Pathology of exocrine pancreatic neoplasms

INTRODUCTION — The pancreas gives rise to several malignant and benign neoplasms. At the histologic level, neoplasms of the pancreas can resemble normal ductal cells, acinar cells, or islet cells. In addition, some pancreatic neoplasms appear to arise from primitive cells that have the potential to differentiate along several lines, giving rise to complex tumors with primitive or mixed cell types (eg, pancreatoblastoma).

The commonly used terms "carcinoma of the pancreas" or "pancreatic cancer" usually refer to ductal adenocarcinoma (including its subtypes). Pancreatic adenocarcinoma is an aggressive malignancy which represents 85 to 90 percent of all pancreatic neoplasms.

The more inclusive term "exocrine pancreatic neoplasms" includes all tumors that are related to the pancreatic ductal and acinar cells and their stem cells (including pancreatoblastoma). More than 95 percent of malignant neoplasms of the pancreas arise from the exocrine elements. Neoplasms arising from the endocrine pancreas (ie, islet cell tumors) comprise no more than 5 percent of pancreatic neoplasms [1].

Although the incidence of pancreatic cancer has been relatively stable over time, the increasing use of imaging techniques such as endoscopic ultrasound and helical (spiral) abdominal computed tomography (CT) scans has revealed an increasing number of incidentally found cystic lesions in the pancreas, many of which are neoplasms. This has focused attention on the diagnosis and management of cystic neoplasms of the pancreas.

Of the cystic neoplasms that arise in the pancreas, some (eg, intraductal papillary mucinous neoplasms [IPMN]) have significant malignant potential (30 to 40 percent in reported series), while others (eg, serous cystadenomas) almost always remain benign. The distinction on clinical grounds between these two types of neoplasms, other cystic neoplasms, and other nonneoplastic cystic pancreatic masses (pseudocysts and developmental cysts) can be difficult. The exclusion of malignancy in a cystic pancreatic lesion often requires surgical resection and histopathologic evaluation [2]. (See "Classification of pancreatic cysts" and "Intraductal papillary mucinous neoplasm of the pancreas (IPMN): Pathophysiology and clinical manifestations".)

The size range of pancreatic neoplasms is broad. Neoplasms begin as microscopic foci (mm in diameter), and the lower size limit for detection is in the range of 2 to 5 mm using the most sensitive imaging techniques (endoscopic ultrasound). However, advanced exocrine neoplasms can range up to 36 cm for large cystic neoplasms. The mean size for resected pancreatic carcinomas is usually in the range of 3 to 5 cm.

In general, carcinomas (ductal as well as other types) arising in the head of the pancreas tend to be diagnosed earlier, when they are smaller and less advanced, than tumors in the body and tail because even small neoplasms near the common bile duct or ampulla of Vater can cause biliary obstruction and painless jaundice [3]. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Clinical presentation'.)

This topic review will cover the gross and histologic pathology of exocrine pancreatic neoplasms, both benign and malignant. Related topics, such as the risk factors and molecular pathology of exocrine pancreatic cancer, are discussed elsewhere, as are the various types of islet cell tumors that arise in the endocrine pancreas. (See "Epidemiology and nonfamilial risk factors for exocrine pancreatic cancer" and "Insulinoma" and "Glucagonoma and the glucagonoma syndrome" and "VIPoma: Clinical manifestations, diagnosis, and management" and "Somatostatinoma: Clinical manifestations, diagnosis, and management" and "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)

CLASSIFICATION — Several malignant and benign neoplasms may arise in the pancreas. More than 95 percent of malignant neoplasms of the pancreas arise from the exocrine elements. The remainder arise from the endocrine elements within the pancreas (the islet cells), and are classified with other neuroendocrine neoplasms arising in the gastrointestinal tract. (See "Pathology, classification, and grading of neuroendocrine neoplasms arising in the digestive system".)

The Armed Forces Institute of Pathology (AFIP) and World Health Organization (WHO) classifications of exocrine pancreatic tumors are most frequently used in the United States [3,4]. These classifications, which were developed beginning in the 1990s, are based on morphologic and histologic features.

The following discussion predominantly uses WHO nomenclature [4], which is now similar to the most recent AFIP classification [3]. An example of a difference in terminology from earlier versions of both classifications is the nomenclature for intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (MCN). The WHO classification recommends use of the term MCN or IPMN in conjunction with a description of the histologic grade (low-grade or high-grade dysplasia) [3,5,6].

Benign — The most common benign pancreatic neoplasm is serous cystadenoma. These tumors are reliably cured with surgical removal alone.

Premalignant lesions — The neoplasms discussed below include some with the potential to progress to malignancy and some that were formerly referred to as tumors of uncertain malignant potential (also called "borderline" tumors). Patients with these neoplasms are considered to be at risk for progression to invasive malignancy, and they are now considered to represent premalignant lesions.

A recent trend in the histopathology of premalignant lesions in the pancreas is to designate the degree of dysplasia as "low grade" or "high grade" (rather than as three grades, such as mild/moderate/severe or low/intermediate/high grade) [7]. When the two-grade convention is used, the low-grade lesions include those formerly classed as mild or moderate dysplasia, whereas high-grade lesions are those classed as severe dysplasia. Three-tiered grading systems are used in older literature.

Malignant — Several types of malignant tumors arise in the exocrine pancreas; in the following list of the main histologic types, the percentages indicate the approximate prevalence of that type:

●Ductal adenocarcinoma and its subtypes – 85 to 90 percent

●IPMN with an associated invasive carcinoma – 2 to 3 percent

●MCN with an associated invasive carcinoma – 1 percent

●Solid pseudopapillary neoplasm – <1 percent

●Acinar cell carcinoma – <1 percent

●Pancreatoblastoma – <1 percent

●Serous cystadenocarcinoma – <1 percent

PANCREATIC DUCTAL ADENOCARCINOMA — As noted above, ductal adenocarcinomas represent the most common type of exocrine pancreatic neoplasm.

Diagnosis — Accurate histopathologic diagnosis requires biopsy or surgical resection of the neoplasm. The need for biopsy arises because of the wide variety of neoplasms that occur in the pancreas and because some forms of pancreatitis (including autoimmune pancreatitis and paraduodenal pancreatitis [groove pancreatitis]) form masses that may be mistaken for carcinoma on imaging studies [8]. (See "Chronic pancreatitis: Clinical manifestations and diagnosis in adults".)

Diagnostic biopsy of a suspected pancreatic malignancy is indicated for treatment planning if neoadjuvant chemoradiation is considered, if there is systemic spread of disease, if there is local evidence of unresectability, or if the patient is unfit for surgery. Nowadays, the diagnosis can often be accomplished by cytologic examination of ultrasound-guided fine-needle aspiration (FNA) or core-needle biopsy.

While a positive biopsy can confirm the suspected diagnosis, a benign sample does not exclude the presence of malignancy. This issue is addressed in detail elsewhere. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Diagnostic algorithm and need for preoperative biopsy'.)

Gross pathology — The majority of ductal adenocarcinomas are gritty, hard, gray-white masses that are poorly circumscribed due to invasion of the adjacent pancreas or nearby tissues. These tumors most commonly arise in the head of the pancreas (the ratio of head to body/tail lesions is 3:1).

The designation as "ductal" is based on histologic features and does not necessarily imply an origin in the main pancreatic duct or major branch ducts. In fact, many ductal adenocarcinomas appear to arise more peripherally, in small ducts within the acinar tissue.

As they grow, pancreatic ductal neoplasms can cause obstruction of the pancreatic duct, leading to chronic pancreatitis in the obstructed segment of the pancreas. However, because the accessory duct of Santorini can allow bypass of the main pancreatic duct, steatorrhea and malabsorption are usually not clinical problems.

Histology and grading — Most pancreatic ductal adenocarcinomas are moderately to poorly differentiated, with varying degrees of duct-like structures and mucin production (picture 1). Histologic grading, which is based on the degree of differentiation and the prevalence of mitotic cells, typically uses three grade levels (grade 1, well differentiated; grade 2, moderately differentiated; grade 3, poorly differentiated), although highly anaplastic tumors are sometimes designated as grade 4.

Dense stromal fibrosis is characteristic of ductal adenocarcinomas and is the reason that they are referred to as "scirrhous" or "desmoplastic" carcinomas (picture 1). The stromal fibrosis is attributed in part to alterations in transforming growth factor beta (TGF-beta) signaling.

Histologic subtypes — Several subtypes of ductal adenocarcinoma are recognized on the basis of distinctive histologic patterns. Examples include adenosquamous carcinoma (picture 2) [9], colloid carcinoma (picture 3), hepatoid carcinoma, anaplastic undifferentiated carcinoma (picture 4), medullary carcinoma, and others. In general, such subtypes individually are rare (in the range of 1 percent or less of pancreatic carcinomas) and share a similar poor prognosis, except for colloid carcinomas, which have a better prognosis than ductal adenocarcinomas. Regardless of prognosis, they are all managed similarly to conventional pancreatic ductal adenocarcinomas.

These subtypes are not further discussed in this chapter, and details can be found in standard references [4].

Patterns of local spread — Local extension typically involves adjacent structures, such as the duodenum (picture 5), the portal vein, or the superior mesenteric vessels. Pancreatic ductal adenocarcinomas also show a striking tendency toward perineural invasion, both within and beyond the pancreas (eg, the retroperitoneum) (picture 6). There is some evidence to support paracrine regulation of pancreatic cancer invasion by peripheral nerves, which may explain this general observation [10].

The difficulty in achieving a wide resection margin due to the proximity to the aorta, the superior mesenteric artery, and the portal vein accounts for the fact that the retroperitoneal tissue behind the head of the pancreas represents the most common site of disease recurrence after resection.

Occasionally, there may be local extension to the spleen, adrenal glands, vertebral column, transverse colon, and/or stomach. In most cases, tumors with this degree of local invasion are not resectable for cure.

Regional peripancreatic lymph nodes frequently harbor metastatic deposits. More distant lymph node groups that are less often involved include the perigastric, mesenteric, omental, and porta hepatis nodes. (See "Clinical manifestations, diagnosis, and staging of exocrine pancreatic cancer", section on 'Definitions of unresectable and borderline resectable disease'.)

PANCREATIC INTRAEPITHELIAL NEOPLASIA — Pancreatic intraepithelial neoplasia (PanIN) refers to a small (generally <5 mm), intraductal, noninvasive lesion that is formed by metaplasia and proliferation of ductal epithelium [11,12]. The epithelium is often columnar and contains increased cytoplasmic mucin. PanIN can occur in the main pancreatic duct and its major branches, but the majority appear to arise in smaller intralobular ducts.

PanIN exhibits varying degrees of dysplasia, which were originally graded as mild, moderate, or severe (designated as PanIN-1, PanIN-2, and PanIN-3, respectively) (picture 7). Higher grade PanIN is often papillary in microscopic appearance. This nomenclature has replaced diverse earlier descriptive terms, such as mucinous hyperplasia, atypical hyperplasia, and carcinoma in situ (now called PanIN-3). Use of a two-tier grading system (low grade, high grade) for PanIN, as discussed above for other premalignant lesions in the pancreas, has been recommended [7,13]. Within this system, PanIN-1 and PanIN-2 are grouped together as low-grade PanIN. (See 'Premalignant lesions' above.)

Some (but not all) PanIN are considered to progress from low-grade to high-grade dysplasia and then to ductal adenocarcinoma. Most ductal adenocarcinomas are considered to arise from PanIN, presumably developing as a result of a series of genetic events. However, although PanIN is considered to represent a precursor lesion to invasive ductal adenocarcinoma, it appears that only a small fraction of low-grade PanIN progress to invasive cancer [14]. The role of PanIN as a precursor lesion for other types of pancreatic neoplasms remains unclear [15].

The incidence and number of PanIN rise with age, and low-grade PanIN is very common in patients older than 50 years (>50 percent prevalence). Noninvasive precursor lesions, such as PanIN, are more common and of a higher grade in patients with a strong family history of pancreatic cancer [16]. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients".)

Little is known about the significance of incidentally discovered PanIN, although case reports suggest a possible association with metachronous pancreatic ductal adenocarcinoma [17-19]. This issue was addressed in a series of 584 patients undergoing pancreatectomy for a reason other than pancreatic ductal adenocarcinoma at a single institution over a 10-year period [20]. PanIN was identified in 153 patients (26 percent); only 13 (8 percent) had PanIN-3. The presence of PanIN of any grade was not associated with an appreciable cancer risk in the pancreatic remnant, at least with short-term follow-up (median 3.7 years, range 0.5 to 12.6). More studies with long-term follow-up are needed before definite conclusions can be made. However, at present, there are no data to support routine surveillance of patients who are found to have low-grade PanIN after undergoing resection for a benign pancreatic lesion.

OTHER NEOPLASMS — Several other pancreatic neoplasms merit comment because of their special characteristics. Many of these are cystic neoplasms that must be distinguished from one another and also from other nonneoplastic cystic pancreatic masses, such as pseudocysts and developmental cysts. Cystic neoplasms comprise approximately 5 percent of exocrine pancreatic neoplasms. (See "Classification of pancreatic cysts" and "Pancreatic cystic neoplasms: Clinical manifestations, diagnosis, and management".)

Intraductal papillary mucinous neoplasms — Intraductal papillary mucinous neoplasms (IPMN) are cystic neoplasms that are clearly derived from the pancreatic ducts. They typically occur in older adults (mean age approximately 65 years).

IPMNs arise in both the main duct and branch ducts. IPMN may be designated as main duct type (MDT-IPMN), branch duct type (BDT-IPMN), or combined type, based on the anatomic involvement of the pancreatic ducts (see "Intraductal papillary mucinous neoplasm of the pancreas (IPMN): Pathophysiology and clinical manifestations"):

●MDT-IPMN involve the main pancreatic duct diffusely or segmentally. The majority arise within the head of the pancreas and progress distally, with or without involvement of the side branches. As a group, these IPMN are more likely to exhibit high-grade dysplasia than BDT-IPMN and are more likely to harbor a malignancy.

●In contrast, BDT-IPMN occur in younger patients and often arise in the uncinate process, although they may also involve the body and tail of the pancreas. BDT-IPMN may have a lower risk of malignant transformation compared with MDT-IPMN lesions, and many small IPMN can be observed rather than resected [21].

It is likely that the malignant potential is determined more by the histologic subtype than by location per se. (See 'Histology and grading' below.)

In both locations, the cystic lesions are usually lined by columnar mucin-secreting epithelium overlying a fibrous wall of variable thickness. They may be multifocal and sometimes involve the entire main duct. IPMN may be found throughout the pancreas but are more frequent in the head of the gland.

The characteristic features include diffuse or segmental dilation of the pancreatic duct, intraductal expansion of mucin-producing ductal cells, and dilation of either the ampulla or minor papillae, through which there may be copious secretion of mucus into the duodenum. The diagnosis is often suspected when thick mucus is seen extruding from the papilla of Vater at the time of endoscopy in a patient with cystic ductal changes in the pancreas.

The mucin content of IPMN is frequently highly viscous and therefore likely to be retained in the duct system, causing dilation. Patients with IPMN can present with repeated episodes of acute pancreatitis, presumably triggered by intermittent duct obstruction caused by mucus plugs.

A number of other names (eg, mucinous duct ectasia) were applied in the older literature, especially preceding publication of the 1996 World Health Organization (WHO) classification [22], in which the group was designated as intraductal papillary mucinous tumors (IPMT). This terminology was revised to IPMN in the more recent classifications [3,5].

Mucinous cystic neoplasms (MCN) have sometimes been confused with IPMN, so some early reports appear to include both. (See 'Mucinous cystic neoplasms' below.)

Histology and grading — IPMN are graded according to the degree of cellular dysplasia and the growth pattern (architecture) of the lining epithelium. They are classified as IPMN with low- or high-grade dysplasia, with or without invasion [5].

The most recent Armed Forces Institute of Pathology (AFIP) fascicle on pancreatic neoplasms [3] emphasizes that IPMN apparently progress from low-grade dysplasia (clinically benign) to high-grade dysplasia, and that neoplasms with high-grade dysplasia sometimes become invasive. Overall, 30 to 35 percent of IPMN have been associated with invasion, but a more recent report suggests that this rate is based on larger, resected IPMN, and that the true rate is lower when smaller IPMN are included [23]. (See "Intraductal papillary mucinous neoplasm of the pancreas (IPMN): Pathophysiology and clinical manifestations", section on 'Pancreatic malignancy'.)

Several histologic subtypes of IPMN that have differing probabilities of progression to malignancy are described [24]. These histologic subtypes are distinguished on the basis of differences in cytologic appearance, architecture, and mucin expression of the epithelial cells of the lesion. The subtypes are usually designated as intestinal (picture 8), gastric foveolar (picture 9), pancreatobiliary (picture 10), and oncocytic (picture 11). The last type is included in the group of IPMN because they are intraductal, although they contain less mucin.

The intestinal type is reported as the most common in some series that are based on resected IPMN, but the gastric type is felt to be more common overall [25,26]. Gastric-type IPMN typically show no more than low-grade dysplasia. Intestinal-type IPMN more often show higher grade dysplasia. The less common pancreatobiliary-type IPMN typically show high-grade dysplasia and are considered to have high malignant potential. Oncocytic-type IPMN typically exhibit high-grade dysplasia.

The intestinal type occurs more frequently in the main duct than in branch ducts, while the other common subtype, the gastric type, characteristically occurs in the branch ducts. It is uncertain whether one type can transform into another, but more than one histologic type may be found in a single neoplasm, most often both gastric foveolar and intestinal.

When there is more than minimal local invasion (sometimes designated as microinvasion), the prognosis is determined by the invasive component, and the designation is IPMN associated with invasion. In approximately one-half of invasive IPMN, the invasive component is ductal adenocarcinoma. In the remainder, the invasive component is noncystic mucinous (colloid) carcinoma, in which interstitial mucin pools contain mucin-secreting malignant cells and some small mucin-filled cysts are partially lined by the malignant epithelium. This invasive pattern is most often associated with intestinal-type IPMN (designated as colloid carcinoma associated with intraductal papillary mucinous carcinoma, intestinal type), although intestinal-type IPMN can also progress to typical solid ductal adenocarcinoma [3]. The distinction between colloid and solid ductal patterns of invasion has clinical significance because the prognosis for patients with colloid carcinoma (when this pattern is clearly dominant) is better than for patients with invasive ductal adenocarcinoma [27].

The nomenclature for IPMN is complex and still evolving. There is likely to be variation in terminology in different institutions, and terminology will likely evolve over time. If the histopathologic diagnosis seems ambiguous or utilizes unfamiliar terminology, the clinician should discuss the findings with the pathologist. (See "Intraductal papillary mucinous neoplasm of the pancreas (IPMN): Pathophysiology and clinical manifestations", section on 'Histologic classification'.)

Intraductal tubulopapillary neoplasm — Intraductal tubulopapillary neoplasm (ITPN) is a rare (<1 percent) intraductal epithelial neoplasm that was originally regarded as a subtype of IPMN but is now increasingly recognized as a distinct entity on the basis of morphologic [28] and genetic differences [29]. ITPN is defined as an intraductal tubule-forming neoplasm with high-grade dysplasia (picture 12). The mean age at diagnosis is approximately 60 years [29,30]. Although it is difficult to differentiate ITPN from IPMN with imaging alone, a solid growth pattern favors ITPN over IPMN [30]. A clear majority of ITPN arise in the main pancreatic duct, although a small number arise in the branch ducts. Their size ranges from 1 to 16 cm (average approximately 3 cm) [29,30]. Approximately one-half are located in the head of the pancreas, and approximately one-third are located in the body and/or tail, with diffuse involvement in the remainder [30]. Cuboidal to low columnar neoplastic cells have a moderate amount of cytoplasm and round to oval nuclei. Tubules are closely packed with focal areas of papillary and cribriform structures. Mucin is absent or minimal. Immunostains for specific mucins are helpful in distinguishing IPMN from ITPN [30]. Approximately one-half of ITPN are associated with an invasive carcinoma that usually lacks a KRAS mutation [30]. Rare cases with multiple liver metastases and postoperative recurrence have been reported. The five-year survival rate of patients with ITPN-associated invasive carcinoma is more than 30 percent, clearly better than conventional pancreatic ductal adenocarcinoma [30]. Similar neoplasms occur in the bile ducts. (See "Pathology of malignant liver tumors", section on 'Intraductal tubulopapillary neoplasm of bile duct'.)

Mucinous cystic neoplasms — MCN are usually sharply demarcated cystic masses with a thick fibrous wall that occur in the body or tail of the pancreas (image 1). Only approximately 10 percent arise in the head of the pancreas. MCN typically occur in younger females (median age in the 40s) than do ductal adenocarcinoma or IPMN (median age in the 60s), although they may be seen in older women. MCN rarely occur in men. MCN are slightly less prevalent than IPMN [31].

MCN typically do not communicate with the pancreatic duct system [3,6], although a single case with involvement of the main pancreatic duct by a neoplasm with features of both MCN and IPMN has been reported [32]. Three decades ago, MCN and IPMN were not consistently recognized as different neoplasms, and some early publications on mucin-containing cystic pancreatic neoplasms seem to have included both MCN and IPMN. The ability to make a histologic distinction between the two entities has improved over the past two decades.

Histology and grading — The epithelium lining the cysts is characteristically columnar with abundant luminal mucin. However, in many large MCN, the epithelium is cuboidal and the cells contain little mucin. In low-grade lesions, the epithelium forms a single layer, sometimes forming papillary folds. As lesions become more dysplastic, they typically become more papillary, and mitoses may be identified.

In contrast to IPMN, subtypes based on epithelial morphology have not been reported in MCN. The histologic hallmark for distinguishing MCN from IPMN is the presence of a highly cellular stromal layer immediately beneath the epithelium (picture 13). This has been called "ovarian stroma" because it is composed of small spindle-shaped cells in which estrogen and/or progesterone receptor expression can be demonstrated by immunohistochemistry. It is suggested that the stroma plays a pathogenetic role in the development of MCN [32].

Some observers have suggested that the distinction between IPMN and MCN should be based on the presence (in IPMN) or absence (in MCN) of communication with the pancreatic duct [8]. However, the presence of ovarian stroma is the most reliable way to distinguish MCN from IPMN [33]. (See "Pancreatic cystic neoplasms: Clinical manifestations, diagnosis, and management".)

The thickness of the cyst wall is sometimes increased by an outer layer of highly collagenous fibrous tissue that may contain calcified foci. In larger cysts, much of the wall may lack epithelium and be highly collagenous without a layer of ovarian stroma.

As regards grading, both the AFIP and WHO have classified MCN into the now recommend a two-tiered grading system, low or high grade, for MCN, similar to IPMN [7]. Low-grade MCN can progress to high-grade dysplasia (picture 14), and to invasive carcinoma.

MCN with high-grade dysplasia may be either noninvasive (in situ) or invasive. In the largest series of MCN reported to date, 17.3 percent were invasive [2]. When there is an invasive component, it most often resembles ductal adenocarcinoma. There is some disagreement as to whether MCN ever invades as colloid carcinoma, and this issue may reflect the past confusion between IPMN and MCN. If invasion as colloid carcinoma occurs, it appears to be rare [34].

Serous cystadenoma — Serous cystadenomas are benign neoplasms that can occur in adults of any age but are most common in older females (mean age in the 60s at diagnosis). A slight majority (50 to 70 percent) arise in the body or tail of the pancreas. Large lesions (>4 cm) are more likely to cause symptoms [35]. Serous cystadenomas classically have a central scar, which may become calcified (picture 15).

The majority of serous cystadenomas are composed of multiple small cysts, and they have a classic "honeycomb appearance." All serous cystadenoma variants have similar cuboidal epithelial cells with clear cytoplasm that form a single layer lining the cysts. Histochemically, the cytoplasm stains positive with the periodic acid-Schiff (PAS) stain due to the presence of glycogen (picture 16). A minority have fewer large cysts and are designated as macrocystic or oligocystic [36,37]. Serous cystadenomas, often multiple, are seen in patients with von Hippel-Lindau syndrome. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

Very few serous adenomas appear solid on gross examination and have microscopic glands (acini) on histologic examination. These have been designated as solid serous adenoma [38].

These lesions are regarded as benign unless there is clear evidence of invasion or metastasis [3]. Progression to malignancy (ie, serous cystadenocarcinoma) is distinctly rare in serous neoplasms [2,39]. However, malignant potential cannot be accurately predicted on the basis of cytologic changes.

Solid pseudopapillary neoplasms — Solid pseudopapillary neoplasms (SPN) are of special interest because they occur predominantly in females (90 percent) and at a younger age (mean age in the 20s) than other pancreatic neoplasms (except pancreatoblastoma) [40,41]. However, SPN are also found in older patients. The most common presenting symptom is abdominal pain (64 percent in a large literature-based review of 2744 reported cases [40]), but many cases are diagnosed incidentally at an asymptomatic stage. The number of incidentally detected SPN has risen dramatically since 2000, coincident with the widespread use of computed tomography (CT), magnetic resonance imaging (MRI), and transabdominal and endoscopic ultrasound imaging. Cross-sectional imaging reveals large, solitary, well-circumscribed lesions that can have a completely cystic, mixed cystic and solid, or purely solid appearance.

SPN are equally distributed throughout the pancreas. They begin as solid neoplasms that often become cystic as they grow large and the cells become so far removed from their blood supply that they undergo apoptosis or necrosis. Histologically, SPN are composed primarily of polygonal cells with a moderate amount of cytoplasm (picture 17). Multiple capillary-sized vessels traverse the tumor, and when they become cystic, these vessels are surrounded by a single or multiple layer(s) of surviving tumor cells, giving the lining an irregular "pseudopapillary" appearance. In the older literature, these neoplasms have been called "solid-cystic tumors," "papillary cystic neoplasms," Hamoudi or Frantz tumors, and many other names, reflecting their complex solid, cystic, and "papillary" morphology [1,40].

In the past, SPN were classified as having uncertain malignant potential, but more recently, they are considered a low-grade malignancy [1,3,42]. Prognosis is generally good [40,41]. Among 1952 patients with SPN treated with surgical resection, with a median follow-up of 36 months, disease-free survival was 95.6 percent, with recurrence in 4.4 percent [40]. Distant metastases were reported in approximately 8 percent of cases [40]. The median time to recurrence was approximately four years, and the author concluded that patients treated for SPN should be followed for a minimum of five years.

At least one study and literature review suggests that tumors with a high proliferation rate (4 percent or more as assessed by the Ki-67 index) may have a less favorable outcome [43]. However, it is not clear what impact, if any, the finding of a high Ki-67 index would have on management of these patients.

Acinar cell carcinoma — Acinar cell carcinomas are rare malignant neoplasms that are usually solid but are sometimes cystic. They occur throughout the pancreas at any age, but they predominantly arise in adults and more often arise in males than in females.

Some acinar cell carcinomas give rise to a clinical syndrome related to lipase hypersecretion with distant manifestations, such as subcutaneous fat necrosis (so-called "pancreatic panniculitis"), and polyarthralgia [1,44]. This syndrome is associated with poor prognosis [44]. (See "Cutaneous manifestations of internal malignancy".)

Histologically, there is clear evidence of acinar cell differentiation, which can be identified immunohistochemically by staining for trypsin, chymotrypsin, elastase, or lipase, or can be ultrastructurally identified by the presence of zymogen granules, although variant histologic patterns reflect different degrees of differentiation (picture 18) [45].

Most acinar cell neoplasms, even those that are highly differentiated, are malignant, although a few benign acinar cell neoplasms have been described. Molecular analyses also suggest that pancreatic acinar cell carcinoma is associated with BRCA2 germline pathologic variants and genomic features of homologous recombination deficiency, which predispose the patient to malignancy [46]. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Hereditary breast cancer: BRCA and PALB2' and "Cancer risks and management of BRCA1/2 carriers without cancer", section on 'Pancreas'.)

The overall prognosis for patients with acinar cell carcinoma is better than for patients with ductal adenocarcinoma [21,47,48], but it is worse than for patients with typical pancreatic neuroendocrine (ie, islet cell) tumors [49].

Pancreatoblastoma — Pancreatoblastomas are malignant neoplasms of presumed stem cell origin. They appear to arise from primitive cells that have the potential to differentiate along several lines.

These tumors most often occur in infants and children (median age four years in a European series of 20 patients [50]); however, they also occur in older children and adults. A slight male predominance is noted in some series, but the ratio is close to unity in most series. They may develop in the head, body, or tail of the pancreas, usually as solid masses. The clinical presentation is that of a large retroperitoneal mass [51]. Approximately 30 percent of pancreatoblastomas secrete alpha-fetoprotein (AFP) [1,3].

Histologically, pancreatoblastomas are composed of primitive, small, polygonal or spindle-shaped cells that may be mixed with acinar, ductal, or islet cells. In some cases, immunostaining reveals acinar, ductal, or endocrine markers among the polygonal cells. Characteristic "squamoid" bodies or nests are found among the primitive cells (picture 19) and provide a useful diagnostic feature [52].

Although all pancreatoblastomas are considered malignant, they are less aggressive than ductal adenocarcinoma and have a higher cure rate after surgical resection [51,53,54]. The prognosis is better in children than in adults [1,54,55].

Other rare types — Neoplasms composed of mixed exocrine and endocrine cell types are recognized (eg, mixed ductal-neuroendocrine carcinoma, mixed acinar-neuroendocrine carcinoma, and mixed acinar-neuroendocrine-ductal carcinoma). While such neoplasms seem likely to reflect an origin of the neoplasm from pluripotent cells, they differ from pancreatoblastoma because they do not contain a recognizable component of primitive (undifferentiated) cells.

Ductal adenocarcinomas and acinar cell carcinomas also commonly contain a minor population of cells with neuroendocrine differentiation that may be detected by immunostains.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pancreatic cancer".)

SUMMARY

●Classification – Several malignant and benign neoplasms may arise in the pancreas.

•Benign pancreatic neoplasms – The most common benign pancreatic neoplasm is serous cystadenoma. Several neoplasms formerly classified as "borderline" or "of uncertain malignant potential" are now accorded "premalignant" status because some will progress to malignancy. These include low-grade intraductal papillary mucinous neoplasms (IPMN) and low-grade mucinous cystic neoplasms (MCN). (See 'Classification' above.)

•Malignant pancreatic neoplasms – Of the malignant tumors that arise in the exocrine pancreas, the commonly used terms "carcinoma of the pancreas" or "pancreatic cancer" usually refer to ductal adenocarcinoma, which (including its subtypes) represents approximately 85 to 90 percent of all pancreatic neoplasms. The more inclusive term "exocrine pancreatic neoplasms" includes all tumors that are related to the pancreatic ductal and acinar cells and their stem cells. More than 95 percent of malignant neoplasms of the pancreas arise from the exocrine elements; the remainder arise from the endocrine elements within the pancreas (the islet cells). (See 'Pancreatic ductal adenocarcinoma' above.)

●Other pancreatic neoplasms – Several pancreatic neoplasms merit comment because of their special characteristics:

•Cystic neoplasms – Cystic neoplasms such as IPMN and MCN comprise approximately 5 percent of exocrine pancreatic neoplasms; they must be distinguished from one another and also from other nonneoplastic cystic pancreatic masses, such as pseudocysts and developmental cysts. (See 'Other neoplasms' above.)

•Solid pseudopapillary neoplasms – Solid pseudopapillary neoplasms occur predominantly in females (90 percent) and at a younger age (mean age in the 20s) than other pancreatic neoplasms (except pancreatoblastoma). (See 'Solid pseudopapillary neoplasms' above.)

•Acinar cell carcinomas – Acinar cell carcinomas are rare malignant neoplasms that are usually solid but are sometimes cystic. Some acinar cell carcinomas give rise to a clinical syndrome related to lipase hypersecretion with distant manifestations, such as subcutaneous fat necrosis (so-called "pancreatic panniculitis") and polyarthralgia. Pancreatic acinar cell carcinoma can be associated with BRCA2 germline pathologic variants and genomic features of homologous recombination deficiency. (See 'Acinar cell carcinoma' above.)

•Pancreatoblastomas – Pancreatoblastomas most often occur in infants and children; however, they also occur in older children and adults. (See 'Pancreatoblastoma' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Daniel S Longnecker, MD, who contributed to earlier versions of this topic review.