Fig. 14.1
Whipple specimen. Voluminous acinar cell carcinoma with multi-nodular aspect involving extensively the head of the pancreas and dislocating the common bile duct. Foci of necrosis are present (asterisk)
Microscopically, ACC is a highly cellular neoplasm that lacks the desmoplastic stroma typically observed in pancreatic adenocarcinoma. The characteristic acinar cells (round nuclei and abundant eosinophilic granular PAS-positive cytoplasm) of ACCs grow in solid, trabecular, or glandular patterns, but at least focally the neoplasm shows an acinar architecture with a structurally almost normal appearance (Fig. 14.2).
Fig. 14.2
Acinar cell carcinoma. a At histological examination, the tumor is mostly characterized by polarized cells resembling acinar cells. An acinar pattern is at least focally present. b These features are retained at cytological examination
Immunohistochemistry can be useful in differentiating ACCs from other rare, non-ductal pancreatic tumors, such as neuroendocrine tumors (NETs) [7, 8], by confirming acinar differentiation and variable positivity for pancreatic enzymes, especially trypsin, chymotrypsin, and amylase (Fig. 14.3). Recently a new antibody, anti-BCL10, was described as a sensitive and specific marker for acinar cells [9].
Fig. 14.3
Acinar cell carcinoma: immunohistochemical staining for trypsin
At the molecular level, ACCs contain a high frequency of APC/β-catenin pathway mutations; a similar pattern is observed in pancreatoblastomas, as opposed to ductal adenocarcinomas. The most common genetic alteration identified in both ACC and pancreatoblastoma is a loss of heterozygosity involving the short arm of chromosome 11p [10]. Alterations in the β-catenin/APC pathway have also been reported in 50–80% of tumors of this type. Of note, aberrations in the APC/β-catenin pathway result in the nuclear migration of β-catenin, which can be documented at immunohistochemistry [10].
ACC may be associated with elevated serum levels of CEA and CA 19.9, and occasionally with elevated serum AFP (4.5–6% of cases) [11–15].
Pre-operative imaging of ACC is generally non-specific, although a few radiologic patterns have been described. The differential diagnosis of ACC includes ductal adenocarcinoma, NETs, solid pseudopapillary tumors, pancreatoblastoma, mucinous cystic neoplasms, and pseudocysts [16]. Computed tomography (CT) and magnetic resonance imaging (MRI) show cystic areas in 55% of the cases [17]. Chiou et al. described the CT appearance of ACCs as hypodense masses with a well-defined enhancing capsule [18]. Occasionally, intratumoral calcification and necrosis have been reported. Doppler ultrasound (US) examination may facilitate the preoperative differential diagnosis with ductal adenocarcinoma and NENs. The former are usually smaller and clearly hypovascular, while non-functioning NENs are larger and clearly hypervascular at imaging, showing large intralesional vessels on Doppler US [19].
The prognosis of patients with ACCs is generally poor, with median overall survival ranging from 5 to 38 months at different institutions [7, 14, 15, 20–22]. Based upon preoperative imaging, the criteria for tumor resectability are the same as those generally used for ductal adenocarcinoma. Thus, up-front surgery is indicated for resectable ACC. In case of locally advanced ACC or metastatic disease, a neoadjuvant approach has yielded good results. Chemoradiation is generally considered in case of borderline resectable and locally advanced ACC [14, 15]. Therefore, based upon our experience as well a literature review, an aggressive approach is warranted for patients presenting with resectable or locally advanced ACC [23–25]. Reiterative surgery, neoadjuvant and adjuvant chemoradiation therapy, and loco-regional treatment may allow long-term survival and clinical benefit [26–28].
14.2 Pancreatoblastoma
Pancreatoblastoma, originally termed “infantile pancreatic carcinoma” [30], is an extremely rare pancreatic tumor mostly occurring during childhood, although several cases in adults have been described.
In the following, both pediatric and adult pancreatoblastomas are discussed, focusing on their clinical presentation, diagnostic tests, pathologic features, and management.
14.2.1 Pediatric Pancreatoblastoma
Pancreatoblastoma is the most common pancreatic neoplasm of childhood, usually occurring at a median age of 4 years [29–31]. There is a slight male predominance (M:F 1.4:1). Some pancreatoblastomas are seen in association with Beckwith-Weidemann syndrome; all those cases were congenital and characterized by cystic lesions [32]. Typically, patients with pancreatoblastomas present with elevated serum AFP [33].
The clinical presentation of pancreatoblastoma may be heterogeneous. Children with this tumor usually present with upper abdominal pain and often have a palpable epigastric mass [1]. Mechanical obstruction of the duodenum and gastric outlet by the tumor in the head of the pancreas has also been observed. Poor nutritional intake and resultant weight loss are characteristic. Pancreatoblastomas average 10.6 cm in size and develop in the head and tail of the gland with equal frequencies; they are usually well-circumscribed and lobulated [34] (Fig. 14.4).
Fig. 14.4.
Whipple specimen of a pancreatoblastoma. A voluminous solid mass with clear-cut margins and extensively involving the head of the pancreas. A central hemorrhagic spot is present
At histological examination, the tumor consists of large lobules of highly cellular tissue separated by broad fibrous bands. Epithelial cells are arranged in solid sheets, mixed with acinar and occasional semi-glandular structures [34] (Fig. 14.5a). Frequently, the cells tend to form clusters, designated as “squamoid nests” (or squamoid corpuscles), which are a constant and characteristic features of pancreatoblastomas (Fig. 14.5b). Finally, the stromal bands between the epithelial islands are composed of hypercellular spindle cells with variable collagenization. The stroma is particularly cellular in pediatric pancreatoblastomas, and in rare cases a neoplastic mesenchymal component is present [34, 35].
Fig. 14.5
Histologic examination of pancreatoblastoma. a Prominent acinar differentiation. b The characteristic squamoid corpuscles (asterisks)
Most often, the molecular alterations involve the β-catenin gene, as discussed previously.
Imaging techniques, such as CT, performed for abdominal pain or other symptoms, or less frequently for unrelated reasons, can show a large, finely calcified mass in the pancreas. Usually, both solid and cystic elements are present, and foci of hemorrhagic necrosis are not infrequently seen [36, 37].
The differential diagnosis includes other solid, cellular neoplasms of the pancreas, such as acinar cell carcinomas, solid pseudopapillary tumors, and NETs [38, 39].
One-third of patients with pancreatoblastomas already present with metastases at the time of diagnosis, while in other patients metastases develop later, as a consequence of tumor progression [34]. The liver is the most common site of metastases, followed by the regional lymph nodes, lungs, and peritoneum [34, 40].
The best treatment for localized tumors in pediatric patients is complete surgical resection, which in these cases is usually curative. Children with metastatic disease generally have a fairly poor prognosis, although in more recent reports favorable responses to chemotherapy and radiation were obtained [41], suggesting that in selected cases long-term survival can be achieved.
14.2.2 Pancreatoblastoma in Adults
In adults, as in children, the differential diagnosis of pancreatoblastoma includes non-functioning pancreatic NETs, acinar cell carcinoma, solid pseudopapillary tumor, and ductal adenocarcinoma. Non-functioning pancreatic NETs typically present with elevated chromogranin A [38, 42]. Solidpseudopapillary tumors are usually well-demarcated, large, and often heterogeneous masses that may contain peripheral calcifications. However, aggressive behavior is rarely observed in these tumors. Furthermore, solidpseudopapillary tumors do not have central calcifications, are mainly seen in young females, and are predominantly cystic. In addition, they do not express AFP, the production of which is closely linked to acinar differentiation [38, 42]. These features may be helpful in distinguishing solid-pseudopapillary tumors from pancreatoblastoma.
In adults and in children, surgical resection is the best curative option to for maximum long-term survival [43–48]. However, curative resection is not always feasible, due to metastatic presentation at the time of diagnosis, which occurs in approximately 25% of patients [34, 43–48]. The reported median survival rate in adults is 18.5 months.
The role of adjuvant therapy after surgical treatment is unclear and mostly based on the preference of single institutions. Some authors have strongly advocated the use adjuvant chemotherapy because of the malignant features of pancreatoblastoma [34, 40].
Given its rarity, the natural history of adult pancreatoblastoma and the prognosis of these patients are poorly understood. In our report of adult patients with this tumor [43], the very long disease-free interval after resection (51 months) in one of the two patients in the series, underscores the efficacy of aggressive surgical treatment as a determinant factor in long-term survival. Notably, no adjuvant therapy was necessary in that particular patient.
14.3 Primary Pancreatic Lymphoma
Primary pancreatic lymphoma is rare, comprising < 0.5% of pancreatic tumors [49]. These patients usually present with symptoms of carcinoma of the pancreatic head. An accurate cytopathologic diagnosis by fine-needle aspiration (FNA) (Fig. 14.6) is of paramount importance because the primary treatment is non-surgical, based on a combination of chemotherapy and radiation therapy.
Fig. 14.6
Large-cell lymphoma of the pancreas, showing large atypical interspersed lymphoid cells
14.3.1 Clinical Presentation
Abdominal lymphoma, which is typically a non-Hodgkin’s lymphoma (NHL), involves extranodal tissues in up to 40% of patients. Furthermore, the gastrointestinal tract, particularly the stomach and small bowel, are the most commonly involved extranodal sites [50]. Primary localization of the NHL in the pancreas is rare and accounts for < 0.5% of all pancreatic malignancies and 1% of all extranodal lymphomas [51, 52].
Primary pancreatic lymphoma is often described as a large, homogeneous mass in the head of the pancreas, with signs of extension outside the gland, with or without associated lymphadenopathy. Less common pancreatic presentations are body or tail masses or, more rarely, involvement of the entire gland [52].
Pancreatic lymphoma may initially mimic pancreatic adenocarcinoma: symptoms at the time of diagnosis include abdominal pain, jaundice, acute pancreatitis, weight loss, and nausea and vomiting. However, involvement of the lymph nodes or other organs is usually present, questioning the diagnosis of pancreatic cancer [53]. Interestingly, the classical symptoms of lymphoma, such as fever and night sweats, are rarely observed. Abdominal pain, unlike adenocarcinoma, rarely radiates to the back [54, 55].
14.3.2 Diagnosis
Although specific biochemical markers for primary pancreatic lymphoma are not available, elevated serum LDH and α2-microglobulin have been shown to be of important diagnostic and prognostic value. In the case of a large mass in the head of the pancreas without biliary obstruction, pain, or weight loss, an elevated serum LDH level helps clarify the diagnosis [55]. CA 19.9 is usually normal, unless biliary obstruction is present. Elevated serum soluble interleukin-2 receptor (sIL-2R) levels have been reported in both hematologic and non-hematologic solid neoplasms. While elevated levels of sIL-2R have not been shown to be associated with cancer, values > 5000 U/ml may are suggestive in the presence of rounded pancreatic lesions [56].
Abdominal ultrasound may show a large, bulky, homogeneous, hypoechoic lesion associated with peri-pancreatic and peri-aortic lymphadenopathy, highly suggestive of the hematologic nature of the disease [57].
CT is usually the method of choice to evaluate a pancreatic solid mass. Pancreatic lymphoma can present as a well-defined mass or as a large infiltrating lesion with poorly defined contours. Most pancreatic lymphomas show homogeneous enhancement after intravenous injection of contrast medium, which helps to discriminate them from more commonly observed adenocarcinomas. The combination of the above-cited characteristics, the absence of dilatation of the main pancreatic duct, and concomitant retroperitoneal lymphadenopathy suggest a diagnosis of lymphoma [58–61].
Positron emission tomography is generally useful in the staging of lymphoma, particularly in differentiating lymphoma from ductal adenocarcinoma [62].
Preoperative tissue sampling should always be performed if lymphoma is suspected, to confirm the diagnosis. Endoscopic US-guided FNA biopsy with flow cytometric analysis is helpful. Despite these sensitive techniques, preoperative diagnosis is still difficult to achieve in most patients (72%) [63–65].
14.3.3 Treatment
For more than 30 years, the treatment of NHL has been based on chemotherapy and radiotherapy regimens. Surgery has been generally restricted to tissue procurement for diagnosis. Behrns et al. retrospectively evaluated 12 patients with pancreatic lymphoma who underwent radiation therapy and/or chemotherapy in a single institution [52]. Ten of those patients (83.3%), all of whom eventually died of progressive lymphoma, received radiation therapy and/or chemotherapy, and no patient remained disease-free at follow-up. Mean survival was 13 months for patients who received chemotherapy alone (n = 2), 22 months for those treated with radiation therapy only (n = 5), and 26 months for those receiving combined radiation therapy and chemotherapy (n = 3).
The most common chemotherapy regimens include CVP (cis-platinum, vincristine, and peplomycin) and CHOP (cyclophosphamide, hydroxyldaunorubicin (doxorubicin), oncovin (vincristine), prednisone). The addition of rituximab to the CHOP regimen was shown to increase the complete response rate and to prolong overall survival in patients with diffuse large-B-cell lymphoma, without a significant increase in toxicity [66]
The role of radiation therapy in management is not well defined, although local radiotherapy up to a total of 40 Gy has been used as consolidation after chemotherapy [67].
14.4 Hepatoid Carcinoma
Pancreatic hepatoid carcinomas are extrahepatic neoplasms exhibiting morphologic and immunohistochemical features of hepatocellular carcinomas [68] (Fig. 14.7). They represent an extremely uncommon group of tumors: to date, fewer than 20 have been reported [69, 70]. They can present in pure forms or in association with other morphological aspects, such as NETs or ductal adenocarcinomas [71]. The biological behavior of the pure forms seems to be more indolent than that of heterogeneous tumors.
Fig. 14.7
a Gross appearance of hepatoid carcinoma; a solid poly-lobulated mass, resembling hepatocellular carcinoma. b Immunohistochemical staining for hepatocyte paraffin-1 antibody
The hepatoid component accounts for the histological features of an expansive tumor composed of large eosinophilic or clear cells, sometimes with granular cytoplasm, growing in a sheet-like or trabecular pattern with sinusoidal vascular channels. Abundant cytoplasmic glycogen, hyaline globules, and especially bile production are other diagnostic features (Fig. 14.8). Although not specific, hepatoid carcinomas are also characterized by AFP production which, apart from a few negative examples, can be detected in the serum or in tumor cells by immunohistochemistry in most cases [72].
Fig. 14.8
Pancreatic hepatoid tumor. a Neoplasm with solid-nested-trabecular architecture; in this case, bile pigment is present (circled). b The tumor is well demarcated from the normal pancreas
Even when preoperative correct diagnosis cannot be reached mainly due to rarity and non-specific imaging features, surgical excision based on typical pancreatic resections may yield good long-term results, but further studies and longer follow up are needed to correctly assess the prognostic features of these tumors.
14.5 Granular Cell Tumor
Granular-cell tumor (GCT) is a rare histotype, first described in 1926 by Abrikossoff. These tumors arise in a large variety of organs (tongue, oral mucosa, skin, and subcutaneous tissue, breast, thyroid, respiratory tract, biliary tree, female genital tract, nervous system, and all segments of the gastrointestinal tract). Only five cases of GCT of the pancreas have been reported to date [73, 74].
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