Pathology of Cancer of the Pancreas

1055-32O7/98 $8.00

PANCREATIC CANCER

+ O. O

PATHOLOGY OF CANCER OF THE PANCREAS Robb E. Wilentz, MD, and Ralph H. Hruban, MD

Cancer of the pancreas is not one disease. Although many researchers have lumped nearly 20 pathologically different neoplasms under the umbrella term cancer of the pancreas, each of these neoplasms is grossly and microscopically distinct. Importantly, each cancer may present uniquely, require a different treatment, and result in a specific outcome. For example, the stereotypical patient with ductal adenocarcinoma is a 65-year-old, male smoker. This patient has less than a 5% chance of surviving 5 years.3"95,132 In contrast, solid and cystic papillary neoplasms of the pancreas occur almost exclusively in young women, and surgery is almost always curative.71An understanding of the pathology of pancreatic cancer forms the cornerstone for rational treatment and prognostication. Cancers of the pancreas are classified broadly as primary, metastatic, or systemic. Primary cancers arise in the pancreas, and they show endocrine or nonendocrine differentiation. Metastatic cancers originate elsewhere and spread hematogenously or lymphatically to the pancreas secondarily. Systemic malignancies derive from the blood or lymph nodes and, by definition, simultaneously involve multiple sites, one of which may be the pancreas. Primary pancreatic cancers are epithelial (carcinomas) or mesenchymal (sarcomas); pathologists further divide the epithelial neoplasms into endocrine, solid (nonendocrine), and cystic (nonendocrine) tumors. For example, ductal adenocarcinoma, the most common primary pancreatic malignancy, is an epithelial, nonendocrine, solid neoplasm. This article focuses on the pathology of primary, epithelial, nonendocrine pancreatic tumors, first the solid and then the cystic ones. Primary mesenchymal tumors, metastatic malignancies, and systemic malignancies are explored only briefly. The clinical relevance of gross and microscopic findings is emphasized.

Supported in part by NIH P50-CA62924

From the Departments of Pathology (REW, RHH), and Oncology (RHH) The Johns Hopkins Medical Institutions, Baltimore, Maryland SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 7 NUMBER I JANUARY 1998

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PRIMARY SOLID NONENDOCRINE EPITHELIAL TUMORS Ductal Adenocarcinoma

Ductal adenocarcinoma, the most common primary malignancy of the pancreas, accounts for almost three-fourths of all primary nonendocrine cancer^.^^,^^ Ductal adenocarcinornas are composed of an infiltrating epithelial malignancies that recapitulate the differentiation of ductal structures. Gross Features

Three-fifths of ductal adenocarcinornas arise in the head of the pancreas, 15% Patients originate in the body and tail, and 20% diffusely involve the gland.28,126 with ductal adenocarcinornasin the head of the pancreas live longer than do those with carcinomas in the body and tail, most likely because they present earlier with obstructive ja~ndice.~ Grossly, ductal adenocarcinomas are white-yellow, poorly defined, firm masses that often obstruct and dilate the distal common bile and pancreatic ducts. Because of the tumor's infiltrative nature, appreciating the true extent of disease grossly is difficult. Indeed, microscopic analysis often reveals adenocarcinomathat extends significantly beyond the grossly recognized tumor mass.lZ6Nonetheless, gross tumor measurement does provide prognostic information. For example, Yeo et al140followed 201 patients who underwent pancreaticoduodenectomies for pancreas cancer and found that patients with carcinomas measuring less than 3 cm in greatest dimension fared significantlybetter than did patients with larger cancers. ~ ~ that patients with localized tumors less Likewise, Cubilla and F i t ~ g e r a l dnoted than 3 cm live a median of 12 months, whereas patients with localized tumors from 3 to 5 cm live a median of only 5 months. Microscopic Appearance

Microscopically, ductal adenocarcinornas contain infiltrating glands of various shapes and sizes surrounded by dense, reactive fibrous tissue (Fig. 1A). The epithelial cells sometimes also form papillae and cribriforming (producing "ducts within ducts") structures, and they typically contain mucin. The nuclei of the cells can show marked pleomorphism (variation in size and shape), hyperchromasia (increased nuclear staining), loss of polarity, and prominent nucleoli. Unfortunately for the pathologist, distinguishing between the common well-differentiated ductal adenocarcinoma and reactive epithelial cells can be extremely difficult. Most ductal adenocarcinornas infiltrate into perineural (Fig. 1B ), lymphatic, and vascular spaces. Nagakawa et ala8identified intrapancreatic neural involvement in 21 of 21 patients with carcinoma of the pancreas, often at the most progressive margin of the tumor. They found that the survival rate of patients with a variety of periampullary cancers with perineural invasion was lower than that of patients with cancers without perineural invasion. In addition to perineural invasion, most resected ductal adenocarcinomas have metastasized to lymph nodes.28,32,39,88 More common in larger tumors, lymph node metastases are asso.~~~~~ several ~ investiciated with a significantly worse patient ~ u r v i v a lAlthough gators maintain that the specific anatomic location of lymph node metastases impacts survival, data from Johns Hopkins suggest that the presence or absence of lymph node metastases is much more significant than the node group inIn addition to lymph nodes, ductal adenocarcinornas frequently metastasize to the liver (up to 80% of all ductal adenocarcinomas), peritoneum (60%), lungs

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Figure 1. A, Moderately differentiated ductal adenocarcinoma. The tumor contains infiltrating glands of various shapes and sizes surrounded by dense, reactive fibrous tissue. The ductforming cells are markedly atypical. B, Perineural invasion. Most ductal adenocarcinomas show perineural invasion, often at the tumor's most progressive margin.

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and pleura (50%-70%), and the adrenals (25%).31,79 Common sites of direct cancer extension include the stomach, spleen, transverse colon, and left adrenal.28Obviously, patients with metastases fare significantly worse than do patients without metastases. Histologic Precursors

Although infiltrating ductal adenocarcinoma of the pancreas has received much attention, the precursors of infiltrating ductal adenocarcinoma have not been well defined. We believe that histologically identifiable precursor lesions to infiltrating ductal adenocarcinoma of the pancreas exist. For example, histologic examination of pancreata resected for pancreatic cancer frequently reveals striking lesions in the pancreatic ducts and ductules adjacent to the cancer^.^^,^^ In these lesions a mucin-producing, proliferative epithelium with varying degrees of cytologic and architectural atypia replaces the normal cuboidal cells of ducts and d ~ c t u l e s .The ~ ~ ,abnormal ~~ epithelium can be flat, papillary without atypia, or papillary with atypia; in fact, the epithelium may even meet histopathologic criAlthough these lesions have gone by a variety of teria for carcinoma in names, we prefer to designate them either nonspecifically (duct lesions) or specifically (low-grade pancreatic intraepithelial neoplasia [low-grade PanIN] or high-grade PanIN) (Figs. 2 and 3). The term pancreatic intraepithelial neoplasia conveys the neoplastic nature of these lesions. Several lines of evidence suggest that these ductal lesions are the precursors of infiltrating ductal adenocarcinoma. First, pathologists frequently find ductal lesions together with cancer. Cubilla and Fitzgerald30compared the duct changes

Figure 2. High-grade pancreatic intraepithelial neoplasia (PanlN).Mucin-producing,papillary, columnar epithelium replaces the normal flat cuboidal cells of the duct. Because of the architectural and cellular atypia, including nuclear pleomorphism and hyperchromasia, loss of cellular polarity, and prominent nucleoli, this is a high-grade lesion.

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Figure 3. Progression from normal duct epithelium (left)to low-grade pancreaticintraepithelial

neoplasia (PanlN)to high-grade PanlN to infiltrating cancer (right).

in 227 pancreata with pancreatic cancer with those in 100 age- and sex-matched controls without pancreatic cancer. They found that papillary duct lesions were three times more common in pancreata from patients w6h pancreatic cancer than they were in pancreata from patients without pancreatic cancer. Remarkably, they identified atypical papillary duct lesions only in pancreata with pancreatic canKozuka et aP7 and Pour et allo2have obtained similar findings. ~er.~O Second, evidence suggests that ductal lesions can progress to infiltrating cancer over time. Furukawa et a1,46 using three-dimensional mapping techniques, have demonstrated a stepwise transformation from mild dysplasia to severe dysplasia in pancreatic duct lesions. More recently, Brat et all4reported three patients who developed infiltrating ductal adenocarcinomas 17 months, 9 years, and 10 years after the diagnosis of high-grade PanIN. Third, ductal lesions display some of the same genetic changes that infiltrating adenocarcinomas show (see the article by Hruban et a1 on page 1).For example, clonal activating point mutations in codon 12 of K-vas, common in infiltrating adenocarcinoma, have been demonstrated in papillary and atypical papillary ductal lesions. In contrast, K-uas mutations have not been found in morphologically ~ ~infiltrating , ~ ~ adenocarcinoma, , ~ ~ , ~ ~ ~atyp, ~ ~ ~ , normal pancreatic d ~ ~ t s . ~ ~ , Like ical duct lesions and carcinoma in situ also may harbor mutations in the p16 and p53 tumor suppressor genes.1"36,50,85 All of these three lines of evidence suggest that, just as progression from adenoma to infiltrating adenocarcinoma occurs in colonic neoplasia, so too does progression occur in the pancreas (Fig. 3) from flat mucinous duct lesions to papillary duct lesions without atypia, to papillary duct lesions with atypia, and finally ~ ~ , ~ ~ , ~ ~ such a progression suggests that to infiltrating a d e n o c a r ~ i n o m a . Importantly, the molecular detection of curable precursor lesions and early cancers is possible. Indeed, mutant K-uas shed from pancreatic intraepithelial neoplasias has been Furtheridentified in stool, duodenal fluid, and pancreatic juice samples.10,15,19,135 more, Berthelemy et all0 reported two patients without clinical or radiologic evidence of cancer who developed ductal adenocarcinomas 18 and 40 months after

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the detection of K-ras mutations in pancreatic juice samples. These mutant copies of K-ras presumably originated in DNA shed from pancreatic intraepithelial neoThus, although the progression of ductal lesions to carcinoma is still plasia~.'~ incompletely understood, ductal lesions are the earliest microscopically and genetically recognizable neoplasms in the pancreas. Histochemistry, Immunohistochemistry, and Electron Microscopy

Infiltrating ductal adenocarcinomas contain mucin, detectable with a mucicarmine or periodic acid-Schiff stain. They almost universally express keratin and epithelial membrane antigen; immunohistochemical stains for carcinoembryonic antigen, carbohydrate antigen 19-9, and B72.3 are usually positive. Unfortunately, nonneoplastic cells also may produce many of these same antigens; therefore, to date, no histochemical or immunohistochemical stain distinguishes between re,~~,"~ immunohistoactive and neoplastic glands in the p a n c r e a ~ . ~ ~Interestingly, chemical stains can show mixed differentiation in some ductal adenocarcinomas. For example, some cancers can express small amounts of chromogranin and other neuroendocrine marker^.^^,'^' Ultrastructurally, the neoplastic cells in ductal adenocarcinoma are similar to those in benign ductal epithelium. That is, they typically contain focal mucigen granules, microvilli, desmosomes, hemidesmosomes, and tight junctions. Zymogen and neurosecretory granules, the hallmarks of acinar and endocrine differentiation, respectively, are not seen.31 Staging and Prognosis

Before the development of the Tumor-Node-Metastasis (TNM) system, clinicians and pathologists described the extent of nonendocrine pancreas cancer as localized (disease confined to the pancreas), regional (disease with regional lymph node metastasis or direct extension into surrounding organs), or distant (disease with distant lymph node, organ, or soft-tissue metastasis).S3After the birth of the TNM system, several groups developed more intricate methods of These systems merged in 1987, when the Unio Internationalis Contra Cancrum (UICC) published the international system for staging pretreatment disease curBriefly, tumors confined to the pancreas (rerently in use (Tables 1 and 2).53,54,n7 gardless of size) and those with extension only to the duodenum, bile duct, or peripancreatic soft tissues are designated Stage I. Cancers with extension to the stomach, spleen, colon, or adjacent large vessels are Stage 11. Stage I11 tumors have metastasized to regional lymph nodes, and Stage IV cancers have metastasized to distant sites. After surgery, patients also receive one of the following designations: RO (no residual tumor), R1 (microscopic residual tumor), or I72 (macroscopic residual tumor).53,54,n7 Prognosis depends heavily on pretreatment and posttreatment tumor stage.

Table 1. PRESURGICAL STAGE FROM TNMIpTNM CLASSIFICATION NO, MO

N1, MO

NO or N1, M I

Stage I Stage I Stage I I

Stage Ill Stage I l l Stage I l l

Stage IV Stage lV Stage IV

-

p

p

p

p

p

From Hermanek P, Sobin LH: UICC: TNM Classif~cationof Malignant Tumors, ed 4. Berlin, SpringerVerlag; 1987; with permission.

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Table 2. TNMIpTNM CLASSIFICATION OF NONENDOCRINE PANCREATIC TUMORS T-Tumor Primary tumor cannot be assessed TX TO No primary tumor Tumor confined to the pancreas TI Tl a Tumor 2 cm or less in greatest dimension Tl b Tumor more than 2 cm in greatest dimension Tumor extending directly to duodenum, bile duct, and/or peripancreatic tissues T2 T3 Tumor extending directly to stomach, spleen, colon, and/or adjacent large vessels N-Nodes Regional lymph nodes cannot be assessed NX No regional lymph node metastasis NO N1 Regional lymph node metastasis M-Metastases MX Distant metastasis cannot be assessed MO No distant metastasis MI Distant metastasis From Hermanek P, Sobin LH: UICC: TNM Classification of Malignant Tumors, ed 4. Berlin, SpringerVerlag, 1987; with permission.

Patients with Stage I, RO tumors survive on average 38.7 months; those with Stage 11, RO tumors live only 8.5 months. Surprisingly, 30% of patients with only one lymph node metastasis live for 5 or more years, whereas no patients with two or more lymph node metastases survive 5 years. Regardless of pretreatment stage, 16% of patients with RO tumors live for 5 or more years, whereas none of those with R1 or R2 disease survive 5 years.53 Unfortunately, most patients with pancreatic cancer do not present with early-stage disease. Indeed, of all patients with resected adenocarcinomas, less than 5% have Stage I di~ease.~~,~6,80 Furthermore, only 40% of tumors less than 2 cm in diameter are Stage I, underscoring pancreatic cancer's ~ i r u l e n c e .This ~~,~~ virulence is compounded because only one tenth of diagnosed pancreatic cancers These data highlight the are smaller than 2 cm in diameter in the first place.53,76,77 need for molecular tests that can be used to diagnose early pancreatic cancer. Surgical resection then will cure many more patients. Adenosquamous Carcinoma

More common in patients who have received chemotherapy or radiation therapy, infiltrating adenosquamous carcinoma of the pancreas is a rare variant of ductal adenocarcinoma that shows both glandular and squamous (Fig. 4) differentiation.'6,24,29,31,57,59,79,116 Although squamous features may predominate, careful examination almost always reveals a glandular component. Perineural invasion and nodal, hepatic, and peritoneal metastases are as common in adenosquamous carcinomas as they are in typical ductal adenocar~inomas.~~ Because of its relatively poor prognosis, recognition of this rare tumor variant is important. The 1year survival rate is only 5%, with no 5-year survivor^.^' Acinar Cell Carcinoma

Although acinar cell carcinomas account for only a small percentage of pancreatic cancers, they have a distinct histologic appearance and clinical presenta-

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Figure 4. Adenosquamous carcinoma. Squamous features, including squamous "eddies" (whorls)and intercellular bridges, predominate in this field. Focal glandular differentiation is seen in almost all squamous carcinomas.

tion.23,63,79,81,134 Although many patients with acinar cell carcinomas complain of obstructive symptoms secondary to the tumor, as many as 20% also develop subcutaneous fat necrosis, an erythema nodosum-like rash, peripheral eosinophila, and polyarthralgias. These signs and symptoms result from the release of massive Acinar cell carcinomas occur priamounts of lipase by the tumor.5,8,18,56,63,74,94,106,134 marily in older patients; nevertheless, children can develop these m a l i g n a n ~ i e s . ~ ~ , ~ ~ Acinar cell carcinomas average 11 cm in diameter, and approximately 60%, 30%, and 10% arise in the head, body, and tail of the pancreas, re~pectively.~~ In contrast to the irregular and scirrhous ductal adenocarcinomas, acinar cell carcinomas are typically smooth, fleshy, lobulated, hemorrhagic, and necrotic. As with ductal adenocarcinomas, acinar cell carcinomas may extend microscopically well beyond their grossly recognizable boundaries. Not surprisingly, acinar cell carcinomas microscopically show acinar differentiation. These tumors typically form acini (clusters of cells surrounding small, central lumina), and their cells display eosinophilic, granular cytoplasm (Fig. 5). In addition, glandular (forming acini with large, irregular lumina), solid (forming sheets and nests without lumina), or trabecular (forming cords of cells) differentiation also may predominate. Even so, careful microscopic examination always reveals an acinar component. In contrast to ductal adenocarcinomas, acinar cell carcinomas do not elicit a reactive stromal response; instead, only thin fibrous bands separate the neoplastic cells. Three-fifths and one-third of tumors show Interestingly, acinar cell carcivascular and perineural invasion, re~pectively.~~ nomas also can show focal ductal or endocrine differentiation or both.63,u2,130,134 Acinar cell carcinomas have distinctive histochemical, immunohistochemical,

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Figure 5. Acinar cell carcinoma. Features include glandular and acinar structures with gran-

ular cytoplasm and basally located nuclei. Almost no reactive stroma exists, in contrast to ductal adenocarcinomas.

and ultrastructural features. More than 90% of these tumors contain small, apical granules highlighted by the periodic acid-Schiff with diastase stain. Three-fourths of these tumors show butyrate esterase activity, a reflection of the presence of l i p a ~ e Immunohistochemistry .~~ often reveals the expression of trypsin, lipase, ~ ~ , ~immunohistochemical ~ markers that somechymotrypsin, or a m ~ l a s e . Other times stain acinar cell carcinomas include a,-antitrypsin, keratin, epithelial membrane antigen, carcinoembryonic antigen, a-fetoprotein, chromogranin, and g l ~ c a g o nUltrastructurally, .~~ acinar cell carcinomas display apically located microvilli, basally oriented nuclei, tight junctions, desmosomes, and, most importantly, zymogen granules.63 The mean overall survival for patients with acinar cell carcinoma of the pansurvive at least 5 years.63These values are creas is 18 months; 6% of these slightly higher than those for infiltrating ductal adenocarcinoma of the pancreas.63 Surgical resection by Whipple procedure improves mean survival to 23 months; for comparison, patients who undergo bypass surgery or no surgical treatment Metastases to the liver, at all survive only 18.5 and 6 months, re~pectively.~~ local lymph nodes, peritoneum, and abdominal- wall are the most common,8,18,63,74,94,106,130

Tumor size, patient age, and clinical features affect survival. Patients with tumors less than 10 cm survive an average of 28 months, whereas those with larger tumors live, on average, only 17 months. Patients younger than 60 years survive an average of 26 months, whereas older persons live, on average, only 13 months. Interestingly, patients with signs and symptoms of lipase production have a particularly grave prognosis and most live less than 9 rnonths.'j3

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Giant Cell Carcinoma

Giant cell carcinoma is one of the most distinct neoplasms of the pancreas. This tumor accounts for approximately 5% of primary nonendocrine pancreatic m a l i g n a n c i e ~ . ~ , ~ Like ~ , ~ ~infiltrating , ~ ~ , ~ ~ ,ductal ~ ~ adenocarcinomas, the mean age of diagnosis occurs in the seventh decade of life; unlike infiltrating ductal adenocarcinomas, giant cell carcinomas arise with equal frequency in the head and body/tail regions of the pancreas. Grossly necrotic and hemorrhagic, these tumors average 11 cm in diameter.31Microscopically, as the name implies, giant cell carcinomas contain large, uninucleated or multinucleated tumor cells, many of which are strikingly pleomorphic. The hyperchromatic nuclei are sharply angulated and contain prominent nucleoli and numerous, sometimes bizarre, mitotic figures. Some tumor cells elongate and take on a spindle shape. Some giant cell carcinomas contain a third population of small tumor cells, and others show poorly differPatients with giant cell carcinomas of entiated glandular structures.2,29,31,49,116,127 the pancreas live, on average, a dismal 2 months. There are no 1- or 5-year survivor~.~~

Giant Cell Carcinoma with Osteoclast-like Giant Cells

Only a handful of giant cell carcinomas with osteoclast-like giant cells have been reported.31,61,100,107,108,125 These tumors are less aggressive, albeit still malignant, variants of the more typical giant cell carcinomas. Indeed, the prognosis for patients with this tumor is significantlybetter than that for patients with giant cell carcinoma, with survival measured in years, not rnonths31 Grossly well-circumscribed, yellow-pink, and fleshy, this tumor, like the typical giant cell tumor, may contain giant cells, spindle cells, and small cells (Fig. 6). In contrast to giant cell carcinomas, however, the nuclei in the giant cells are round and uniform. The giant cells thus more closely resemble the osteoclasts of resorbing bone than the monster giant cells of a giant cell carcinoma. In addition, these tumors may contain abundant osteoid (unmineralized bone) and poorly formed glandular structures. The vastly different prognoses of giant cell carcinomas and giant cell carcinomas with osteoclast-like giant cells highlight the importance of proper categorization of tumors that contain giant cells. The mere presence of a giant cell does not warrant placement into either of these categories. The degree of atypia and pleomorphism of the giant cells must be considered.

Pancreatoblastoma

Pancreatoblastoma or pancreatic carcinoma of infancy, is a rare neoplasm that Even in childhood, occurs primarily in children aged 1 to 15 years.9,17,45,55,124,129 however, these tumors are less common than the more aggressive infiltrating ductal adenocar~inomas.'~ Pancreatoblastomas have unique gross and microscopic appearances. Firm, lobulated, centrally necrotic, and white-gray, some appear well encapsulated; others are poorly circumscribed. They average 9 cm in diameter.17Microscopically, like many childhood neoplasms, pancreatoblastomas contain undifferentiated and differentiated components. The undifferentiated part consists of back-to-back small cells with a syncytial growth pattern, eosinophilic cytoplasm, and round,

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Figure 6. Giant cell carcinoma with osteoclast-like giant cells. The giant-cell nuclei are round and uniform, and the giant cells resemble osteoclasts. In contrast, the giant cells in a typical giant cell carcinoma are strikingly pleomorphic and may contain bizarre mitoses.

benign-appearing nuclei. The differentiated segment can show a spectrum of appearances, including squamous, acinar, and endocrine differentiations. Typically, these tumors contain nests of squamous cells in a sea of small, uniform, undifferentiated cells (Fig. 7). Immunohistochemistry and electron microscopy have been used to demonstrate a variety of directions of differentiation in these tumors. For example, Buchino et all7reported a pancreatoblastoma that stained focally for somatostatin and carcinoembryonic antigen, and electron microscopy can reveal a variety of cell types, some with zymogen granules and others with neuroendocrine granules. The survival rate for patients with pancreatoblastomas is better than it is for ~ , ~eight ~ , ~ ~of,the ~ ~ ~patients patients with infiltrating ductal a d e n o c a r c i n o m a ~ . ~ All reviewed by Buchino et all7presented with Stage I disease, and six were alive and tumor free after surgical resection for an average of at least 4 years.

PRIMARY CYSTIC NONENDOCRINE EPITHELIAL TUMORS

Only 5% to 15% of pancreatic cysts are neoplastic.1~3~7~21~35~51~118 The remaining nonneoplastic cysts include pseudocysts (extrapancreatic inflammatory cavities without an epithelial lining), congenital cysts, and retention cysts (localized dilation of pancreatic ducts secondary to obstruction). Despite their rarity, cystic neoplasms are important to recognize because their management is so different from that of nonneoplastic cysts.

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Figure 7. Pancreatoblastoma.This "pancreaticcarcinoma of infancy"shows the typical nests of squamous cells (center) in a sea of small, uniform, undifferentiated cells with clear cytoplasm.

Serous Cystadenoma and Serous Cystadenocarcinoma

Serous cystadenomas, also known as microcystic adenomas and glycogenrich cystadenomas, are more common in women than in men.3,7,",2"35,72,81,91,115 The average age at diagnosis is in the seventh decade, and patients often present with abdominal pain, weight loss, and a palpable mass. Patients with von Hippel-Lindau syndrome may be predisposed to develop serous cystadenomas. Large (mean diameter = 11 cm), spongy, well-circumscribed, and multilocular, serous cystadenomas sometimes contain a central, calcified scar.25The cysts are small and harbor watery, clear, or brown fluid. Microscopically, a layer of simple cuboidal cells lines the cysts, separated from one another by dense fibrous bands (Fig. 8). The cells show clear cytoplasm and round, uniform, centrally located nuclei. Although a small degree of pleomorphism is not unusual, necrosis and mitoses usually are not identified. Because the cells contain an abundance of glycogen, they stain strongly with the periodic acid-Schiff technique but not at all for mucin. Immunohistochemistry reveals the expression of keratin and epithelial membrane antigen but not carcinoembryonic antigen or chromogranin. Electron microscopy confirms the presence of cellular glycogen and can reveal apical microvilli. Most serous cystic neoplasms are benign, even if incompletely n,20,25,35,72,81,91,115 Recently, however, several groups have reported malignant behavior in serous cystic neoplasms (serous cystadenocarcinomas).For example, we recently saw a woman whose serous cystic neoplasm recurred in her liver even after complete resection of the primary pancreatic tumor several years earlier. have reported serous cystic neoplasms Similarly, George et a148and Yoshimi et of the pancreas metastasizing to the stomach and liver.

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Figure 8. Serous cystadenoma. A layer of simple cuboidal cell line cysts separated from one another by fibrous bands. Because of abundant glycogen, the cells are strongly positive with the periodic acid-Schiff (PAS) stain.

Mucinous Cystic Neoplasms

Morphologically heterogeneous, rnucinous cystic neoplasms range from tumors with small cysts lined by a single layer of benign-appearing columnar epithelium to those with larger cysts associated with an infiltrating carcinoma. Indeed, some researchers have suggested that if untreated, virtually all of these neoplasms eventually develop into cancer.26Therefore, treatment of these neoplasms differs greatly from that of serous cystadenomas. Mucinous cystic neoplasms are more common in women than they are in men, and the mean age of diagnosis is in the late fifth decade. Although patients usually present with epigastric pain or discomfort and an abdominal mass, they generally do not exhibit obstructive j a ~ n d i c e . ~ ~ ~ ~ With a mean size of 10.5 cm, the tumor contains cysts lined by tall, mucinproducing columnar cells.26Importantly, the cysts do not communicate with the main pancreatic duct. They house a cloudy, tenacious fluid, and expectedly, stains for mucin are positive. Some tumors are remarkable for the presence of a dense stroma beneath the epithelial cells (Fig. 9). This stroma resembles that seen in the ovary, and it occurs only in women. The clinical significance of this finding is not clear, but this stroma suggests a common origin for some neoplasms in the ovary and pancreas. Microscopic analysis differentiates among three types of rnucinous cystic neoplasms: the rnucinous cystadenoma, the borderline rnucinous cystic neoplasm, and the rnucinous cystadenocarcinoma. Mucinous cystadenomas contain a single layer of epithelium that lacks significant atypia. In borderline rnucinous cystic neoplasms, the epithelium may form papillae and complex architectural patterns. The epithelial cells in these tumors show significant atypia (high nuclear-to-cytoplas-

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Figure 9. Mucinous cystadenoma.Tall, mucin-producing,columnar cells line acyst most likely containing a cloudy,tenacious fluid that stains for mucin. Because of the lack of cellular and architectural atypia, this mucinous cystic neoplasm is a rnucinous cystadenoma. The lack of atypia in this field does not rule out invasive cancer elsewhere in the tumor; the entire neoplasm must be removed and examined histologically for cancer. This tumor also has the "ovarian"stroma often seen in rnucinous cystadenomas in women.

mic ratio, loss of nuclear polarity, and pleomorphism), but no invasive tumor is seen. The sine qua non of a rnucinous cystadenocarcinoma is invasion of the neoplastic epithelial cells into surrounding stroma. Importantly, otherwise benignlooking rnucinous cystic neoplasms may show small foci of carcin~ma.~~Therefore, the surgeon should resect completely all rnucinous cystic neoplasms, and the pathologist must submit the entire neoplasm for histologic examination and examine carefully each slide to rule out any foci of invasive cancer. Immunohistochemically, rnucinous cystic tumors of the pancreas express carcinoembryonic antigen, carbohydrate antigen 19-9, cytokeratin, and epithelial membrane antigen. Electron microscopy confirms the presence of mucin-containing cells. The prognosis for patients with rnucinous cystic neoplasms varies significantly. When rnucinous cystadenomas are resected completely,most patients with these benign neoplasms are cured.123 Similarly, most patients with borderline mucinous cystic neoplasms fare well; however, a borderline rnucinous cystic neoplasm may recur, particularly if it is not resected completely or adequately sampled for histologic examination to rule out invasive cancer. Finally, although rnucinous cystadenocarcinomas are fully malignant tumors, patients with these neoplasms usually live longer than patients with typical infiltrating ductal adeno carcinoma^.^^^ In fact, approximately 50% of patients with rnucinous cystadenocarcinomas live at least 5 years.26Thus, distinguishing among the types of mucinous cystic neoplasms is important; the discovery of a rnucinous cystic neoplasm requires the tumor's complete surgical removal and pathologic submission for thorough histologic analysis.

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lntraductal Papillary-Mucinous Neoplasms

First described in Japan in the 1980s, the intraductal papillary-mucinous neoplasm (IPMN), also known as intraductal mucin-hypersecreting neoplasm, mucinous duct ectasia, ductectatic rnucinous cystadenoma, and intraductal papillary neoplasm, occurs with approximately equal frequency in both sexes. Diagnosed primarily in the seventh decade, patients with this tumor typically have mucin oozing from the ampulla of Vater that can be observed during endoscopy.* Soft and villous, these neoplasms reside within mucus-filled, dilated pancreatic ducts. In contrast to rnucinous cystic neoplasms, these lesions, by definition, communicate with the pancreatic duct system. Microscopically, columnar, mucinsecreting cells line papillary projections (Fig. 10). IPMNs show varying degrees of atypia, and they may contain invasive carcinoma. The ultrastructural appearance of IPMNs is identical to that of rnucinous cystic neoplasms. Most patients with IPMNs fare well, but metastases and death do occur. Therefore, the World Health Organization has suggested a three-tiered classification for IPMNs, similar to that for rnucinous cystic neoplasms. Intraductal papillary-mucinous adenomas are IPMNs without significant cytologic or architectural atypia. Borderline IPMNs show a moderate amount of dysplasia. Finally, the term papillary-mucinous carcinoma applies only to those cases in which the intraductal lesion displays significant cytologic and architectural atypia (carcinoma in situ) or in which associated invasive cancer is identified.66,n3

Solid and Cystic Papillary Neoplasms

Solid and cystic papillary (Hamoudi) neoplasms of the pancreas occur primarily in women in their third decade. The patients usually present with upper Usually, well-deabdominal discomfort, distention, or pain.1Z,65,68,69,78,84,90,98,111,119 marcated masses ranging from 5 to 15 cm in diameter, the solid and cystic papillary neoplasms contain cysts, hemorrhage, and necrosis.12,65,68,69,78,84,90,98,111,119 AS its name implies, the tumor microscopically shows solid, cystic, and papillary components. The solid areas comprise nests and sheets of small, uniform cells with eosinophilic cytoplasm and benign-appearing nuclei. Acellular pools of blood form the cystic component, and the papillae usually have fibrovascular cores (Fig. 11). Electron microscopy of solid and cystic papillary neoplasms supports an epithelial differentiation (most cells contain cell junctions), and most cells resemble those of ducts or acini.I2Some tumors contain rare neurosecretory or zymogen granules; some of these same tumors focally express a,-antitrypsin or lipase or Although most patients survive for many both by immunohistochemistry.65~69~111 years after surgical resection, metastases do occur, and surgeons should try to remove these neoplasms completely. Venous invasion may be more common in those tumors that m e t a s t a s i ~ e . ~ ~

Acinar Cell Cystadenocarcinoma

Rarely, acinar cell carcinomas present as cystic masses. For example, in 1981, Cantrell et alzl reported the case of a 42-year-old physician with a 25-cm mass in the body of the pancreas. Pathologic analysis revealed a cystic neoplasm lined by

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Figure 10. lntraductal papillary-mucinous neoplasm (IPMN). This papillary growth resides within a mucus-filled, dilated pancreatic duct. Endoscopy often reveals mucus oozing from the main pancreatic duct.

Figure 11. Solid and cystic papillary neoplasm. Typically a tumor in young women, the solid and cystic papillary neoplasm contains small cells forming solid nests and papillae. Cystic areas are not true cysts; rather, "cystic" refers to the acellular component surrounding the nests and papillae.

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cells with granular cytoplasm. Electron microscopy demonstrated numerous zymogen granules, thereby establishing the diagnosis of a cystic acinar cell carcinoma (acinar cell cystadenocarcinoma). Stamm et alH8noted similar findings in a 64-year-old man with an abdominal mass, pain, and diarrhea. The behavior of these rare neoplasms is probably similar to that seen in its solid variant. PRIMARY MESENCHYMAL TUMORS

Benign and malignant mesenchymal tumors of the pancreas are extremely rare. A literature review reveals reports of such tumors as schwannoma, leiomyosarcoma, liposarcoma, primitive neuroectodermal tumor, and malignant fibrous h i ~ t i o ~ y t o m a . ~ ~ , Generally, ~ ~ , ~ ~ ,survival ~ ~ , ~ rates ~ , ~for ~ ~patients , ~ ~ ~with , ~ ~sarcomas ~ are low, as they are for sarcomas primary to other locations. METASTATIC MALIGNANCIES

Although cancers of the pancreas more commonly spread to other organs, extrapancreatic cancers sometimes do metastasize to the pancreas. A review of pancreatic cancers by Cubilla and Fitzgerald31shows that the most common metastases to the pancreas originate in the breast (20%),lung (19761,colorectum (lo%), skin (melanoma, 9%), and stomach (7%).We recently reported a patient with a renal cell carcinoma that metastasized to the pancreas.22 SYSTEMIC MALIGNANCIES

Leukemia and lymphoma simultaneously involve more than one site, one of which may be the pancreas. In fact, the pancreas is sometimes the presenting site for these cancers.lo3Of the 67 patients with systemic malignancies involving the pancreas who were reviewed by Cubilla and Fitzgera1d:l three fourths had lymphomas. Sixty-five percent of the lymphomas were non-Hodgkin's lymphomas; 15% were Hodgkin's lymphomas, and 2% were multiple myelomas. At least 25% of lymphoma patients show pancreatic i n v o l ~ e m e n t . These ~ ~ , ~ tumors ~~ are important to recognize because lymphomas generally are not treated surgically. The remaining one-fourth of patients with systemic malignancies have leukemia. The most common leukemias are chronic myelogenous leukemia (21%), acute lymphoblastic leukemia (21761, and acute lymphocytic leukemia (16%).31 CONCLUSIONS

Pancreatic cancer is a diverse disease. Although the overwhelming majority of primary pancreatic malignancies are ductal adenocarcinomas, one always must consider a number of other benign and malignant neoplasms. Because the prognosis varies significantly among these entities, establishing the correct diagnosis for a pancreatic neoplasm is an important task. Therefore, knowledge of the pathology of pancreatic cancer is essential to anyone who treats patients with pancreatic masses. Unfortunately, however, our overall understanding of pancreatic neoplasms is far from complete. We comprehend only partially the pathologic and genetic progression of PanINs to ductal adenocarcinoma. We know even less about the pathogenesis of the other types of pancreatic neoplasms. Still, because of a new emphasis on molecular biology, early diagnosis of pancreatic cancer, when it is

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still confined to the pancreas or even when it is still a precursor lesion, soon may be possible. Then, surgical resection of the pancreas will cure a great many more patients.

ACKNOWLEDGEMENTS The authors would like to thank Michele Heffler for her hard work and dedication. To learn more about pancreas cancer, visit our Website at http://pathology.jhu.edu/pancreas.

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