Mucinous cystic neoplasm (mucinous cystadenocarcinoma of low-grade malignant potential) of the pancreas: a clinicopathologic study of 130 cases.

Thompson LD, Becker RC, Przygodzki RM, Adair CF, Heffess CS.
Am J Surg Pathol. 1999 Jan;23(1):1-16.
Mucinous cystic neoplasms (MCNs) of the pancreas are uncommon tumors. The classification and biologic potential of these neoplasms remain the subject of controversy. Attempts to classify these tumors in a similar manner to ovarian MCNs remains controversial, as even histologically benign-appearing pancreatic MCNs metastasize and are lethal. One hundred thirty cases of MCNs were identified in the files of the Endocrine Pathology Tumor Registry of the Armed Forces Institute of Pathology from the years 1979 to 1993. The pathologic features, including hematoxylin and eosin staining, histochemistry, immunohistochemistry (IHC), cell cycle analysis, and K-ras oncogene determination were reviewed. These findings were correlated with the clinical follow-up obtained in all cases. There were 130 women, aged 20-95 years (mean age at the outset, 44.6 years). The patients had vague abdominal pain, fullness, or abdominal masses. More than 95% of the tumors were in the pancreatic tail or body and were predominantly multilocular. The tumors ranged in size from 1.5 to 36 cm in greatest dimension, with the average tumor measuring >10 cm. A spectrum of histomorphologic changes were present within the same case and from case to case. A single layer of bland-appearing, sialomucin-producing columnar epithelium lining the cyst wall would abruptly change to a complex papillary architecture, with and without cytologic atypia, and with and without stromal invasion. Ovarian-type stroma was a characteristic and requisite feature. Focal sclerotic hyalinization of the stroma was noted. This ovarian-type stroma reacted with vimentin, smooth muscle actin, progesterone, or estrogen receptors by IHC analysis. There was no specific or unique epithelial IHC. K-ras mutations by sequence analysis were wild type in all 52 cases tested. Ninety percent of patients were alive or had died without evidence of disease (average follow-up 9.5 years), irrespective of histologic appearance; 3.8% were alive with recurrent disease (average 10 years after diagnosis); and 6.2% died of disseminated disease (average 2.5 years from diagnosis). Irrespective of the histologic appearance of the epithelial component, with or without stromal invasion, pancreatic MCNs should all be considered as mucinous cystadenocarcinomas of low-grade malignant potential. Pancreatic MCNs cannot be reliably or reproducibly separated into benign, borderline, or malignant categories.
PubMed ID: 9888699
Article Size: 4 MB

A clinicopathologic and immunohistochemical study of 22 intraductal papillary mucinous neoplasms of the pancreas, with a review of the literature.

Paal E, Thompson LD, Przygodzki RM, Bratthauer GL, Heffess CS.
Mod Pathol. 1999 May;12(5):518-28.
Intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas are rare lesions. We undertook this study to analyze these tumors by focusing on the diagnostic criteria and correlating the histologic features with clinical prognosis. Twenty-two cases of IPMN were retrieved from the Endocrine Tumor Registry of the Armed Forces Institute of Pathology. Blocks or unstained slides were available for histochemical and immunohistochemical studies (including proliferative markers and cell cycle regulators) and K-ras oncogene mutations in 15 cases. Patient follow-up was obtained in all of the cases. IPMN occurs in both genders with a slight male predominance, with a mean age at presentation of 64.4 years (range, 48-85 yr). The patients presented with abdominal pain. The neoplasms were radiologically and grossly cystic, usually (18 cases of 22) located in the head of the pancreas. Histologically, the tumors consisted of intraductal papillary proliferations protruding into and expanding the pancreatic ducts. Invasion into the surrounding pancreatic parenchyma was detected in 15 cases. Chronic pancreatitis was present in all of the cases. p27 immunoreactivity always exceeded the immunoreactivity of cyclin E. K-ras oncogene mutations were detected in two cases. Patients were treated with a complete surgical resection (n = 7) or a Whipple procedure (n = 13). Only 2 of 22 patients died of disease (3 died immediately postoperatively and 3 died of unrelated causes), whereas the remaining 14 patients were alive at last follow-up, without evidence of disease, an average of 58.2 months after initial presentation. IPMNs are rare, distinctive neoplasms, with complex intraductal papillae, that can be easily separated from in situ ductal adenocarcinoma and mucinous cystic neoplasms. The high ratio of p27 protein to cyclin E supports the excellent prognosis of these neoplasms, despite the presence of invasion and K-ras oncogene mutation.
PubMed ID: 10349991
Article Size: 8.5 MB

Adenosquamous carcinoma of the pancreas: a clinicopathologic series of 25 cases.

Kardon DE, Thompson LD, Przygodzki RM, Heffess CS.
Mod Pathol. 2001 May;14(5):443-51.
BACKGROUND: Adenosquamous carcinoma is a rare aggressive subtype of pancreatic adenocarcinoma. We describe the clinical, pathologic, and molecular characteristics of 25 of these lesions, the largest series to date.
METHODS: Twenty-five cases of adenosquamous carcinoma of the pancreas diagnosed between 1961 and 1994 were retrieved from the files of the Endocrine Registry of the Armed Forces Institute of Pathology. Histologic features were reviewed, histochemical, immunohistochemical, and molecular (k-ras) studies were performed, and patient follow-up was obtained.
RESULTS: The patients included 17 men and eight women, aged 28 to 82 years (mean, 65.4 y). The patients usually experienced weight loss (n = 17) or painless jaundice (n = 11), while also presenting with other abdominal symptoms. The tumors affected the head most frequently (n = 17), followed by the tail (n = 9) or body (n = 4). Five cases involved more than one anatomic region of the pancreas. Microscopically, all tumors demonstrated dual differentiation toward adenocarcinoma and squamous cell carcinoma. All cases tested were immunoreactive with keratin (AE1:AE3 and CK1), whereas other keratin markers were variably expressed: CK5/6 (88%), CK7 (68%), Cam5.2 (41%), and CK20(26%). CA-19-9 (84%) and CEA (74%) were positive in the majority of the cases. K-ras oncogene mutations were identified in seven of 13 cases. All patients died from their disease an average of 5.8 months after diagnosis (range, 1 to 33 months).
CONCLUSIONS: Adenosquamous carcinoma of the pancreas represents a distinct clinical and pathologic entity, demonstrating the expected immunoprofile and k-ras oncogene mutation of a ductal origin, with a worse prognosis than ductal adenocarcinoma.
PubMed ID: 11353055
Article Size: 2.5 MB

A clinicopathologic and immunohistochemical study of 35 anaplastic carcinomas of the pancreas with a review of the literature.

Paal E, Thompson LD, Frommelt RA, Przygodzki RM, Heffess CS.
Ann Diagn Pathol. 2001 Jun;5(3):129-40.
Anaplastic pancreatic carcinomas are rare tumors, frequently displaying a variety of growth patterns. The literature lacks a comprehensive study of this tumor. Thirty-five cases of anaplastic carcinoma of the pancreas diagnosed between 1955 and 1997 were retrieved from the Endocrine Registry at the Armed Forces Institute of Pathology. Histology, immunophenotype, molecular analysis, and patient follow-up were analyzed. The tumors of 10 women and 25 men, aged 34 to 85 years (mean age at presentation, 62.5 years), were studied. Patients had vague symptoms (weight loss, pain, and fatigue, nausea, or vomiting), lasting an average of 13.2 weeks. The tumors, of an average size of 9.2 cm, were usually in the head or tail of the pancreas. The tumors were widely infiltrative, histomorphologically separated into predominantly large, pleomorphic cell, or spindle cell groups. Tumor phagocytosis and necrosis were noted. Immunohistochemical studies confirmed an epithelial origin with at least one epithelial marker in 78% of the tumors. K-ras mutations by sequence analysis were found in eight of 12 cases tested. Surgical biopsy/excision was used in all patients. Twenty-nine of 35 patients died of disease (average, 5.2 months), three died with no evidence of disease (average, 56.9 months), and three patients were alive at last follow-up (average, 94.0 months), one with residual disease. There was no statistically significant difference in survival between patients with and without a K-ras mutation. Anaplastic carcinoma of the pancreas usually occurs in the head of the pancreas in older men. The epithelial nature of the pleomorphic cells (giant or spindled) can usually be documented. Patients with K-ras mutations have a shorter survival time, even though the overall prognosis for all anaplastic carcinomas is fatal (93% fatality; average survival, 448 days). Ann Diagn Pathol 5: 129-140, 2001. This is a US government work. There are no restriction on its use.
PubMed ID: 11436166
Article Size: <1 MB

Renal cell carcinoma to the pancreas in surgical pathology material.

Thompson LD, Heffess CS.
Cancer. 2000 Sep 1;89(5):1076-88.
BACKGROUND: Clear cell carcinomas of the pancreas are rare and more likely represent metastatic renal cell carcinoma (RCC).
METHODS: Twenty-one cases of metastatic RCC to the pancreas were retrieved from the files of the Endocrine Registry of the Armed Forces Institute of Pathology. Histologic features were reviewed, special stains and immunohistochemical studies were performed, and patient follow-up data were obtained.
RESULTS: The patients included 9 women and 12 men ages 47-76 years (mean, 64.4 years). Patients experienced weight loss, abdominal pain, or a mass lesion. The tumors occurred anywhere within the pancreas. The mean size of the tumors was 4.0 cm. Histologically, the tumors were comprised of clear cells with a rich vascular network. The RCC was diagnosed before (n = 17 patients; ages up to 32.7 years) or after (n = 4 patients; ages up to 13.2 years) the pancreatic metastases were discovered. Surgery was used in all patients. Adjuvant chemotherapy was used in 4 patients. From the date of the diagnosis of pancreatic metastasis, 13 patients were dead with disseminated disease (DD) (mean, 4.5 years), and 8 patients were without disease (mean, 9.0 years). From the date of the diagnosis of primary RCC, 13 patients were DD (mean, 12.7 years), and 8 patients were without disease (mean, 24.7 years).
CONCLUSIONS: Although histochemical and immunohistochemical studies may help in the distinction between patients with primary versus metastatic clear cell tumors of the pancreas, clinical confirmation should be obtained. Surgical resection of the pancreatic metastatic disease is suggested, because the patient may still have a prolonged survival.
PubMed ID: 10964338
Article Size: 1 MB

A clinicopathologic and immunohistochemical study of ten pancreatic lymphangiomas and a review of the literature.

Paal E, Thompson LD, Heffess CS.
Cancer. 1998 Jun 1;82(11):2150-8. — Erratum in: Cancer 1998 Aug 15;83(4):824.
BACKGROUND: Pancreatic lymphangiomas are rare benign tumors, of which only a few cases have been reported in the literature. In this study, the authors present a series of primary pancreatic lymphangiomas.
METHODS: Cases of nonepithelial pancreatic cystic tumors (lymphangiomas) diagnosed between 1966 and 1994 were retrieved from the Endocrine Pathology Registry of the Armed Forces Institute of Pathology. Histologic features (in 10 cases) as well as histochemical and immunohistochemical studies (in 6 cases) were reviewed. Long term patient follow-up data were obtained in 9 cases.
RESULTS: The patients included 8 females and 2 males ages 2-61 years (mean age, 28.9 years) at initial presentation. The tumors were circumscribed and occurred predominantly (in 6 of 10 cases) in the tail of the pancreas. The multicystic, serous, or chylous fluid-filled cystic tumors ranged from 3 to 20 cm (average, 12.7 cm) in greatest dimension. Histologically, the tumors consisted of multilocular cystic spaces of various sizes, lined by endothelial cells. The stroma contained smooth muscle and mature lymphocytes. Immunohistochemistry determined the endothelial lining cells to be factor VIII-R antigen and CD31 positive (in all cases tested) but usually CD34 negative. All patients for whom follow-up data were obtained (n=9) were alive without evidence of disease an average of 7.2 years after initial diagnosis.
CONCLUSIONS: Pancreatic lymphangiomas occur predominantly in females within a wide age range. Multilocular, fluid-filled cysts, with endothelial immunoreactivity for factor VIII-R antigen and CD31, are characteristic of these tumors. Complete surgical excision of these benign tumors resulted in excellent long term prognoses for all patients studied.
PubMed ID: 9610694
Article Size: <1 MB

Mucinous cystic neoplasms of the pancreas: radiologic-pathologic correlation.

Buetow PC, Rao P, Thompson LD.
Radiographics. 1998 Mar-Apr;18(2):433-49.
Mucinous cystic neoplasms of the pancreas are rare primary tumors. They have pathologic and clinical similarities to biliary cystadenomas of the liver and mucinous cystic tumors of the ovary. Mucinous cystic neoplasms of the pancreas typically affect middle-aged women and arise in the tail of the pancreas. Gross pathologic and imaging features usually are those of a large, multilocular cystic mass. There is, however, a spectrum of radiologic findings that overlaps with those of other entities including pancreatic pseudocyst, other primary epithelial and nonepithelial tumors of the pancreas, and metastases. In most cases, ultrasound and computed tomography are the mainstays for radiologic evaluation, with magnetic resonance imaging having a complementary role. All mucinous cystic neoplasms should be considered as mucinous cystadenocarcinomas of low-grade malignant potential. Complete surgical excision alone results in an excellent clinical outcome and disease-free survival, irrespective of histologic or radiologic parameters in over 90% of cases studied.
PubMed ID: 9536488
Article Size: 1.5 MB

Monoclonal origins of malignant mixed tumors (carcinosarcomas). Evidence for a divergent histogenesis.

Thompson L, Chang B, Barsky SH.
Am J Surg Pathol. 1996 Mar;20(3):277-85.
Malignant mixed tumors (carcinosarcomas) are examples of unusual neoplasms whose occurrences have been observed in increasingly diverse sites but whose pathogenesis remains a complete mystery. Two antithetical hypotheses that have been advanced to explain the histogenesis of these tumors include the convergence hypothesis, which proposes an origin from two or more stem cells (multiclonal hypothesis), and the divergence hypothesis, which proposes an origin from a single totipotential stem cell that differentiates into separate epithelial and mesenchymal directions (monoclonal hypothesis). To test these hypotheses, a novel strategy for the determination of clonality from as few as 100 tumor cells obtained by enzymatic digestion of either fresh or formalin-fixed, paraffin-embedded tissues and cell sorting was used that exhibited the polymerase chain reaction (PCR) in amplifying a 511-bp region located within the first intron of the human hypoxanthine phosphoribosyl transferase gene, a site that contains inactive X chromosomal obligately methylated HpaII/MspI sites and single-base allelic polymorphisms in 5% females. Carcinoma cells gated on the basis of fluorescein isothiocyanate (FITC)-anti-cytokeratin and sarcoma cells gated on the basis of FITC-antivimentin or FITC-anti-desmin were sorted to homogeneity on FACSTAR and then subjected to genomic DNA extraction and Hpa II digestion before PCR amplification and subsequent analysis of the product on denaturing gradient gel electrophoresis. The comigrations of the single homoduplexes generated from both the carcinoma cells and sarcoma cells in six different malignant mixed tumors obtained from four different organs indicated clonal identity and monoclonality in all cases. These findings of monoclonality were confirmed independently by two other methods of clonality determination. The findings of a monoclonal origin of carcinosarcomas support the single totipotential stem-cell-divergence hypothesis.
PubMed ID: 8772780
Article Size: 2.5 MB