplasms were frequent in either benign (70.6%) or malignant (81.4%) differentiated tumors, thus not allowing the use of this protein for the differential diagnosis of malignant neoplasms as suggested for endocrine tumors of parathyroid and pituitary. Poorly differentiated endocrine carcinomas, which differred from the differentiated tumors for their very high Ki67 levels and frequent p53 expression, showed low or absent p21 and p27 in most cases.

Classical midgut carcinoids were characterized by a sharp discrepancy between malignant behavior and very bland proliferative pattern, with Ki67 and p27 expressions similar to that of benign tumors.

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors.

Wang GG, Yao JC, Worah S, White JA, Luna R, Wu TT, Hamilton SR, Rashid A.

1Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mod Pathol. 2005 Aug;18(8):1079-87. Abstract quote  

Carcinoid tumors and pancreatic endocrine tumors are uncommon neuroendocrine neoplasms, and their genetic alterations are not well characterized. These tumors have site-specific differences in neuroendocrine characteristics, clinical course and genetic alterations.

We compared clinicopathological features and loss of heterozygosity of chromosomes 11q, 16q and 18, and BRAF gene mutations in 47 patients with neuroendocrine tumors including 16 with pancreatic endocrine tumors, 15 with nonileal carcinoid tumors and 16 with ileal carcinoid tumors. Patients with carcinoid tumors had more frequent history of alcohol consumption compared to patients with pancreatic endocrine tumors (P=0.02), and patients with ileal carcinoid tumors more frequently had liver metastasis compared to patients with nonileal carcinoid tumors and pancreatic endocrine tumors (P=0.02). Allelic loss of chromosome 11q was present in 21% of tumors, chromosome 16q in 13%, and chromosome 18 in 30%. These alterations differed with the anatomical subsite of tumor: allelic loss of chromosome 18 was present in 69% of ileal carcinoid tumors, 13% of nonileal carcinoid tumors and 6% of pancreatic endocrine tumors (P=0.001). In contrast to pancreatic endocrine tumors and nonileal carcinoid tumors, all 11 ileal tumors with loss of chromosome 18 had complete loss of both chromosomal arms. No BRAF mutations were identified. Complete allelic loss of chromosome 18 was associated with smaller tumor size (P=0.02).

Our study indicates that genetic alterations vary by tumor subsite and clinicopathologic features, and ileal carcinoid tumors have distinctive clinicopathologic and genetic profiles.



Fine needle aspiration biopsy of the islet cell tumor of pancreas: A comparison between computerized axial tomography and endoscopic ultrasound-guided fine needle aspiration biopsy.

Jhala D, Eloubeidi M, Chhieng DC, Frost A, Eltoum IA, Roberson J, Jhala N.

Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham, AL.

Ann Diagn Pathol 2002 Apr;6(2):106-12 Abstract quote

The objective of the present study is to compare the cytologic features of islet cell tumor (ICT) of pancreas obtained by endoscopic ultrasound guided fine needle aspiration (EUS-FNA) and computed tomography guided FNA (CT-FNA).

We also describe the cytologic features associated with malignant ICT. Eleven cytology samples from 121 CT- FNA and 30 EUS- FNA of the pancreas were obtained from nine patients with ICT. Diff-Quik, Papanicolaou, and immunohistochemical stains to determine neuroendocrine differentiation and the hormonal status were evaluated. Cytologic features and specimen adequacy were compared between the two techniques. Cytologic features noted in both benign and malignant ICT were also compared. Nine patients (5 men, 4 women) ranging in age from 29 to 84 years (mean age, 53.8 years). Diagnoses consisted of benign (4) and malignant (5) ICT. EUS-FNA was superior to CT-FNA in obtaining adequate cells (2/2 v 7/9) for the diagnosis and increased cellularity to perform additional immunohistochemical stains (2/2 v 4/7).

Single, plasmacytoid cells with finely granular chromatin distribution characterized ICT on cytology. Mitoses (3/5) and necrosis (1/5) were noted in malignant ICT but not in benign ICT. EUS-FNA is superior to CT- FNA for obtaining cells for the diagnosis of ICT. Detection of mitoses and or necrosis from patients with ICT should initiate a search for metastasis.


Classic well differentiated  
Poorly differentiated (small cell) carcinoma  

Most common functioning endocrine tumor
30-60 years of age
Multiple in 7.5-13% of cases

Present with hypoglycemia and inappropriate plasma insulin levels after periods of fasting

Occurs anywhere in pancreas


5% of clinically relevant pancreatic endocrine tumors and 8% of functioning tumors

Mean 55 years (40-70 years)
Women 55% of cases
Occasionally part of MEN 1 syndrome

Skin rash (necrolytic migratory erythema) occurring on buttocks, groin, thighs, perineum

Stomatitis, angular cheilitis, glossitis, mild diabetes mellitus, weight loss

Most are in distal pancreas

Usually single with mean size of 7.6 cm


<1% of active pancreatic endocrine tumors
Head of pancreas in 56.5% of cass
Mean 6.7 cm

Mean 53.9 years (30-84 years)
Females favored slightly

Somatostatinoma syndrome with diabetes mellitus, cholelithiasis, diarrhea, hypochlorhydria, weight loss, and anemia

Somatostatin levels 10-100x normal


Multiple in 30%, usually MEN 1 cases
20% of all pancreatic endocrine tumors and 30% of all functioning tumors
Usually uniformly distributed

Male:female 3:2
Mean 38 years
MEN 1 found in 21% of cases

Association with the Zollinger-Ellison syndrome with massive gastric acid hypersecretion and peptic ulceration-basal serum gastrin levels >200 pmol/L


Produces the Verner-Morrison or WDHA (Watery diarrhea, hypokalemia, achlorhydria) syndrome by secreing VIP (vasoactive intestinal peptide), PHM (peptide histidine methionine, and other hormones

8% of all pancreatic endocrine tumors

Females slightly favored
Mean age 48 years (19-79 years)
Occasional association with MEN 1

Serum levels of VIP usually >60 pmol/L

47% of tumors in tail of pancreas

Enterochromaffin cell tumor causing the carcinoid syndrome

Very rare

Carcinoid syndrome and may cause diarrhea, cutaneous flushing, hypotension, bronchospasm, and right heart endocardial fibrosis

Caused by secretions of serotonin, kallikreins, substance P, and tachykinins

Tumors producing Acromegaly  
Tumors producing Cushing's syndrome  
Tumors producing hypercalcemia  
Tumors with multiple syndromes Two or more hormonal syndromes
Nonfunctioning tumors (Including PP tumors)

Pancreatic tumors with endocrine differentiation but no clinical syndrome or hormone hyperfunction

Incidental finding in up to 10% of autopsies

Mean age 70 years
Usually <1 cm



Epithelial tumor with small to medium sized cells, mild to moderate atypia, forming trabeculae, ribbons, solid nests, acini, rosettes, tubules, and sheets

Trabecular pattern more common in benign tumors

Glandular and solid pattern more common in malignant tumors

Adenomas Usually<3 cm
0-2 mitotic figures/10 hpg
Minimal cellular atypia
Microadenomas 0.5 mm to 0.5 cm
Form prominent lobular and ribbons with or without cellular palisades
Clinically silent
Macroadenomas >0.5 cm
Well circumscribed, completely or partially encapsulated
No signs of perineural or vascular invasion
May be functioning
Tumors of uncertain malignant potential >2 cm with mean of 5-6 cm
Well differentiated histologic pattern
Mild cellular atypia
May have capsular, peritumor, or venular invasion
May be functioning
Low-grade carcinomas >3 cm with mean of 6 cm
Partly encapsulated tumor grossly invading parapancreatic tissues, large vessels, or adjacent organs
Mild to moderate atypia
1-10 mitotic figures/10 hpf
Vascular or perineural invasion of capsular and parenchymal tissue
Insulinoma (B cells, islet cell tumor associated with persistent hyperinsulinemic hypoglycemia) Amyloid in stroma close to tumor cells very common
Glucagonoma (A cells) Amyloid deposits rare
Somatostatinoma (D cells) No distinguishing features
Gastrinoma (G cells) No distinguishing features
VIPoma No distinguishing features
Enterochromaffin cell tumor causing the carcinoid syndrome No distinguishing features
Tumors producing Acromegaly May have a prominent zellballen pattern
Tumors producing Cushing's syndrome No distinguishing features
Tumors producing hypercalcemia No distinguishing features
Tumors with multiple syndromes No distinguishing features
Nonfunctioning tumors (Including PP tumors) No distinguishing features

Cystic Endocrine Tumors of the Pancreas Clinical, Radiologic, and Histopathologic Features in 13 Cases

Blandine Ligneau, etal.

Am J Surg Pathol 2001;25:752-760 Abstract quote

Cystic endocrine tumors of the pancreas are rare and raise difficult clinical problems. Our aims were to reevaluate the diagnostic and therapeutic strategy and to assess their histopathologic characteristics.

Thirteen cystic endocrine tumors diagnosed in 10 patients were included. Clinical, radiologic, and pathologic data were reviewed. There were 6 male and 4 female patients (median age, 46 yrs). Six patients had evidence of multiple endocrine neoplasia type 1 (MEN1) disease. Four had a functional endocrine syndrome. Ten tumors were visible on imaging studies. The most suggestive radiologic features were the existence of a peripheral hypervascular rim (10 cases) and images of cyst into cyst (two cases).

On gross and histologic examinations, two distinct types were present. Macrocystic tumors (six cases) were unilocular and limited by a thick wall containing nests of tumor cells. Microcystic tumors (seven cases) were characterized by the presence of multiple cystic spaces directly lined by tumor cells.

Surgical resection was performed in all cases. Three patients had lymph node metastases at the time of diagnosis. One patient is dead with metastatic dissemination. The others are alive without recurrence or metastasis.

The diagnosis of endocrine tumor must be considered for any pancreatic cyst discovered in a patient with a history of MEN1 syndrome or with clinical features suggestive of this syndrome. Cystic pancreatic endocrine tumors must be treated by surgical resection because of their possible malignant evolution.

Ductuloinsular tumors of the pancreas: endocrine tumors with entrapped nonneoplastic ductules.

van Eeden S, de Leng WW, Offerhaus GJ, Morsink FH, Weterman MA, de Krijger RR, Kloppel G, Klimstra DS.

Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
Am J Surg Pathol. 2004 Jun;28(6):813-20. Abstract quote  

Rare pancreatic neoplasms have been reported that show both endocrine and exocrine differentiation in the neoplastic components. In addition, pancreatic endocrine tumors may contain small, cytologically bland ductules intimately admixed with the endocrine component. It was recently suggested that these ductules represent an intrinsic part of the tumor, ie, that the ductules are neoplastic, and the term "ductulo-insular tumors of the pancreas" was proposed.

In the present study, the nature of the ductular component of 16 cases of ductule-containing pancreatic endocrine tumors was investigated at the molecular level. Molecular genetic changes often present in ductal pancreatic neoplasms were not found by immunohistochemistry for DPC4, p53, and ERBB2 and by sequence analysis of KRAS codon 12. An X-chromosome inactivation clonality assay of one such tumor from a female patient indicated that the neuroendocrine component was monoclonal, contrasting with the ductular component that was polyclonal. The lymph node and liver metastases from three patients only contained the neuroendocrine component, and no ductules were observed. Although certain morphologic features of ductule-containing endocrine tumors are reminiscent of the embryonic development of the human pancreas, none of the tumors expressed PDX-1, a transcription factor essential in pancreatic organ development.

Based on our results, it is suggested that the ductular component occasionally found in pancreatic endocrine tumors is the result of entrapment of preexisting nonneoplastic ductules and that the tumors are otherwise not distinctive from conventional pancreatic endocrine tumors. Although the phenomenon is rare, it is important to recognize and to distinguish these tumors from true mixed ductal-endocrine neoplasms, which are generally more clinically aggressive.

"Pancreatic endocrine tumors with entrapped ductules" would be the preferred nomenclature since it better reflects the nonneoplastic nature of the ductules.

Ductulo-insular Pancreatic Endocrine Neoplasms: Clinicopathologic Analysis of a Unique Subtype of Pancreatic Endocrine Neoplasms.

Deshpande V, Selig MK, Nielsen GP, Fernandez-Del Castillo C, Lauwers GY.


Am J Surg Pathol 2003 Apr;27(4):461-8 Abstract quote

Pancreatic neoplasms with mixed ductal and endocrine components are a heterogeneous group of tumors. The least recognized of these are pancreatic endocrine tumors (PETs) displaying benign-appearing tumor-associated ductules.

To characterize these ductulo-insular pancreatic endocrine tumors (DI-PETs), we reviewed a series of 92 resected PETs. To be considered as a DI-PET we required the presence and tight intermingling of ductules with the dominant endocrine component (including the presence of ductulo-insular units). A total of 15 PETs fulfilled our criteria (16.3%). The average age of the DI-PET patients was similar to typical PETs (54 years vs 56 years). These tumors were smaller and more often insulin positive than typical PETs (p <0.05). Diffuse stromal fibrosis was more frequent in DI-PETs (11 of 15; 73.3.7%) compared with PETs (8 of 72; 11.1%) (p <0.05).

The tumor-associated ductules were composed of cuboidal cells with dense eosinophilic cytoplasm and round nuclei without atypia or mitoses. They were positive for cytokeratin 7 and cytokeratin 19 and lacked any neuroendocrine markers. Reversibly, the endocrine component was negative for cytokeratin 7 and cytokeratin 19 and positive for neuroendocrine markers.

Ultrastructural examination of ductulo-insular units confirmed a dual ductal and endocrine differentiation with amphicrine differentiation in one case. Follow-up was available in 12 cases with an average follow-up of 70.1 months (range 25-203 months). Ten patients are currently alive, and two patients died 81 and 158 months after surgery.

We conclude that DI-PETs are not uncommon and that they are biologically similar to other PETs. We also hypothesize that the ductal cells develop by transdifferentiation of the endocrine cells.

Lipid-Rich Variant of Pancreatic Endocrine Neoplasms.

Singh R, Basturk O, Klimstra DS, Zamboni G, Chetty R, Hussain S, La Rosa S, Yilmaz A, Capelli P, Capella C, Cheng JD, Adsay NV.

From the *Department of Pathology, Harper Hospital and Karmanos Cancer Institute, Wayne State University, Detroit, MI; daggerDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY; double daggerDepartment of Pathology, Verona University, Italy; section signDepartment of Pathology, University Health Network and University of Toronto, Toronto, Ontario, Canada; parallelDepartment of Pathology, University of Insubria, Varese, Italy; and paragraph signDepartment of Pathology, University of Calgary, Calgary, Alberta, Canada.

Am J Surg Pathol. 2006 Feb;30(2):194-200. Abstract quote  

Most pancreatic endocrine neoplasms (PENs) show characteristic and well-recognized endocrine morphology; however, a lipid-rich pattern, which can present a diagnostic problem in biopsies, has been reported, mostly as individual cases. Some have been included in descriptions of the rare clear-cell variant associated with von Hippel-Lindau (VHL) syndrome. The histogenesis, clinicopathologic characteristics, and significance of this lipid-rich pattern have not been unraveled.

In this study, 11 PENs exhibiting foamy, microvesicular cytoplasm were analyzed. In some cases, the nuclei were distorted by the vesicles, and the usual endocrine chromatin pattern was not evident. The growth pattern was relatively diffuse, with vague compartmentalization of the cells by a delicate vasculature; prominent nesting was noted in only 4 cases.

Pathology reports indicated substantial diagnostic challenge in these cases; on biopsies, 1 case was originally diagnosed as adrenal cortical carcinoma, another as renal cell carcinoma, a third as solid-pseudopapillary tumor, and a fourth had a fine needle aspiration cytologic diagnosis of adenocarcinoma. All cases were chromogranin and synaptophysin positive. Electron microscopy in 3 cases confirmed the cytoplasmic vesicles to be lipid vacuoles. Neurosecretory granules were also evident. Clinically, as in conventional PENs, there appeared to be two distinct subsets: Two cases were familial or functional/syndromic (1 with VHL and the other with MEN-1 and glucagonoma syndrome) and occurred in younger adults (ages 41 and 47 years); the majority (n = 9) were nonfunctional/nonsyndromic and nonfamilial. The latter group was mostly represented by elderly males (mean age: 65 vs. 58 years in conventional sporadic PENs). Immunohistochemically, markers implicated in VHL-associated neoplasia, including HIF-1alpha, inhibin, and Melan-A (in clear-cell PENs) and MUC6 (in serous cystadenomas) were mostly negative in lipid-rich PENs (1 of 10, 1 of 10, 0 of 10 and 0 of 10, respectively).
In conclusion, the lipid-rich pattern, reminiscent of adrenal cortical cells, represents a distinct subset of PENs. It presents a diagnostic challenge for surgical pathologists, especially in biopsies. EM supports the name lipid-rich for this variant. The findings suggest that the pathogenesis of lipid-rich tumors may be different from the VHL-associated clear-cell variants of PENs.

Neuroendocrine carcinomas of the pancreas with 'Rhabdoid' features.

Perez-Montiel MD, Frankel WL, Suster S.


Am J Surg Pathol 2003 May;27(5):642-9 Abstract quote

Neuroendocrine carcinomas of the pancreas are rare neoplasms whose morphologic features generally mirror those seen in neuroendocrine tumors in other organs. Rarely, however, they may display unusual morphologic appearances that can introduce difficulties for diagnosis.

We report four cases of primary neuroendocrine carcinomas of the pancreas (islet cell tumors) that were characterized by prominent "rhabdoid" features of the tumor cells. The lesions occurred in two men and two women 37-79 years of age who presented with symptoms of biliary obstruction and epigastric pain; one patient had recurrent gastric ulcers and an elevated gastrin level.

The tumors were located in the head and tail of the pancreas and measured 2.5-4.5 cm in greatest diameter. Histologic examination revealed sheets of monotonous tumor cells with uniform round nuclei showing dispersed chromatin and containing abundant densely eosinophilic cytoplasmic inclusions that displaced the nuclei toward the periphery. In all cases, the rhabdoid elements appeared to merge with areas showing a more conventional neuroendocrine morphology.

Immunohistochemical studies in all cases showed strong cytoplasmic positivity of the rhabdoid tumor cells for chromogranin, synaptophysin, and cytokeratin. Recognition of this unusual morphologic appearance is of importance to avoid mistaking these lesions for other types of malignant neoplasm.


Malignant Islet Cell Tumor with Sarcomatous Differentiation

Lyska Emerson, M.D., Lester J. Layfield, M.D., Russell Reiss, M.D., Sean Mulvihill, M.D. and Joseph Holden, M.D.

Departments of Pathology (LE, LJL, JH) and Surgery (RR, SM), University of Utah Health Sciences Center, Salt Lake City, Utah

Mod Pathol 2001;14:1187-1191 Abstract quote

Malignant mesenchymal neoplasms of the pancreas are rare and malignant islet cell tumors with sarcomatous dedifferentiation are rarer still.

We present a case of malignant islet cell tumor with sarcomatous differentiation, which to our knowledge is only the second reported case showing such a combination of morphologic features. Clinically, the neoplasm was not hormonally active and immunohistochemical staining was negative for gastrin, glucagon, insulin and somatostatin. The sarcomatous component strongly reacted with an antibody directed against vimentin, and a minority of cells stained strongly with antisera directed against desmin and smooth muscle actin. The spindle cell component was nonreactive with antibodies directed against Factor VIII. The myogenous direction of differentiation in the present tumor is similar to that seen in the prior case report of malignant islet cell tumor with rhabdomyosarcomatous differentiation.


General Neuroendocrine markers such as chromogranins, synaptophysin, and neuron specific enolase
Insulinoma Insulin and proinsulin
50% are multihormonal
Glucagonoma Glucagon
Rarely multihormonal
Somatostatinoma Somatostatin
Rarely multihormonal
Gastrinoma Gastrin
Rarely multihormonal
Enterochromaffin cell tumor causing the carcinoid syndrome Serotonin
Tumors producing Acromegaly GRF or GH
Tumors producing Cushing's syndrome ACTH
Tumors producing hypercalcemia PTH and parathrin
Tumors with multiple syndromes  
Nonfunctioning tumors (Including PP tumors)  
CD10 expression in pancreatic endocrine tumors: correlation with prognostic factors and survival.

Deschamps L, Handra-Luca A, O'toole D, Sauvanet A, Ruszniewski P, Belghiti J, Bedossa P, Couvelard A.

Department of Pathology, AP-HP, Beaujon Hospital, 92110 Clichy, France.

Hum Pathol. 2006 Jul;37(7):802-8. Epub 2006 Jun 2. Abstract quote  

CD10 is a cell surface metalloprotease expressed by a variety of hematopoietic and solid tumors. Immunohistochemical expression of CD10 was examined in 91 pancreatic endocrine tumors (PETs) included in tissue microarrays and representing various stages of tumorigenesis as well as in 10 normal pancreas tissues. The results were correlated with histoprognostic factors, namely, Ki-67 index and microvascular density.

Thirty PETs (33%) presented positive cytoplasmic staining, and in 7 cases (8%), membranous staining also was observed. Stromal CD10 positivity was observed in 29 PETs (32%). In nontumoral pancreatic tissue, the islets were consistently negative. Epithelial cytoplasmic expression of CD10 increased with World Health Organization classification: CD10 was detected in 12% of benign tumors, 29% of tumors of uncertain prognosis, 38% of well-differentiated carcinomas, and 86% of poorly differentiated carcinomas. Membranous expression of CD10 correlated with poor differentiation (P = .0004). Expression of CD10 also correlated significantly with a high proliferative index (P = .020), low microvascular density (P = .043), large tumor size (P = .023), and presence of metastasis (P = .013). Expression was associated with poorer survival (P = .017). No statistical relation was observed between stromal CD10 expression and any of the histopathologic criteria examined.

In conclusion, CD10 is expressed in a subset of PETs and correlates with histopathologic indicators of poor outcome, suggesting a role for this molecule in tumorigenesis and prognostic analysis.

Cytokeratin 7 and 20 and thyroid transcription factor 1 can help distinguish pulmonary from gastrointestinal carcinoid and pancreatic endocrine tumors

Yun-Cai Cai, MD, PhD
Barbara Banner, MD
Jonathan Glickman, MD, PhD
Robert D. Odze, MD, FRCP

Hum Pathol 2001;32:1087-1093. Abstract quote

Expression of cytokeratin (CK) 7 and 20 is commonly used to help distinguish adenocarcinomas from different sites. Thyroid transcription factor 1 (TTF-1) is a 38-kd protein, located primarily in the nucleus of type 2 pneumocytes and clara cells. TTF-1 has been shown to be present in a variety of lung and thyroid tumors and in pulmonary small-cell carcinomas. Carcinoid tumors from the lung and the gastrointestinal (GI) tract are histologically similar and thus are difficult to differentiate from each other based on histologic criteria. Pancreatic endocrine tumors (PET) have a similar histologic appearance to these other tumors.

The purpose of this study was to determine the efficacy of differentiating these 3 groups of tumors by their expression of CK7, CK20, and TTF-1.

Routinely processed paraffin-embedded tissue sections from 62 carcinoid tumors (lung, 16; gastrointestinal [GI] tract, 46) and 12 PETs were immunohistochemically stained for CK7, CK20, and TTF-1. The degree of expression in each tumor was graded as 1+ (1% to 10% of cells positive), 2+ (11% to 25%), 3+ (26% to 50%), and 4+ (>50%). The data were compared between tumor types and between carcinoid tumors from the various locations in the GI tract (stomach, 8; small intestine, 19; large intestine, 17; appendix, 2).

CK7 was expressed in 10 (63%) of 16 pulmonary carcinoid tumors and only 5 (11%) of 46 GI carcinoid tumors (P < .001). Pancreatic endocrine tumors showed CK7 positivity in 6 (50%) of 12 cases, which was similar to the findings in lung carcinoids and significantly higher than in GI carcinoids (P < .01). CK20 was expressed in 0 (0%) of 16 pulmonary carcinoid tumors, in contrast to 24% and 33% of GI carcinoid tumors (P < .05) and PETs (P < .05), respectively. TTF-1 expression was highly specific for pulmonary carcinoid tumors. This peptide was present in 11 (69%) of 16 pulmonary carcinoid tumors and in only 1 (2%) of 46 and 0 (0%) of 12 GI carcinoid tumors (P < .001) and PETs (P < .001), respectively. A CK7+/CK20/TTF-1+ immunopanel result was moderately sensitive (sensitivity, 50%), and highly specific (specificity, 100%), for a diagnosis of pulmonary carcinoid tumor. CK7, CK20, and TTF-1 did not differ significantly between carcinoid tumors located in different sites of the GI tract. However, a trend was observed toward a lower prevalence of CK20 positivity in gastric tumors (P = .06) than in GI carcinoid tumors from the small intestine, colon, or appendix.

Expression of CK7 and CK20, and particularly TTF-1, may be useful in distinguishing pulmonary from GI carcinoid tumors and PETs, especially when evaluated as a panel of markers. TTF-1 is highly specific for pulmonary carcinoid tumors.

Neuroendocrine Secretory Protein-55 (NESP-55) Expression Discriminates Pancreatic Endocrine Tumors and Pheochromocytomas From Gastrointestinal and Pulmonary Carcinoids.

Srivastava A, Padilla O, Fischer-Colbrie R, Tischler AS, Dayal Y.

*Tufts-New England Medical Center, Boston, MA; and daggerDepartment of Pharmacology, University of Innsbruck, Innsbruck, Austria.

Am J Surg Pathol. 2004 Oct;28(10):1371-1378. Abstract quote  

Neuroendocrine secretory protein-55 (NESP-55), the latest addition to the chromogranin family, is a product of a genomically imprinted gene transcribed exclusively from the maternal allele. Initial studies have shown it to have a less widespread distribution than that of chromogranin A in normal tissues. It has also been suggested that NESP-55 may be a marker of neuroendocrine tumors differentiating toward the adrenal chromaffin and pancreatic islet cells. Metastatic gastrointestinal and pulmonary carcinoids may occasionally be difficult to distinguish from pancreatic endocrine tumors (PETs) and pheochromocytomas on morphologic grounds alone.

We studied neuroendocrine tumors from these sites to see if NESP-55 expression could reliably discriminate pulmonary and gastrointestinal carcinoids from neuroendocrine tumors arising in the pancreas or the adrenal medulla. Sixty-three neuroendocrine tumors positive for one or more immunohistochemical marker of neuroendocrine differentiation (chromogranin A, chromogranin B, synaptophysin, secretogranin II, neuron-specific enolase) were selected for the study and consisted of 34 typical carcinoids (15 pulmonary, 11 ileal, 4 gastric, and 4 rectal), 19 PETs, and 10 pheochromocytomas (4 sporadic, 3 MEN-2, 2 neurofibromatosis type 1, and 1 VHL). All cases were stained for NESP-55 after microwave antigen retrieval using a rabbit polyclonal antibody at a dilution of 1:1000. Sections of normal adrenal medulla were used as positive controls for NESP-55 staining. Negative controls consisted of omission of primary antibody and replacement with normal rabbit serum at an equivalent concentration. NESP-55 immunoreactivity was seen as brown finely granular cytoplasmic staining with prominent perinuclear accentuation. All gastric and ileal carcinoids studied were completely negative for NESP-55. One of four rectal and 1 of 15 pulmonary carcinoids showed focal positivity for it in less than 5% of tumor cells.

In contrast, all 10 pheochromocytomas and 14 of 19 PETs showed strong immunohistochemical staining in a variable proportion of tumor cells. Diffuse positivity (>75% of tumor cells) was seen in 6 of 14 PETs and 8 of 10 pheochromocytomas.

Our results indicate that, in contrast to the other granins, NESP-55 reactivity is restricted to endocrine tumors of the pancreas and the adrenal medulla. Immunohistochemical expression of NESP-55 may thus be useful in assigning a pancreatic or adrenal origin to metastatic endocrine tumors of unknown orgin.


Benign versus malignant tumors

Unequivocal evidence of malignancy:

Gross invasion of adjacent organs
Metastases to regional lymph nodes or other organs
Blood vessel invasion

>3cm usually malignant
>6cm almost always malignant
Histological parameters suggestive of malignancy High mitotic index above 12-4/10 hpf
Tumor necrosis
Definitive invasion of tumor capsule, adjacent normal pancreas, lymphatics, or perineural spaces



90-95% tumors are benign

Tumors >3 cm and 5 or more mitoses/10 hpf more likely to be malignant

50% are invasive and 80% are malignant
70% metastatic at diagnosis
74% malignant

68-85% malignant, greater than duodenal gastrinomas (25-57%)

54% associated with WDHA syndrome were malignant at presentation
Enterochromaffin cell tumor causing the carcinoid syndrome
50% of well differentiated tumors were metastatic
15/17 tumors associated with carcinoid syndrome were metastatic

Prevalence and prognostic significance of acinar cell differentiation in pancreatic endocrine tumors.

Yantiss RK, Chang HK, Farraye FA, Compton CC, Odze RD.

Department of Pathology, University of Massachusetts Memorial Medical Center (R.K.Y.), Worcester, Massachusetts, U.S.A.; Kosin University Medical Center (H.-K.C.), Pusan, Korea.


Am J Surg Pathol 2002 Jul;26(7):893-901 Abstract quote

We have noted that many histologically and immunohistochemically confirmed pancreatic endocrine tumors show immunophenotypic evidence of acinar cell differentiation, but the clinical relevance of this finding is unknown.

We performed this study to evaluate the prevalence and prognostic significance of exocrine differentiation by immunohistochemistry in pancreatic endocrine tumors that do not show morphologic features of acinar cell differentiation. Routinely processed tissue sections from 87 pancreatic endocrine tumors were immunohistochemically stained with monoclonal antibodies against acinar (lipase, chymotrypsin, trypsin) and endocrine cell markers (chromogranin A, neuron-specific enolase, synaptophysin, Leu-7) and for the proliferation-associated peptide Ki67. The degree of staining with each marker was graded on a three-tier scale for acinar markers (grade 0, <5%; grade 1, 5-10%; grade 2, 11-25%; and grade 3, >25%) and on a four-tier scale for endocrine markers (grade 0, <5%; grade 1, 5-25%; grade 2, 26-50%; grade 3, 51-75%; and grade 4, >75%), and the results were correlated with clinical outcome (mean follow-up 53 months). Greater than 75% of the tumor cells stained for chromogranin A, neuron-specific enolase, synaptophysin, and Leu-7 in 100%, 96%, 93%, and 27% of cases, respectively.

Overall, 66% of tumors stained positively for at least one acinar cell marker, 31% stained for at least two acinar cell markers, and 13% stained for all three acinar cell markers. Forty-seven percent stained for lipase (23 grade 1, 11 grade 2, seven grade 3), 37% for trypsin (22 grade 1, three grade 2, seven grade 3), and 25% stained for chymotrypsin (13 grade 1, five grade 2, four grade 3). No correlation was noted between the presence or extent of expression of any single or combination of acinar cell markers and clinical outcome. However, higher tumor stage correlated with a poor clinical outcome (p = 0.002), and location in the tail of the pancreas was associated with a longer interval to tumor recurrence (p = 0.03). The presence of synaptophysin (p = 0.03) and Leu-7 expression (p = 0.03) correlated significantly with less aggressive clinical behavior.

An association was observed between increased Ki67 labeling and poorer clinical outcome, but this was not statistically significant (p >0.05). In conclusion, immunophenotypic evidence of acinar cell differentiation is common in pancreatic endocrine tumors, but this feature does not have any relevance to clinical prognosis. However, in addition to tumor stage, location in the pancreatic tail and the immunohistochemical expression of synaptophysin and/or Leu-7 may be useful prognostic indicators in patients with these lesions.

The Predictive Value of CK19 and CD99 in Pancreatic Endocrine Tumors.

Department of Pathology, University Health Network/Toronto Medical Laboratories, University of Toronto, Canada.


Am J Surg Pathol. 2006 Dec;30(12):1588-94. Abstract quote

Prediction of behavior in pancreatic endocrine tumors (PETs) is reliant on clinicopathologic features. However, there remains a cohort of PETs that behave aggressively despite showing indolent pathologic features. Recently, it has been suggested that CK19 and CD99 are sensitive ancillary markers that predict outcome in PETs.

An analysis of 54 PETs and 2 resected liver metastases was undertaken to examine the relationship of CK19 and CD99 and the pathologic criteria in the WHO classification of PETs. CK19 was found to correlate with mitotic count (>5/50 high-power fields), an MIB-1 labeling index of >/=2%, lymphovascular/perineural permeation, lymph node involvement, and liver spread. Although not statistically significant, CK19-negative tumors tended to be smaller than the average tumor size in the series (2.5 vs. 3.6 cm). CD99 did not show any significant correlation with any of the WHO criteria.

Tumors that are confined to the pancreas with low mitotic count and MIB-1 labeling index, tended to be CD99-positive. Both CK 19 (negative) and CD99 (positive) correlated with insulin-positive PETs.

In conclusion, CK 19 may prove to be a useful ancillary diagnostic test in the routine work-up of PETs. CD99 does not appear to be as useful.

There is no compelling evidence, from our study, to suggest that both these markers may be used in concert to predict the behavior of PETs.
Cytokeratin 19 Is a Powerful Predictor of Survival in Pancreatic Endocrine Tumors.

Deshpande V, Fernandez-Del Castillo C, Muzikansky A, Deshpande A, Zukerberg L, Warshaw AL, Lauwers GY.

*Gastrointestinal Pathology Service, Department of Pathology and the Departments of daggerSurgery and double daggerBiostatistics, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Am J Surg Pathol. 2004 Sep;28(9):1145-1153. Abstract quote  

The prediction of the behavior of pancreatic endocrine tumors (PETs) is a difficult exercise. CK19, a marker of pancreatic ductal cells, does not stain normal islet cells.

Our aim was to evaluate the prognostic value of traditional parameters, including the Capella classification, as well as CK19. We evaluated the clinicopathologic features of 101 curatively resected PETs. The influence on survival of size, functional status of tumor, growth pattern, nuclear grade, mitoses (>2/10 HPF), vascular and perineural invasion, and necrosis was determined.

Immunohistochemistry for Ki-67 and CK19 was performed in 45 and 54 cases, respectively. Cases were categorized as per the Capella classification as: benign, borderline, low-grade, and high-grade malignant. The different variables were tested by standard univariate and multivariate analyses. Mitoses (P = 0.03), solid pattern (P = 0.04), necrosis (P = 0.01), vascular invasion (P = 0.003), perineural invasion (P = 0.02), CK19 staining (P = 0.0008), and Ki-67 (P = 0.02) were significant prognostic indicators by univariate analysis while the Capella classification was not significant. By multivariate analysis, only CK19 was significant (P = 0.0008). None of the CK19-negative cases died of disease, while 10 of 28 CK19-positive cases died of disease and 3 are alive with disease. The Capella classification includes malignant tumors in its benign and borderline categories. CK19 is a powerful predictor of survival and can potentially segregate benign and malignant PETs.

We suggest that all PETs with any one of the following features be diagnosed as malignant: presence of necrosis, vascular invasion, perineural invasion, or CK19 positivity. We hypothesize that a subgroup of PETs may share a common histogenesis with pancreatic adenocarcinomas.

Immunohistochemical expression of transforming growth factor and epidermal growth factor receptor in pancreatic endocrine tumors

Amitabh Srivastava, MD
Julian Alexander, MBBS
Inna Lomakin, MS
Yogeshwar Dayal, MD

Hum Pathol 2001;32:1184-1189. Abstract quote

Coexpression of transforming growth factor (TGF-) and its receptor epidermal growth factor receptor (EGFR) is known to be associated with aggressive biologic behavior and adverse clinical outcome in a variety of tumors, including pancreatic adenocarcinomas. However, very little information is currently available as to whether this is true of pancreatic endocrine tumors (PETs) as well.

Thirty-five PETs were retrospectively studied for immunohistochemical expression of TGF-, the intracellular and extracellular domains of EGFR, and various hormonal secretory products. Proliferative activity was additionally studied (in 20 cases only) using the MIB-1 antibody. Thirty-one (89%) of 35 tumors were reactive for 1 or more of the peptide hormones tested; 22 (63%) tumors were positive for TGF-; and 23 (65%) were positive for the intracellular and/or extracellular domain of EGFR. Based on their TGF- and EGFR expression, these tumors could be classified into 4 groups. Of the 10 tumors in group I (positive for TGF- and the complete EGFR molecule), 3 were malignant, 6 were >2 cm in diameter, 5 were functional, and 1 had a proliferative index of >40%. The 12 tumors in group II (positive for TGF- but negative for the intracellular and/or extracellular domain of EGFR) included 4 malignant tumors, 4 PETs >2 cm in diameter, 8 functional, and 1 with a proliferative index of >40%. The 7 PETs in group III (positive for the intracellular/extracellular domain of EGFR alone) included 3 malignant tumors, 3 PETs >2 cm in diameter, and 3 functional tumors. The 6 tumors in group IV (completely negative for both TGF- and EGFR) included 4 malignant tumors, 3 PETs >2 cm in diameter, and 4 functional lesions.

Therefore, immunohistochemical expression of TGF- and EGFR, either alone or in concert, shows no correlation with size, functional status, secretory profile, or biologic behavior and hence cannot be used as a marker of malignancy in this group of tumors.

Loss of p27 Nuclear Expression in a Prognostically Favorable Subset of Well-Differentiated Pancreatic Endocrine Neoplasms

Ayman Rahman, 1 Anirban Maitra, MD, 1 Raheela Ashfaq, MD, 3 Charles J. Yeo, MD,2 John L. Cameron, MD, 2 and Donna E. Hansel, MD, PhD .
Am J Clin Pathol 2003;120:685-690 Abstract quote

Decreased expression of p27 occurs in aggressive colon, breast, and prostate neoplasms; p27 loss often correlates with worsened prognosis. Paradoxical over expression has been described in benign and malignant pancreatic endocrine neoplasms (PENs).

To investigate prognostic usefulness of p27 expression in PENs, we immunolabeled 42 primary PENs, with or without metastases, for p27 and separated lesions using a nuclear labeling index (NLI) of 10%. Of the 42 lesions, 26 demonstrated a 10% or higher NLI and 16 an NLI less than 10%. Comparison of lymph node status revealed that 50% of primary PENs with a 10% or higher NLI (13/26) demonstrated lymph node metastases, whereas only 6% of lesions with an NLI of less than 10% (1/16) demonstrated lymph node metastases ( P = .0067). We next examined 11 liver and 7 lymph node metastases for p27 immunolabeling to determine whether p27 also is paradoxically retained in lesions that have metastasized. All 18 lesions demonstrated an NLI of 10% or higher for p27.

Expression of p27 protein therefore appears to be lost in a subset of well-differentiated PENs with indolent features but paradoxically retained in PENs associated with metastatic disease.

Low nuclear proliferative activity is associated with nonmetastatic islet cell tumors.

Jorda M, Ghorab Z, Fernandez G, Nassiri M, Hanly A, Nadji M.

Departments of Pathology (Drs Jorda, Ghorab, Nassiri, Hanly, and Nadji) and Clinical Oncology (Dr Fernandez), University of Miami, Jackson Memorial Medical Center, Miami, Fla.


Arch Pathol Lab Med 2003 Feb;127(2):196-9 Abstract quote

Context.-Traditional morphologic features of tumor aggression are of limited value in predicting the malignant behavior of endocrine neoplasms. We explored the potential value of nuclear proliferative activity (using Ki-67 immunostaining with semiquantitative scoring) in predicting the clinical behavior of pancreatic islet cell tumors (ICTs), and we correlated this characteristic with hormone expression.

Objective.-To evaluate whether Ki-67 immunostaining using a semiquantitative scoring system has value in predicting the clinical behavior of pancreatic ICTs.

Design.-We studied 39 pancreatic ICTs from 39 patients. Twenty-two ICTs did not metastasize in a median follow-up period of 91 months. The remaining 17 neoplasms did produce metastases (8 in liver, 7 in regional lymph nodes, and 2 in peritoneum). Immunohistochemistry was performed using antibodies to Ki-67 and pancreatic hormones (insulin, glucagon, gastrin, somatostatin, pancreatic polypeptide, vasoactive intestinal polypeptide, and corticotropin). A semiquantitative Ki-67 grading system was followed. The nuclear proliferative activity, as determined by a positive reaction for Ki-67, was considered low (<5% of cells staining positively), intermediate (5%-25% of cells staining positively), or high (>25% of cells staining positively). Results.-The majority of the nonmetastatic ICTs (16 cases, 73%) demonstrated either negative or low staining for Ki-67 (P <.001). Conversely, all metastatic ICTs expressed at least an intermediate-grade reaction. High nuclear proliferative activity was only seen in metastatic neoplasms (3 cases, 17%). There was no relationship between immunoexpression of pancreatic hormones and nuclear proliferative activity by either group of tumors.

Conclusion.-An ICT with low nuclear proliferative activity is unlikely to metastasize, whereas high proliferative activity is associated with a metastatic phenotype. Immunohistochemical assessment of Ki-67 using a semiquantitative scoring system is a simple and reliable detection method of cellular proliferative activity in ICTs of the pancreas.

Median survival of 4 years for malignant tumors with metastasis undergoing palliative resection
3/13 patients cured after resection
Most die within 2 years of diagnosis
MEN 1 patients have 10 year survival of 93%
Sporadic tumors have 10 year survival of 74%
Tumors with liver metastasis have 7 year survival

Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients.

Solorzano CC, Lee JE, Pisters PW, Vauthey JN, Ayers GD, Jean ME, Gagel RF, Ajani JA, Wolff RA, Evans DB.

Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Tex. 77030, USA.

Surgery 2001 Dec;130(6):1078-85 Abstract quote

BACKGROUND: The natural history of nonfunctioning islet cell carcinoma of the pancreas is poorly defined. We therefore reviewed our institutional experience during a period of 12 years to define more clearly the natural history of this disease as a basis for individual therapeutic recommendations.

METHODS: The records of all patients who had histologically or cytologically confirmed nonfunctioning islet cell carcinoma of the pancreas were retrospectively reviewed. Patients were grouped by extent of disease at diagnosis and by initial treatment. Survival distributions were estimated by Kaplan-Meier analysis.

RESULTS: One hundred sixty-three patients with nonfunctioning islet cell carcinoma of the pancreas were identified. The overall median survival duration was 3.2 years. The median survival was 7.1 years in patients with localized disease who underwent a potentially curative resection and 5.2 years in those with locally advanced, unresectable, nonmetastatic disease (P = .04). Patients with metastatic disease that could not be resected had a median survival of 2.1 years.

CONCLUSIONS: Patients with completely resected localized disease had a long median survival. Patients with nonmetastatic but unresectable locally advanced disease also had a surprisingly long median survival; major treatment-related morbidity may be hard to justify in this subgroup. The short median survival in patients with metastatic disease suggests that the frequent practice of observation in this patient subgroup needs to be reexamined and that continued investigation of regional and systemic therapies with novel agents is warranted.


Liver, abdominal lymph nodes

Occasionally bone, peritoneum, lung, kidney, thyroid


Cellular proliferative fraction measured with topoisomerase IIalpha predicts malignancy in endocrine pancreatic tumors.

Diaz-Rubio JL, Duarte-Rojo A, Saqui-Salces M, Gamboa-Dominguez A, Robles-Diaz G.

Department of Gastroenterology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico.
Arch Pathol Lab Med. 2004 Apr;128(4):426-9. Abstract quote

CONTEXT: Endocrine pancreatic tumors (EPTs) are rare lesions with varying biological behavior. Establishing malignancy is a challenge for clinicians and pathologists.

OBJECTIVE: To establish the role of proliferative, apoptotic, angiogenic, and hormonal markers as predictors of malignancy in EPTs.

DESIGN: Paraffin-embedded EPT samples were studied for prognostic markers.

PATIENTS: Twenty-one consecutive patients with a diagnosis of EPT.

MAIN OUTCOME MEASURES: The proliferative fraction (topoisomerase IIalpha), microvascular density (CD34), vascular endothelial growth factor expression, and estrogen receptor-beta (ERbeta) expression were studied by immunohistochemistry on all EPTs. Apoptosis was also assessed with terminal deoxynucleotidyl transferase nick-end labeling.

RESULTS: We identified 13 benign and 8 malignant tumors. Topoisomerase IIalpha was significantly increased in malignant tumors (P =.001), while there were no differences in apoptosis, microvascular density, or vascular endothelial growth factor expression in association with malignancy. No correlation could be identified between microvascular density and vascular endothelial growth factor expression, and ERbeta was not detected. A receiver operating characteristic curve for topoisomerase IIalpha disclosed that above a labeling index of 13, the test had 88% sensitivity and 100% specificity for predicting malignancy.

CONCLUSION: Cellular proliferation measured with topoisomerase IIalpha is a simple prognostic marker for malignancy in EPTs, unlike apoptosis, angiogenesis, or the presence of ERbeta, which were not associated with malignant behavior. These findings designate a defined field for future research on endocrine pancreatic carcinogenesis and a possible target for chemotherapeutic agents.

Surgical excision

Antihormonal therapy
Cytotoxic therapy
Hepatic arterial embolization

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Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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