Unusual cancers of the pancreas

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Редкие опухоли поджелудочной железы

Textbook of Uncommon Cancer, Fourth Edition. Edited by Derek Raghavan, Charles D. Blanke, David H. Johnson, Paul L. Moots, Gregory H. Reaman, Peter G. Rose and Mikkael A. Sekeres.  John Wiley & Sons, 2012.


Introduction

Tumors of the pancreas collectively are the fourth leading cause of neoplastic death despite being only the 10th most common site of cancer in the United States.1 In 2011, it is expected that over 44,000 Americans will be diagnosed with pancreatic cancer and 37,660 will die from this disease. Approximately 95% of pancreatic cancers arise from the ductal epithelium, and another 3–4% arise from the islet cells. This chapter will review the unusual, remaining 1–2% (Box 29.1), particularly epithelial malignancies of nonneuroendocrine origin. The nonepithelial pancreatic malignancies, including lymphomas, sarcomas, primitive neuroectodermal tumor, and desmoplastic small round cell tumor, are treated similarly to those arising from other sites and will not be addressed in this chapter.

Uncommon exocrine tumors of the pancreas

Cystic neoplasms

Both malignant and benign cystic neoplasms may arise in the pancreas. Each has unique features but the evaluation and diagnostic workup are common for these lesions. It is important to try to distinguish these lesions, because of the impact on management.

Cystic neoplasms are classified as serous (benign or malignant), mucinous (benign or malignant), and intraductal papillary mucinous neoplasm (IPMN), a premalignant lesion that appears to lead to adenocarcinomas. Two recent reviews of all cystic neoplasms have been published.2

The most common clinical presentation for cystic neoplasms is an incidental finding on radiographic studies performed for other reasons.2,3 Symptoms, when they occur, are nonspecific and include bloating, abdominal discomforts and other symptoms of mass effect from the lesions. Most commonly, the patients have had either a computed tomography (CT) scan or magnetic resonance imaging (MRI). These tests can differentiate cystic neoplasms from nonneoplastic lesions such as pancreatic pseudocyst. Pseudocyst generally presents with history of pancreatitis and on CT or MRI inflammation of the pancreas is usually seen.4 Magnetic resonance cholangiopancreatography can help determine the etiology of the cystic lesion as well, showing biliary and pancreatic ductal structure. Endoscopic retrograde cholangiopancreatography (ERCP) may also be useful. One finding, that of a swollen papilla with mucin oozing from the papilla, is considered pathogenomic of IPMN but is not a common finding.4

Surgery is the diagnostic test of choice for cystic neoplasms but among less invasive testing, endoscopic ultrasound (EUS) should be considered. This procedure allows evaluation of the cyst, biopsy and aspiration of the cystic fluid for diagnostic testing. Cyst fluid analysis had been utilized prior to EUS but EUS provided a new modality for evaluating size, structure, and cyst fluid. In the Cooperative Pancreatic Cyst Study, 341 patients underwent EUS and cyst fluid aspiration, 112 of whom had subsequent surgical resection. The study demonstrated that cyst fluid carcinoembryonic antigen (CEA) was more accurate (79% accuracy) than cyst morphology (51% accuracy) or cytology (59% accuracy) in distinguishing mucinous from nonmucinous cysts. In this study, a cut-off of 192 ng/mL was used for CEA levels but the sensitivity and specificity of this test can be changed by using a different CEA level. It is clear that a CEA level of <3.1 ng/mL is almost diagnostic of a serous cyst while levels above 480 ng/mL are diagnostic of a mucinous neoplasm.

However, it is more complex to determine malignant versus nonmalignant cystic neoplasms. Very high levels of CEA of ≥6000 ng/mL are suggestive of malignancy.

Box 29.1. Classification of pancreatic neoplasms.

Epithelial malignancies

Exocrine neoplasms

  1. Serous cystadenocarcinoma
  2. Invasive carcinoma associated with mucinous cystic neoplasm (mucinous cystadenocarcinoma)
  3. Invasive carcinoma associated with intraductal papillary mucinous neoplasm
  4. Adenocarcinoma variants:
    • Adenosquamous carcinoma
    • Colloid carcinoma (mucinous noncystic adenocarcinoma)
    • Medullary carcinoma
    • Hepatoid carcinoma
    • Undifferentiated carcinoma
    • Undifferentiated carcinoma with osteoclast-like giant cells
  1. Acinar cell carcinoma
  2. Acinar cell cystadenocarcinoma

Endocrine malignancies

  1. Well-differentiated pancreatic neuroendocrine tumor:
    • Oncocytic carcinoma
  1. Poorly differentiated neuroendocrine carcinoma:
    • Small cell carcinoma
    • Large cell endocrine carcinoma

Epithelial malignancies with multiple directions of differentiation

  1. Mixed acinar-neuroendocrine carcinoma
  2. Pancreatoblastoma

Epithelial neoplasms of uncertain direction of differentiation

  1. Solid-pseudopapillary neoplasm

Nonepithelial malignancies

  1. Leiomyosarcoma and other sarcomas
  2. Primitive neuroectodermal tumor
  3. Desmoplastic small round cell tumor
  4. Non-Hodgkin lymphoma

Cystadenocarcinoma

Serous cystic neoplasms

Most serous cystic neoplasms (SCNs) are benign, and malignant transformation is thought to be very rare.8,9 Serous cystic neoplasms make up approximately 1.1% of exocrine pancreas tumors.8 However, in a single-institution experience of 158 resected SCNs, only one was initially diagnosed as malignant although a second later presented with metastatic disease, demonstrating that cystadenocarcinoma represent fewer than 1% of serous cystic neoplasms.9

Serous cystic neoplasms can present at almost any age, although the median age at presentation is 61–2.9,10 The majority of patients are female (75–80%) and one study suggested that female patients tend to present at a lower median age.10

Unusual Cancers of the Pancreas 1

Figure 29.1. Serous cystadenocarcinoma is composed of uniform cuboidal cells with clear cytoplasm forming microcysts.

In single-institution studies, 36–47% of patients were asymptomatic with the finding arising from diagnostic workup for a separate problem.9,10 SCNs are more likely to be found in asymptomatic patients as the use of CT and MRI imaging has increased in recent years. Both studies found the most common symptom was abdominal pain with other symptoms being weight loss, fatigue, abdominal fullness, jaundice, and gastrointestinal bleed. The majority of patients were Caucasian. In a Mayo Clinic review of 21 cases collected over 48 years, median age for cystadenocarcinoma was also 61 but a higher percentage of patients were males.11 A higher percentage of patients presented with symptoms, with 81% having abdominal pain and nearly half presenting with weight loss. Jaundice, belching, nausea/vomiting, diarrhea, and fatigue were also reported.

As previously noted, cystadenocarcinoma is rare among the SCNs. By definition, serous cystadenocarcinoma is a serious cystic neoplasm of the pancreas with unequivocal metastases to extrapancreatic organs or tissues.12 Grossly, they usually present with a large mass with multiple compartments filled with numerous microcysts. They frequently invade adjacent organs. Histologically, serous cystadenocarcinomas are identical to serous cystadenoma, being composed of uniform cuboidal, glycogen-rich cells that form numerous cysts containing serous fluid (Fig. 29.1). The presence of local invasion, involvement of regional nodes, cyst wall invasion, and/ or histological dedifferentiation separate malignant from benign SCNs.

Diagnosis of cystic neoplasms is discussed above. For SCNs, CT and MRI of are variable accuracy.13 Endoscopic ultrasound may also be helpful, particularly because fluid can be obtained for evaluation. The diagnostic accuracy of EUS is as low as 40%, and it cannot evaluate benign versus malignant lesions. As mentioned above, cyst fluid analysis adds to the diagnostic accuracy of EUS, and low CEA (<5 ng/mL) and low viscosity are among the most consistent tests for differentiating SCNs from mucinous cysts.7,13

Unusual Cancers of the Pancreas 2aUnusual Cancers of the Pancreas 2b

Figure 29.2. (a) Grossly, mucinous cystadenocarcinoma is a well-circumscribed, multilocular cystic mass with solid areas. (b) Microscopically, an invasive carcinoma (left) with ductal differentiation arises from cysts (right) lined by atypical epithelium associated with an underlying subepithelial ovarian-like stroma.

Therapy of SCNs is surgical. Tumors smaller than 4 cm can be observed, although the frequency of follow-up scans ranges from 6 months to 2 years.13,14 If lesions show evidence of symptoms or rapid growth, or a definitive diagnosis cannot be obtained, surgery should also be considered. However, comorbidities and other risks for the surgery should be considered, due to the normally slow-growing, benign behavior of SCNs. For serous cystadenocarcinoma, with only one report of over 20 patients, there are few data as to the proper therapy.11

Surgery is still the treatment of choice. For patients with fully resected lesions (n = 13), 5-year survival was much better than for those with partial excisions (n = 7) (68% versus 14%, respectively). As the 5-year survival for resected cystadenocarcinoma appears to be much better than that for typical adenocarcinoma, it is difficult to recommend adjuvant therapy. However, typical regimens for pancreatic adenocarcinoma could be used if the clinician opts for therapy. Of note, the survival curve for partially excised tumors indicates that five of the seven patients died within the first year after surgery, which does not match the table that suggests that four patients survived for more than 1 year.11 The most common site of metastasis (5/7 patients) was the liver. For those with metastatic disease, there is no reason to believe that chemotherapy regimens used for pancreatic adenocarcinoma would be any more or less effective in cystadenocarcinoma, and treatment using standard regimens for pancreatic adenocarcinoma is recommended, based on performance status and comorbidities.

Mucinous cystadenocarcinoma

Mucinous cystic neoplasms represent 10–45% of cystic neoplasms.5 In contrast to serous cystic neoplasms, mucinous cystic neoplasms are more prone to malignant transformation. Mucinous cystadenocarcinomas may represent 8–39% of mucinous cystic neoplasms.15–17 Overall, they are felt to represent ~1% of pancreatic cancers.18 This variability may be due to methods for collecting patient data as well as the size of the series.

Mucinous cystadenocarcinoma of the pancreas is an invasive adenocarcinoma arising in mucinous cystadenoma. Grossly, it is a well-circumscribed, multilocular cystic lesion that does not communicate with the pancreatic duct (Fig. 29.2a). The majority of mucinous cystic neoplasms are located in the body or tail of the pancreas.15,19 Benign mucinous cystadenomas have smooth cystic walls. Intracystic papillary excrescence and solid mural nodules are seen in mucinous cystadenocarcinomas. Microscopically, the cysts are lined with columnar epithelium with/without mucin, showing variable degrees of architectural and cytological atypia (Fig. 29.2b). The cystic walls contain ovarian stroma. Most mucinous cystadenocarcinomas are either undifferentiated carcinoma or adenocarcinoma similar to conventional ductal adenocarcinoma (see Fig. 29.2b).20

There is a female predominance for both mucinous cystadenoma (86–100% female) and mucinous cystadenocarcinoma (71–100% female). Cystadenomas tend to present at an earlier age than cystadenocarcinomas. In the largest series, mucinous cystadenoma presented at a median age of 52 while cystadenocarcinomas presented at a median age of 63.6 years.15 In case series, the majority of patients with mucinous cystadenocarcinoma present with symptoms, the most common being abdominal pain in 41–64%, while only 11–25% presented as an incidental finding in patients without symptoms from the tumor.15,16,21 Mucinous cystadenoma presented without symptoms more often (26%) than mucinous cystadenocarcinomas (14%) in one series.15 Other series did not show a difference, with 25% of malignant and 28% of benign mucinous cystic neoplasms presenting as asymptomatic.21 However, most of these series do not account for the greater availability of CT scans and other tests that will likely increase the percentage of asymptomatic patients over time. Other presenting symptoms or findings include mass, fatigue, weight loss, and pancreatitis. Few data exist on CA 19-9 elevations but in one series, there were elevations in 21% of mucinous cystadenoma cases while mucinous cystadenocarcinoma patients presented with CA 19-9 elevations 70% of the time.15 However, other series have not shown a difference in CA 19-9 levels between benign and malignant lesions.21

Consistently, malignant lesions present on average at larger sizes. In one study, the differences were 82.5 mm versus 45 mm (p <0.001) for malignant versus benign.21 In a pooled analysis of multiple studies, mean size of malignant tumors was 10.2 cm with only one malignant tumor under 4.5 cm.22 Mucinous cystadenoma and cystadenocarcinomas predominantly develop in the body and tail of the pancreas with some studies reporting no head lesions.21,22

Treatment of mucinous cystic neoplasms is surgical. Mucinous cystadenomas appear to all be cured with surgical resection, with 99–100% surviving the disease.21,22 The prognoses for resected mucinous cystadenocarcinoma patients are fairly good but only 57–62% are disease free at 5 years. One series reported 23% of patients alive at 10 years.23 An analysis of pathological features predicting recurrence suggested that patients with peritumoral invasion were more likely to experience recurrence than those with only tumor wall invasion.16

Those with no evidence of invasion had no recurrences. Recurrences tend to be in the peritoneum and liver when they occur. Once disease recurs, mean survival is as short as 6.5 months.21 In addition, patients undergoing resection can subsequently develop exocrine or endocrine insufficiency, with both being more likely in patients with cystadenocarcinoma than those with cystadenoma.21 Subsequent exocrine insufficiency occurred in 21.5% versus 4.5% malignant versus benign lesions (p = 0.007) and subsequent endocrine insufficiency developed in 43% versus 18.5% malignant versus benign lesions (p = 0.005).

Little is known about patients with unresectable disease or the effects of systemic therapy. One small series suggested that patients with subtotal resections may also have a long survival, 30 months from diagnosis to death.24 However, patients unable to undergo any resection tend to have poor prognoses, with a 1-year survival rate of only 10% in one study.15 Little is known about the effects of radiotherapy and chemotherapy in this entity. In the absence of any data, it is likely best to treat these patients with chemotherapy and/or chemoradiotherapy regimens used for adenocarcinoma of the pancreas.

Intraductal papillary mucinous neoplasm

Intraductal papillary mucinous neoplasm (IPMN) is not a malignant neoplasm of the pancreas but it remains in the differential diagnosis with other cystic neoplasms of the pancreas. This entity has been known for almost 30 years but was not well defined until 1996.13 The incidence of IPMN is increasing but this most likely reflects increased awareness and improved technology as well as increased access to technology.25 IPMNs represent 20–50% of pancreatic cystic neoplasms. They are of significant importance because they appear to be precursor lesions to the common form of pancreatic cancer. Most recently, three families were described with what appears to be a familial pattern of IPMN.26 None of the mutations already known for familial pancreatic cancer (BRCA2, P16, and CDKN2A) were found in these families. An additional report suggested that this entity may occur with greater frequency in patients with Carney complex, a disorder most commonly associated with a germline PRKAR1A mutation.27

As expected for a precursor lesion of pancreatic cancer, IPMN most often occurs in older age and is more common in the head of the pancreas than in the body or tail.13 There is also a male predominance. IPMNs are divided into those of branch duct origin and those of main duct origin. Main duct IPMNs appear more likely to undergo malignant transformation. In a study of 349 Japanese patients with branch duct IPMNs followed closely, the median age for these lesions was 66 years with only a slight male predominance of 51%.28

Of note, only 1.7% of patients were symptomatic. Median cyst size was 19 mm. While 55% of the lesions were found in the head of the pancreas, 66% of those that progressed during the observation period arose in the head. Patients were observed for a median of 3.7 years and during that time, 17% exhibited progression. Surgery was performed on 29 patients on the study. During the observation period, a total of seven (2%) patients developed pancreatic ductal adenocarcinoma. A separate report of 46 patients with main duct IPMNs showed very different results.29 Median age was 74.6 years with male predominance (59%). Half the lesions were located in the pancreatic head and 30% presented with symptoms. Twenty patients (43%) underwent resection of their IPMNs. Those patients who underwent resection were more likely to have symptoms, be of younger age and have lesions in the head of the pancreas. Malignancy was found in 35% of patients with main duct IPMNs. Data suggesting that main duct IPMNs have greater potential for malignancy than branch-type IPMNs have been shown elsewhere, with 23–57% of main duct IPMNs and only 0–31% of branch duct IPMNs demonstrating invasive carcinoma (adenocarcinoma and IPMN with invasion).30

Pathologically, IPMNs are characterized by proliferation of mucinous cells within the ducts13 and the formation of papillae. There are four histological subtypes of IPMNs: intestinal, pancreatobiliary, oncocytic, and gastric.25 These four subtypes have different expressions of MUC 1, MUC 2, MUC5AC, and MUC6 gastric.25,31 The intestinal type is most common in main duct IPMN gastric.25 It most frequently is associated with a colloid carcinoma that has a fairly favorable prognosis (57% 5-year survival rate). The pancreatobiliary variant occurs more often in main duct IPMN but overall is less common than the intestinal type. The oncocytic variant was once called intraductal oncocytic papillary neoplasm and is the rarest form. It usually has high-grade dysplasia.31 In contrast, the gastric type of IPMN is the most common form and is largely associated with branch-type IPMN.25 Gastric and pancreatobiliary subtypes are associated with ductal adenocarcinoma and oncocytic forms are associated with oncocytic adenocarcinoma (discussed below). A consensus conference determined that IPMNs are characterized by a lack of ovarian stroma as is seen

in mucinous cystic neoplasms of the pancreas.32 IPMNs can have mutations of kRas, BRAF, and PIK3CA as well as loss of SMAD4 expression and overexpression of p53, similar to pancreatic ductal adenocarcinoma but not necessarily with the same incidence.25,31 These findings have now been detected in all subtypes of IPMN although the results thus far are highly variable. They can present with dilation of the pancreatic duct as well as accumulation of mucus.

Management of IPMNs is observation or surgery. Indications that have been used for resection include invasive component on biopsy, symptoms, and progression on radiographic imaging. In addition, presence of mural nodules in pancreatic cysts is more likely to predict dysplasia or invasive carcinoma than lack of mural nodules (23% versus 3%, respectively, p = 0.02).33 Observation is much more likely to be used in branch-type than in main duct IPMNs.13 It appears that the survival for resected IPMNs with invasion is much better than that for resected pancreatic ductal adenocarcinoma.13,34 Although 5-year survival for resected IPMN without invasive component is at least 70%, historically 5-year survival with invasive component is only 30–50%.13 However, a more recent report of 59 patients had 5-year survival for IPMN with an invasive carcinoma at 68%.34 In that study, multivariate analysis showed that nodal involvement and tubular carcinoma subtype predicted poorer prognosis. Other authors have found that when controlled for T and N staging, carcinoma arising from IPMN has no better prognosis than pancreatic ductal adenocarcinoma.35,36

There are no guidelines on the frequency of follow-up for patients for whom observation is chosen rather than surgical resection. There is also no consensus on follow-up of patients with resected IPMNs but it is common to perform at least annual imaging (either CT or MRI).13 Tumor markers appear of limited utility. There are no data on adjuvant therapy with either chemotherapy or chemoradiation. It is not currently recommended that these patients receive adjuvant therapy.

Adenocarcinoma variants

Adenosquamous carcinoma

Adenosquamous carcinoma is one of the more frequently occurring of the adenocarcinoma variants, ranging in autopsy and case series from <1% to as much as 11% of all pancreatic tumors.8,14,37–40 The largest series place the incidence at less than 1%.14,37,38 In the larger case series, adenosquamous carcinomas have a male predominance (~60% or more male).14,39

Seventy-five to 88% were Caucasian and median age was 65–68.14,39,41 There appears to be predominance for head of pancreas primaries. Patients most often present with metastatic disease (53%) and less often with regional (38%) or localized (9%) disease. Using the California Cancer Registry database, researchers compared 95 adenosquamous carcinoma patients to pancreatic adenocarcinoma patients and found that the two populations were very similar in presentation, demographics, and outcomes.14

Adenosquamous carcinoma is a rare variant of pancreatic adenocarcinoma with both glandular and squamous differentiation. The gross appearance is similar to that of conventional ductal adenocarcinoma and it usually presents as a large, firm, ill-defined mass. Microscopically, there are adenocarcinoma and squamous cell carcinoma components, which can be intimately admixed (Fig. 29.3a) or topographically separate within the neoplasm (Fig. 29.3b). When they are separated, the adenocarcinoma portion is indistinct from conventional ductal adenocarcinoma (see Fig. 29.3b). The squamous component can be either keratinizing or nonkeratinizing. In adenosquamous carcinoma, at least 30% of the neoplasm should be squamous cell carcinoma.12 In a single analysis of immunohistochemical staining of 19 primary cases of adenosquamous carcinoma, 100% stained with cytokeratin (AE1/AE3 and CK1), 84% stained for CA 19-9, and 74% for CEA.41 In addition, 68% stained for CK7 and 26% for CK20. Only six metastases were evaluated but staining patterns were similar to the primary tumors. Mutations in K-Ras have been identified in 50–100% of adenosquamous carcinoma.39,42 A detailed analysis found similar mutations to pancreatic adenocarcinoma, including frequent loss of DPC4, and p16 proteins as well as strong nuclear positivity for p53.42 However, the squamous component stained for p63, which does not happen in adenocarcinoma of the pancreas.

Unusual Cancers of the Pancreas 3aUnusual Cancers of the Pancreas 3b

Figure 29.3. Adenosquamous carcinoma has two growth patterns: squamous cell carcinoma component intimately intermixed with adenocarcinoma with luminal formation (a), and nests of squamous cell carcinoma (right lower half ) separated from adenocarcinoma (left upper corner) (b).

Several series have suggested a worse outcome for patients with adenosquamous carcinomas versus those with adenocarcinomas.39,41 However, in the largest series the outcomes for adenosquamous carcinoma were similar provided that similar treatments were used.14

Treatment for localized disease is surgery. When surgery is performed, nodal involvement is common, occurring in 57–76% of cases.14,41 In one study, margin involvement was found in 37% of cases.41 Patients with locoregional disease treated with surgical resection have a median survival of 10.9–12 months. This may be better than in older, smaller series as a review of case reports and series from 1980 to 2007 revealed a median survival after surgery of only 6.7 months.43 Adjuvant chemoradiation was associated with an improved overall survival compared to those patients who underwent surgical resection alone. Patients with locoregional disease who did not have resection had much shorter survival, in the range of 5 months.14 Survival for metastatic disease patients is particularly poor, with a median of 4.5 months for those receiving chemotherapy and only 2 months for those who do not.

Stage for stage, the treatment of adenosquamous carcinoma should be the same as for patients with adenocarcinoma of the pancreas. Of note, the data for adjuvant therapy, though limited, exist only for chemoradiation and not for either therapy alone. No data exist for the use of FOLFIRINOX in patients with unresectable adenosquamous carcinoma but data suggest that patients benefit from chemotherapy.14 Considering the squamous component of the disease, there may be a good rationale for using a platinum-containing regimen in this setting to improve outcomes.

Colloid carcinoma (mucinous noncystic carcinoma)

Colloid carcinoma, a variant of pancreatic adenocarcinoma with abundant mucin pools, arises in association with IPMN. With recognition of the IPMN as the precursor lesion for this adenocarcinoma variant, less literature is available separating this entity from its apparent precursor, already discussed. The frequency of this lesion is not certain, as it is a variant of adenocarcinoma and includes both IPMN with minimally invasive disease and true invasive carcinoma, although IPMN can progress to pancreatic ductal adenocarcinoma, whereas colloid carcinoma appears to arise from the intestinal form of IPMN.30,44

Radiographic imaging of colloid carcinoma can include EUS, CT, and/or MRI. On CT, one small study described “peripheral and internal mesh-like progressive delayed enhancement,” with contrast administration as well as multiple small cystic areas.45 Similarly, a study of eight patients with colloid carcinoma who underwent MRI found a mesh-like appearance to the tumors as well as high intensity on T2-weighted images and nondistinct borders.46

Colloid carcinoma is usually larger than conventional ductal adenocarcinoma, with a mean size of 5.3 cm in one series.47 On cross-section, they are well circumscribed with a soft gelatinous appearance (Fig. 29.4a). Microscopically, colloid carcinoma is predominantly composed of pools of extracellular mucin with few strips of neoplastic epithelium (Fig. 29.4b). Pools of mucin infiltrate and dissect through the stroma. Mucin-producing neoplastic epithelial cells are usually well differentiated. Strips of the cells may float freely in or partially line the pools. Signet ring cells are frequently present in the mucin pool. Careful examination of the specimens always reveals associated IPMN. A minor component of conventional duct adenocarcinoma may be present. However, at least 80% of the neoplasm should be colloid component.47 Unlike conventional ductal adenocarcinoma which expresses MUC1 and is negative for CDX2, colloid carcinoma strongly expresses MUC2 and CDX2, indicating intestinal differentiation.44

Unusual Cancers of the Pancreas 4aUnusual Cancers of the Pancreas 4b

Figure 29.4. (a) Grossly, colloid carcinoma presents as a well-circumscribed mass with a soft gelatinous appearance. (b) Microscopically, there are pools of mucin associated with strips of neoplastic epithelium dissecting the stroma.

Unusual Cancers of the Pancreas 5aUnusual Cancers of the Pancreas 5b

Figure 29.5. Medullary carcinoma is a poorly differentiated carcinoma with a pushing border (a) and prominent intratumoral lymphocytes (b).

As mentioned earlier, the historical 5-year survival rate for IPMN with an invasive component is 30–50% with more recent articles suggesting a rate as high as 68%. The latter may reflect increased recognition of IPMNs and/or more aggressive surgical management.13,34 However, these figures likely include minimally invasive IPMN, colloid carcinoma and early forms of pancreatic ductal adenocarcinoma. A study that focused on only colloid carcinoma suggested a 5-year survival rate of 57%.47

Treatment data for colloid carcinoma are lacking. The majority of cases appear to remain localized with only ~30% presenting with metastases to lymph nodes and beyond.35 For localized disease, the treatment of choice is surgery. In the face of limited efficacy data, standard chemotherapy regimens for pancreatic ductal adenocarcinoma are appropriate alternatives for unresectable disease; radiation may be considered as part of the therapy of localized, unresectable colloid carcinoma.

Medullary carcinoma

Medullary carcinoma is a more recently described variant of pancreatic carcinoma. In one analysis of 18 patients, 67% were male and all but one were Caucasian.48 Age ranged from 33 to 85 years with a median of 69. A significant number of cancers were identified in other family members of patients with medullary pancreatic cancers. In fact, only one of the 18 patients had no family history of cancers while four others had unknown histories. Five-year survival for this cohort was 13%.

Medullary carcinoma of the pancreas is morphologically and genetically very similar to its counterpart in the colon. Grossly, medullary carcinomas are well circumscribed with a soft consistency. Microscopically, they have pushing rather than infiltrating borders. Dense lymphocytic infiltrates and/or lymphoid aggregates may be observed in the peripheral area (Fig. 29.5a). Prominent intratumoral lymphocytes may also be seen in some cases. Medullary carcinomas are frequently poorly differentiated with a syncytial growth pattern (Fig. 29.5b). Immunohistochemical studies may show loss of expression of mismatch repair genes.49 An evaluation of 18 patients with medullary carcinoma demonstrated that the majority (67%) had wild-type Ras tumors and a significant portion (22%) had microsatellite instability, including a case with hereditary nonpolyposis colorectal cancer.48 Subsequently, a case report identified another medullary pancreatic carcinoma in a patient with hereditary nonpolyposis colorectal cancer (HNPCC) and MSH2 mutation.50

As with other rare tumors, there are no data on treatment. Surgical resection is recommended when able to be performed. Single-agent fluoropyrimidines may be considered, if these tumors behave like HNPCC-associated colorectal cancers.

Hepatoid carcinoma

Hepatoid carcinoma is extremely rare. It occurs in a variety of locations and is characterized by varying degrees of hepatic differentiation. There are only about 12 case reports of pancreatic hepatoid carcinoma but when reviewed, the majority of these stained for α-fetoprotein (AFP) and many had elevated serum levels of AFP.51 However, little else is really known. In one case report, sorafenib was attempted as therapy for this disease; it would be as reasonable to treat this similarly to hepatocellular carcinoma as it is to try proven therapies for standard pancreatic cancer.

Undifferentiated carcinoma

Undifferentiated carcinoma of the pancreas is an aggressive variant of pancreatic carcinoma with no definable direction of differentiation. Grossly, it is similar to classic ductal adenocarcinoma with infiltrating borders. Microscopically, the neoplastic cells can have anything from an epithelioid appearance to a spindle cell appearance, and frequently infiltrate as individual cells (Fig. 29.6). Mitosis and necrosis are the prominent features of undifferentiated carcinoma. A minor component of conventional ductal adenocarcinoma may be present.

Unusual Cancers of the Pancreas 6aUnusual Cancers of the Pancreas 6b

Figure 29.6. Undifferentiated carcinoma may be composed of neoplastic cells with an epithelioid appearance(a) or a spindle cell appearance (b).

Undifferentiated carcinoma with osteoclast-like giant cells

Undifferentiated carcinomas with osteoclast-like giant cells are a variant of undifferentiated carcinoma with reactive osteoclastlike giant cells. Grossly, they tend to be soft and hemorrhagic. Microscopically, they are mainly composed of two groups of cells: large, reactive multinucleated osteoclast-like giant cells with multiple uniform small nuclei and atypical mononuclear cells with single large pleomorphic nuclei. Classic ductal adenocarcinoma or mucinous cystic neoplasm can be focally present. The presence of KRAS2 mutations in the neoplastic cells establishes the ductal origin of this neoplasm.

Acinar cell carcinoma

Acinar cell carcinoma represents 1–2% of pancreatic cancers.8,52,53 These lesions tend to be large (up to 15 cm) upon presentation. In a review of the Surveillance, Epidemiology, and End Results (SEER) database, of 672 patients with acinar cell carcinoma over 53% were male, while the majority with adenocarcinoma were female.53 The average age at presentation is much younger than for pancreatic adenocarcinoma (70.2 versus 56.7 years, p <0.0001). These patients were more likely to present either unstaged or with localized disease and were far more likely to have resection (38.7% versus 11.0%, p <0.0001) than patients with adenocarcinoma. Location of the primary also differed, with head and body/tail occurring in 28% and 42% of cases of acinar cell respectively but 77% and 12% of cases of adenocarcinoma.

Common clinical presentations (generally listed as occurring >20% of the time) include pain (usually listed in >60% of patients), weight loss, anorexia, jaundice, and nausea/ vomiting.54–58 However, acinar cell carcinoma has been associated with two unique situations: a syndrome of panniculitis, polyarthritis and pancreatic disease, and presentation without a primary lesion. Several decades ago, a syndrome including malaise, eosinophilia, nodular skin lesions, and polyarthritis was described in association with pancreatic disease including neoplasm.59–62 The panniculitis comes with fat necrosis and has been observed to regress with treatment of the underlying pancreatic disease.62 The skin lesions can be mistaken for erythema nodosum, initially presenting on the lower extremities but then they tend to become more widespread which is not typical for erythema nodosum.59–61 The arthritis or synovitis has been described in both small and large joints without significant swelling, erythema or warmth in affected joints. Eosinophilia of up to 21% has been reported in this syndrome.60

Elevated lipase was associated with this syndrome in at least one patient.61 The other syndrome is one of presenting without an obvious pancreatic primary. In one small series of three patients, all had nodal disease, while liver and colon were also involved.63 A paraneoplastic syndrome with thrombotic nonbacterial endocarditis has also been reported in association with acinar cell carcinoma.54

Diagnostic evaluation can include CA 19-9 and CEA, both of which have been reported to be elevated in some cases.54,64

Imaging has been described in a few series. CT demonstrates a large, exophytic lesion with a cystic or necrotic component in 53% of cases and an enhancing capsule in 53% of cases.64 In one study, ultrasound showed a heterogeneous, hyperechoic mass and MRI showed hypervascular lesions in the majority of cases.58

Acinar cell carcinoma is characterized by exocrine enzyme production by the neoplastic cells. Acinar cell carcinomas tend to present as a large, well-circumscribed mass. The cut surface is typically soft, fleshy, and focally necrotic and hemorrhagic. Unlike ductal adenocarcinoma, acinar cell carcinomas feature high neoplastic cellularity and a paucity of fibrous stroma. The neoplastic cells have abundant eosinophilic and granular cytoplasm, and are generally arranged in acinar or solid patterns (Fig. 29.7). The nuclei in acinar cell carcinomas are relatively uniform with prominent nucleoli. Mitosis is frequent. Immunohistochemical studies demonstrate that the neoplastic cells produce exocrine enzymes including trypsin, chymotrypsin, and lipase. On electron microscopy, the cytoplasm contains abundant rough endoplasmic reticulum, numerous mitochondria and, usually, electron-dense zymogen granules.54 Although ductal components are seen in acinar cell carcinoma, there is also an entity of mixed acinar and neuroendocrine tumor.56

Unusual Cancers of the Pancreas 7

Figure 29.7. Neoplastic cells in acinar cell carcinoma have abundant eosinophilic cytoplasm and prominent nucleoli. Note: cells with dark eosinophilic cytoplasm (upper right) are benign acinar cells.

Mixed acinar-neuroendocrine carcinoma exhibits both acinar cell and neuroendocrine differentiation. However, the acinar cell component is always predominant. Most mixed acinar-neuroendocrine carcinomas are grossly solid, well circumscribed with a fleshy consistency. Microscopically, two cell types may be recognizable: cells with neuroendocrine differentiation with salt and pepper chromatin and cells with acinar cell differentiation with granular eosinophilic cytoplasm and prominent nucleoli (Fig. 29.8). Immunohistochemical labeling shows regions with acinar cell differentiation (trypsin, chymotrypsin, and lipase) and neuroendocrine differentiation (chromogranin and synaptophysin). Occasionally, the neoplastic cells demonstrate both acinar cell and neuroendocrine differentiation.

Unusual Cancers of the Pancreas 8aUnusual Cancers of the Pancreas 8bUnusual Cancers of the Pancreas 8cUnusual Cancers of the Pancreas 8d

Figure 29.8. (a) Grossly, mixed acinar-neuroendocrine carcinomas present as a large, well-circumscribed mass with a fleshy consistency. (b) Microscopically, there are neoplastic cells with D-PAS positive granules in cytoplasm and prominent nucleoli and (c) labeled with chymotrypsin, and (d) neoplastic cells labeled with chromogranin.

Table 29.1. Comparison of survivals for acinar cell and adenocarcinoma of the pancreas from SEER data.

Acinar cell* Adenocarcinoma
Overall Resected Unresected Overall Resected Unresected
Median survival 47 months 123 months 25 months 4 months 15 months 3 months
1 year survival 78.5% 92.3% 69% 19.8% 57.3% 16%
2 year survival 67.0% 88.2% 52% 8.2% 33.6% 6%
5 year survival 42.8% 71.6% 22% 3.8% 16.3% 2%

* p <0.0001 for differences in survival in every category.

Acinar cell carcinoma cytogenetics has been evaluated. Mutations in KRAS have not really been seen.65,66 Additionally, p53 mutations, loss of DPC4 and mutations in LKB1 are rare.66,67 However, in one study of five patients, amplifications of chromosomes 20q and 19p occurred in 100% and 80% of cases respectively, and 80% had hypermethylation of at least one tumor suppressor gene.66 An analysis of acinar cell carcinoma patients looking for changes in the APC/β-catenin pathway found alterations in 23.5% of cases.67 The most common alteration found was allelic loss of 11p in 50% of analyzable cases. One patient with microsatellite instability-high phenotype had medullary features.

Acinar cell carcinoma is more indolent than adenocarcinoma. In the SEER database, overall median survival was much better for both resectable and unresectable acinar cell carcinoma (Table 29.1).53 Surgery remains the treatment of choice when possible. Aggressive approaches including resecting patients with regional lymph nodes and limited metastatic disease have been undertaken and results were promising, although some of this may be due to the indolent nature of this disease.55 A multimodality approach has been recommended for advanced disease.55,58 The treatment of metastatic disease usually parallels that for metastatic adenocarcinoma of the pancreas, though reports have noted little effect from radiation or chemotherapy.57 However, with mixed acinar and endocrine carcinoma, treatment of the endocrine component should be considered, especially in cases where the endocrine component is high grade, requiring a platinum-based regimen similar to small cell carcinoma.

Pancreatoblastoma

Pancreatoblastoma is a very uncommon pancreatic malignancy, representing less than 1% of pancreatic cancers.51 It presents in a very young population, with an age range of 15 months to 13 years in one series.68,69 Common presentations include abdominal mass and discomfort. Vomiting, jaundice, and weight loss have also been reported in more recent series.69

The primary lesions are distributed throughout the pancreas without a predominant location. The majority of tumors were large (>5 cm) in 85% of cases and metastatic in 45% of patients. AFP was significantly elevated in 70% of patients. Imaging, including CT and MRI, shows large, heterogeneous masses with calcifications.70

Pancreatoblastomas are mostly solid, well-circumscribed, lobulated masses present in the head or tail of the pancreas. They tend to be large with an average size of 10.6 cm. They can be soft and fleshy or firm and fibrotic, depending on the proportion of stromal component. Microscopically, they are mainly composed of three cell types: cells with acinar differentiation, squamoid nests, and cells with neuroendocrine differentiation. A distinct ductal component may be seen in some cases. The neoplastic cells grow in a nested or organoid pattern separated by a relatively acellular stroma. Occasionally, focal osseous and cartilaginous differentiation may be seen in the stroma.

Immunohistochemically, acinar component labels with trypsin, chymotrypsin, and lipase, the neuroendocrine component with chromogranin and synpatophysin. The squamoid component usually does not express these markers.

Pancreatoblastoma is occasionally associated with Beckwith–Wiedemann syndrome and has been reported at least once in a patient with familial adenomatous polyposis.67,69

In an assessment of nine cases of pancreatoblastoma, allelic chromosome loss of 11p was the most common finding.67

Alterations of p53 and kRas were not observed and DPC4 loss occurred in two of seven cases. In contrast, five of nine patients had activating mutations in the β-catenin oncogene and seven showed accumulation of the β-catenin protein.

Standard therapy is multimodal, including chemotherapy, radiation therapy, and surgery. Neoadjuvant therapy is commonly used for stages II–IV. Surgery is the definitive therapy for this disease. Chemotherapy regimens used have multiple cytotoxic agents including dacarbazine, vincristine, cisplatin, gemcitabine, ifosfamide, cyclophosphamide, and/or doxorubicin, although there is no single standard regimen. In one series, this type of aggressive approach to therapy resulted in 5-year eventfree survival of 58.8% and 5-year overall survival of 79.4%.69

Solid-pseudopapillary neoplasm

Solid-pseudopapillary neoplasm is a low-grade malignant epithelial neoplasm of the pancreas with unknown direction of differentiation. Grossly, solid-pseudopapillary neoplasms are well demarcated, solid and cystic masses with a soft consistency (Fig. 29.9). Recent or remote hemorrhage is common. Microscopically, the tumor is composed of sheets of relatively uniform polygonal cells admixed with delicate capillary-sized vessels. The neoplastic cells away from the vessels become loosely cohesive, thereby forming pseudopapillary structures (see Fig. 29.9). The nuclei of the neoplastic cells are round to oval with frequent longitudinal nuclear grooves. Prominent extracellular eosinophilic hyaline globules are often present. Immunohistochemically, solid-pseudopaillary neoplasms express α1-antitrypsin, CD10, progesterone receptors, and synaptophysin. In contrast to pancreatic neuroectodermal tumors, solid-pseudopapillary neoplasms do not express chromogranin. In addition, almost all solid-pseudopapillary neoplasms have somatic mutations in β-catenin genes. Immunohistochemical labeling shows nuclear accumulation of β-catenin in the neoplastic cells.

Unusual Cancers of the Pancreas 9aUnusual Cancers of the Pancreas 9bUnusual Cancers of the Pancreas 9cUnusual Cancers of the Pancreas 9d

Figure 29.9. (a) Grossly, solid-pseudopapillary tumor is well circumscribed, with cystic and hemorrhagic areas on the cut surface. (b) Microscopically, it is composed of sheets of relatively uniform polygonal cells admixed with delicate capillary-sized vessels. Extracellular hyaline globes are common. (c) Immunohistochemistry shows membranous labeling for CD10 and (d) nuclear labeling for β-catenin in the neoplastic cells. Note: predominantly membranous labeling for β-catenin in the bengin acinar cells (left lower corner).

Conclusion

Rare, nonendocrine tumors of the pancreas are heterogeneous in origin, presentation, and prognosis. Many of these rare tumors can be difficult to diagnose on histology alone and special immunohistochemistry or consultation with specialty centers may be crucial in confirming these rare disorders. These tumors are largely treated similarly to adenocarcinoma of the pancreas, though many have unqiue features that may suggest other therapies, such as treating hepatoid carcinoma like hepatocellular cancer.

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