Tumors of the pancreas and ampulla

Pathologic features

Low-grade PanIN lesions have flat or mildly papillated and polarized mucinous epithelium, which reveal mild to moderate nuclear atypia ( Fig. 59.1 A–B). High-grade PanIN lesions exhibit increased architectural complexity with prominent epithelial papillation, cribriforming, budding micropapillae, loss of cellular polarity, marked cytologic atypia with nuclear pleomorphism, and frequent mitosis (see Fig. 59.1 C). The biomarker expression in high-grade PanIN usually mirrors that of ductal adenocarcinoma with positive immunoreactivity to mucin 1 (MUC1) and abnormal expression of carcinoembryonic antigen (CEA).

The presence of high-grade PanIN is virtually indicative of invasive adenocarcinoma in the pancreas. When PanIN-3 is identified in the absence of established invasive adenocarcinoma, it is prudent to re-examine the specimen thoroughly to exclude any occult or overlooked early-stage adenocarcinoma. When high-grade PanIN is present at the resection margin, it is considered to be a microscopically positive margin (R1).

Molecular biology and genetics

Most PanINs, including both high- and low-grade lesions, harbor KRAS mutations, with significantly increased clonality in high-grade PanINs. High-grade PanIN shares some genetic abnormalities with invasive ductal adenocarcinoma, including biallelic inactivation of CDKN2A (p16) and a wide spectrum of clonal copy number changes but lacks TP53 and SMAD4 mutations, which are commonly seen in invasive ductal adenocarcinoma ^, (see Chapter 9D ).

Epidemiology and clinical features

PDAC is the most common neoplasm of the pancreas (>90%). Most cases of PDAC are sporadic, but about 10% of cases have a documented familial history of the disease, in which a deleterious germline mutation has been identified in 10% to 20% of patients. Adenocarcinoma is more commonly located in the head of the pancreas (two thirds) than in the distal portion of the gland. Although extremely rare, it can also occur in pancreatic heterotopia present in the upper gastrointestinal (GI) tract. The median age at diagnosis for PDAC is approximately 70 years. The most common clinical presentation is unexplained weight loss, back pain, jaundice, decreased appetite, and new-onset DM. Rare symptoms include migratory thrombophlebitis and acute pancreatitis (AP).

PDAC is usually diagnosed when an infiltrative solid mass is detected by computed tomography (CT) scans with multiphase-dynamic contrast or by magnetic resonance imaging (MRI). Endoscopic ultrasound (EUS) can facilitate sampling of the mass or lymph node for definitive diagnosis. Serum biomarker CEA and CA 19-9 may be elevated (see Chapter 17 ).

The prognosis of PDAC remains poor for most patients with an overall 5-year survival of less than 10%. The most effective treatment is complete surgical resection of the tumor and adjuvant systemic therapy with a corresponding 5-year survival of about 12% to 20%, but, unfortunately, this modality is only possible in approximately 20% of patients at the time of diagnosis (see Chapter 62 ). Neoadjuvant therapy may improve surgical resectability and survival of PDAC patients in some cases. Patients with untreated PDAC, or with metastatic disease, have a mean survival of less than 6 months.

Pathologic features

The macroscopic appearance of PDAC is a solid firm mass with an irregular contour. The mean size of lesions amenable to resection is roughly 3.5 cm, although tumors located in the distal pancreas are usually larger. Focal cystic changes may be observed distal to the tumor secondary to obstruction of pancreatic ducts. Obstruction of the common bile duct (CBD) and the main pancreatic duct is common when the tumor is located in the head of the pancreas ( Fig. 59.2 ). The tumor may grossly infiltrate the ampulla, duodenal wall, superior mesenteric vein, or uncinate process and retroperitoneum.

Conventional ductal adenocarcinoma.

Microscopically, most PDAC has gland formation but exhibits significant heterogeneity in an histologic pattern with distorted glands/tubules of varying sizes and shapes. Large glands may have a cribriform and papillary pattern, and the small units may reveal incomplete gland/tubular structure or single cell–infiltrating pattern ( Fig. 59.3 A). Both intracellular and extracellular mucin are common within the tumor. A desmoplastic reaction surrounding the malignant epithelium is typical in PDAC, although, in some cases, the tumor stroma may appear hypocellular with dense and pink collagen. The epithelium in PDAC can be either columnar or cuboidal with considerable nuclear pleomorphism. The nuclear membrane of the neoplastic cells is irregular and has a smudged appearance. Better differentiated PDAC with well-formed glands usually shows vesicular/foamy intracellular mucin with a condensed and thickened apical border of the cytoplasmic membrane (see Fig. 59.3 B). PDAC metastases to the lung and omentum may present paradoxically with better differentiation and may be diagnostically challenging during the pathologic workup to exclude lung or other potential primary sites (see Fig. 59.3 C). Immunohistochemical and molecular studies can facilitate a more definitive diagnosis.

The immunoprofile of conventional PDAC is that of typical pancreatobiliary phenotype, which is not entirely specific, and the workup is usually for a diagnosis of exclusion of adenocarcinoma from other primary sites. The tumor cells of typical PDAC are positive for CK7 and negative for CK20 and CDX2; they express carcinoma biomarkers MUC1, CEA, CA125, and B72.3. PDAC with DPC4 and CDKN2A gene mutations has loss of nuclear SMAD4 and p16 expression, respectively (see Chapter 9D ).

Adenosquamous carcinoma.

Although homogenous squamous cell carcinoma of the pancreas is uncommon, varying extents of squamous differentiation can occur in association with conventional ductal adenocarcinoma ( Fig. 59.4 A). The classification of an adenosquamous carcinoma requires the presence of greater than or equal to 30% squamous component. The pitfall associated with this subtype is that exclusively squamous carcinoma may be present in small biopsies or at the site of metastasis, which would raise the differential diagnosis of a primary squamous cell carcinoma from other sites including the lung—which is a common metastatic site for PDAC.

Molecular biology and genetics

Somatic genetic drivers of PDAC include oncogenic mutations of KRAS (>90%) and mutation or deletion of TP53 (75%) , SMAD4 (55%) , or CDKN2A (80%). Other less common somatic mutations are found in genes involved in DNA repair and epigenetics, including PALB2, ATM, CHEK2 , and RAD51.

Hereditary cases of PDAC are associated with several, well-established susceptibility genes, including BRCA2 , ATM, BRCA1, PALB2, CDKN2A, STK11, PRSS1, and SPINK1 , as well as DNA mismatch repair genes. However, the majority of familial aggregations of PDAC have uncertain underlying genetic abnormalities.

Epidemiology and clinical features

Pancreatic intraductal neoplasms can occur in a wide range of age groups but are more common in older adults in their 50s and 60s. Location in the head of the pancreas is more common than in the distal portion of the pancreas and lesions can be multifocal. The most common and better evaluated intraductal neoplasm is IPMN, which can involve (1) the main pancreatic duct with prominent dilation, (2) branch ducts with an isolated cystic lesion but no apparent communication with the main duct, or (3) mixed main-branch duct type. Clinical symptoms associated with intraductal neoplasms are relatively nonspecific and include pain, chronic pancreatitis (CP), DM, and jaundice. In the absence of invasive carcinoma, markers such as CEA and CA19-9 may not be elevated in serum but only in the cyst fluid from aspiration samples.

The prognosis of IPMN without invasive carcinoma is favorable, particularly in those cases with branch-duct subtype (5-year survival of >85%). The main-duct subtype is often associated with multifocal lesions, greater risk of high-grade dysplasia and carcinoma, and higher risk of recurrence. The prognosis of IPMN with invasive carcinoma depends on the tumor stage and subtype; the 5-year survival ranges from 35% to 90%. Patients with IPMN and associated colloid carcinoma have a significantly better outcome than those with conventual PDAC. ^, The subtypes of IOPN and ITPN with invasive carcinoma also appear to have better prognoses, although this observation may not be conclusive given the recent establishment of these pathologic entities and the rarity of the disease. ^,

Pathologic features

Intraductal papillary mucinous neoplasm (see Chapter 60 ).

Main-duct IPMN may involve a portion of the duct or the entire duct, including the ampulla where mucin extrusion may be visualized by upper GI endoscopy or endoscopic retrograde cholangiopancreatography (ERCP). The dilated duct is usually filled with mucin and soft papillary projections ( Fig. 59.5 A). Branch-duct IPMN may lack a visible connection to the main duct and is usually present as multilocular cysts filled with mucin (see Fig. 59.5 B). Larger IPMNs (>3 cm) and those with mural nodules or intracystic masses are more likely to harbor high-grade dysplasia or invasive carcinoma.

Microscopically, IPMNs show intraductal proliferation of columnar epithelium with abundant intracellular and extracellular mucin. The neoplasm is categorized as either low- or high-grade dysplasia based on the histologic complexity and cytologic atypia.

Intestinal-type IPMN is commonly associated with main-duct IPMN ( Fig. 59.6 A). The neoplastic epithelium forms villous papillary architecture and contains tall columnar intestinal-type cells with elongated nuclei and apical intracellular mucin. High-grade dysplasia is commonly observed in this subtype. The neoplastic cells are immunoreactive to CK20, CDX2, and MUC2; they are negative for CK7 and MUC1.

Gastric-type IPMN is often found in branch ducts (see Fig. 59.6 B). The lining epithelium has a gastric foveolar phenotype, often with low-grade dysplasia, although high-grade dysplasia and invasive carcinoma can occur as well. ^, The neoplastic cells are immunoreactive to CK7 and MUC5AC, and they are negative for CK20, CDX2, MUC2, and MUC1.

Pancreatobiliary-type IPMN usually involves the main pancreatic duct. The neoplastic epithelium has a more complex architecture with anastomosing papillae composed of cuboidal cells with eosinophilic or amphophilic cytoplasm that may or may not contain intracellular mucin. Most pancreatobiliary-type IPMNs have high-grade dysplasia within the lesion. The neoplastic cells are immunoreactive to CK7, MUC1, and MUC5AC; they are negative for CK20, CDX2, and MUC2.

Adenocarcinoma arising in IPMN can be either of the colloid type (see Fig. 59.6 A) or conventional PDAC type. The former is associated with intestinal-type IPMN, and the latter is commonly associated with pancreatobiliary-type or gastric-type IPMN. It is important to emphasize that thorough examination and adequate sampling are crucial to identify occult carcinoma within IPMNs, particularly in large lesions or cysts with complex architecture.

Molecular biology and genetics

Somatic mutations of KRAS and GNAS are identified in 60% to 80% and 50% to 70% of IPMN cases, respectively, particularly the intestinal phenotype. ^, RNF43 mutations have been found in approximately 50% of IPMN cases. ^, Although KRAS mutation is also common in PDAC, GNAS mutation appears to be unique to IPMN (see Chapter 9D ).

There are no defining genomic alterations in most IOPN and ITPN cases, which may be because of the rarity of these entities. Recurrent mutations of ERBB4, ARHGAP26, ASXL1, and EPHA8 have been identified in some IOPN cases. ITPN has been reported to have alterations in certain chromatin remodeling genes, such as MLL1-3, BAP1, and PI3K pathway genes.

Epidemiology and clinical features

MCN occurs almost exclusively in women (>98%) and the mean onset age is 48 years. Patients with mucinous cystadenocarcinoma are 5 to 10 years older on average than those with mucinous cystadenoma at the time of diagnosis, suggesting a potential malignant progression from mucinous cystadenoma carcinoma. The majority of the tumors are located in the body and tail of the pancreas (>98%). Radiographically, MCNs present as thick-walled cystic lesions without communication with the pancreatic ducts. Cystic fluid from preoperative aspiration shows elevated CEA levels, which can help to distinguish MCNs from nonmucinous cystic lesions, such as serous cystadenoma, cystic neuroendocrine tumor, and solid pseudopapillary neoplasm.

The prognosis for noninvasive MCN is favorable with a 5-year survival of 100%. The outcome for patients with invasive mucinous cystadenocarcinoma depends on the pathologic stage (i.e., tumor size and metastatic status), with an estimated 5-year survival of 26%.

Pathologic features

The median diameter of MCN is approximately 6 cm. The cyst wall is fibrotic and may have peripheral calcifications that have been termed “egg-shell calcifications.” MCNs with invasive carcinoma are reportedly larger. The cyst lining is relatively smooth in low-grade MCNs ( Fig. 59.7 A), whereas irregularities, such as papillary projections and nodules of various sizes, may be present in high-grade MCNs or mucinous cystadenocarcinoma. The cyst can be unilocular or multilocular and contains thick mucin or necrotic debris.

Microscopically, typical MCN is lined by tall columnar cells with abundant apical intracellular mucin (see Fig. 59.7 B). In many cases, however, the cyst wall may be denuded and lack epithelial lining; in other cases, the epithelium is cuboidal in appearance and devoid of intracellular mucin. The defining features of MCN are the presence of subepithelial spindle cell–rich and ovarian-like stroma (see Fig. 59.6 B). Within this stroma, nests of epithelioid cells resembling luteinized cells can be identified. The density of the ovarian-like stroma varies depending on the age of the patient (more cellular in younger patients and less so in postmenopausal patients) and on the size of the tumor (larger tumors tend to have less dense stroma).

The grading of mucinous cystic adenoma is based on the degree of epithelial atypia as either low- or high-grade dysplasia. Low-grade MCN maintains cellular polarity with minimal nuclear stratification and mild to moderate cytologic atypia. High-grade MCN exhibits increased architectural complexity with cribriform and branching epithelium and budding papillae; there is loss of cellular polarity with significant cytologic atypia and frequent mitotic activity.

When invasive carcinoma is present in MCN, it recapitulates the phenotype of PDAC, including conventional tubular type adenocarcinoma, adenosquamous carcinoma, or undifferentiated carcinoma with osteoclast-like giant cells.

Because the neoplastic epithelium lining MCNs is predominately of the pancreatobiliary type, MCNs also exhibit the pancreatobiliary immunophenotype with reactivity to CK7 and CEA. Mucinous cystadenocarcinoma expresses MUC1 and may lose nuclear SMAD4 expression. The ovarian-like stromal cells are positive for estrogen and progestogen receptors (see Fig. 59.7 C), and luteinized cells are immunoreactive to α-inhibin and calretinin.

Molecular biology and genetics

The malignant epithelium of MCNs harbor activating KRAS mutations in codon 12 and RNF43 gene alterations in 50% to 66% of cases (see Chapter 9D ).

Epidemiology and clinical features

Serous cystadenoma accounts for 1% to 2% of all pancreatic neoplasms and 10% to 16% of operation for pancreatic cystic lesion. Most serous cystadenomas are discovered incidentally by abdominal imaging. They are typically identified in the age group of 50 to 60 years old (mean age of 58) with a female predominance of 7 to 3. Patients may have nonspecific symptoms secondary to local mass effect, but more than 50% are asymptomatic.

On CT scans, the tumor is a well-circumscribed and multinodular cystic or microcystic mass. A characteristic central scar with a sunburst calcification pattern is observed in approximately 30% of cases. The tumor does not have communication with the PD system. ^,

Considering its indolent clinical behavior, the prognosis for patients with serous cystadenoma is generally excellent and surgical resection is almost always curative. Because of its benign nature, radiographic observation is considered appropriate for patients with asymptomatic tumors after establishment of the diagnosis.

Pathologic features

Serous cystadenomas are most commonly located in the body or the tail of the pancreas (>50%) as a solitary tumor. When they are associated with germline VHL gene alterations, however, they can present as multifocal lesions throughout the entire pancreas. ^, The size of serous cystadenomas varies and can be relatively large (up to 25 cm). The microcystic variant of serous cystadenoma is usually well demarcated and typically composed of numerous minute cysts (1 to 2 mm in diameter), which gives rise to the macroscopic appearance of a sponge-like texture ( Fig. 59.8 A). Calcifications may be observed in the central scar. The macrocystic (oligocystic) type lacks the central scar and can present with larger cysts (1–3 cm in diameter) that are either unilocular or multilocular. No cystic formation is apparent in the rare solid-type serous cystadenoma. Serous cystadenomas do not usually communicate with the PD system.

Microscopically, the cysts of serous tumors are lined by a single layer of nonmucinous and cuboidal epithelium with sharp cell borders, glycogen-containing clear cytoplasm, and homogeneously hyperchromatic, round nuclei. A distinctive capillary-rich network underlies the tumor epithelium (see Fig. 59.8 B). Nuclear atypia and mitotic activity are uncommon in serous cystadenomas. The cytoplasm of the tumor cells and the cyst contents are devoid of the mucin and mucin-related glycoproteins and oncoproteins (e.g., monoclonal CEA, CA125, CA19.9, MUC1) that are typically found in ductal adenocarcinomas of the pancreas. This feature may help to establish the preoperative diagnosis by analyzing biomarkers in either the cystic fluid or biopsy tissues by immunohistochemistry. The cytologic features of microcystic-serous tumors, macrocystic-serous tumors, and solid serous tumors are identical. The solid variant lacks cystic dilation and is composed of back-to-back acinar architecture with or without appreciable small lumens.

When associated with VHL disease (50%–90% of cases), serous cystadenoma usually presents as multifocal lesions throughout the entire pancreas (diffuse serous cystadenoma) and can occur in either the microcystic or macrocystic form. There is no significant morphologic distinction between sporadic and familial VHL-associated serous cystadenoma.

In addition to serous cystadenoma, neuroendocrine neoplasms, including neuroendocrine microadenomatosis, can also develop in VHL disease (10%–17% of PanNET and 70% of neuroendocrine microadenomas, respectively). Serous and neuroendocrine tumors can exist independently or intermingle with each other to give rise to the mixed serous-neuroendocrine phenotype (see Fig. 59.8 C).

Unequivocal examples of malignant serous tumors (serous cystadenocarcinomas or carcinomas ex serouscysticadenoma) are exceedingly rare (<0.2%) and require evidence of distant metastasis, which is often to the liver. Large tumors may exhibit locally aggressive features, such as direct extension or adhesion to the adjacent organs or structures, including the liver, but they do not fulfill the typical definition of malignancy.

Serous neoplasms appear to recapitulate centroacinar cells in terms of both histopathology and immunophenotype. They express low molecular weight, as well as broad-spectrum cytokeratins, EMA, MUC6, and inhibin.

Molecular biology and genetics

VHL gene alterations account for both familial and sporadic serous cystic tumors. Somatic VHL mutations at 3p25.3 and loss of heterozygosity of 3p are observed in 50% and 90% of cases, respectively. ^, In addition, allelic loss of chromosome 10p has been reported in 50% of serous cystadenomas.