Pancreatoblastoma in Elderly Adults: Report of Two Patients

Introduction

Pancreatoblastoma is a rare malignant epithelial neoplasm of the pancreas accounting for less than 1% of pancreatic tumors in adults. ¹ These neoplasms may have multiple lines of differentiation but are defined by the presence of acinar differentiation and squamoid nests. Other components may be variably present, including neuroendocrine, rarely ductal, or even mesenchymal elements.^2,3

Pancreatoblastoma most commonly occurs in childhood, typically within the first decade of life, and accounts for approximately 15% of malignant pancreatic neoplasms in pediatric patients. ⁴ Approximately one-third of pancreatoblastomas occur in adults. The mean age at diagnosis in adults is 41 years, but they have been reported across a wide range of ages from 18 to 78 years-old.^1,5 Pancreatoblastomas have also been associated with Beckwith-Wiedemann syndrome (BWS) and rare cases have been reported in adult patients with familial adenomatous polyposis (FAP).^6–11 The most common somatic genetic alterations in pancreatoblastoma include loss of chromosome 11p (the same region affected in BWS) and in the wnt/β-catenin signaling pathway.^1,6,8,12

Herein, we present the clinical and pathologic features of two rare cases of pancreatoblastoma occurring in elderly patients, the two oldest reported patients to date. While many individuals with an inherited cancer predisposition syndrome develop cancer at a younger age, one of the cases we present highlights the importance of also considering inherited predisposition in the elderly.

Materials and Methods

Two cases were identified, including one during routine sign-out and one through our pancreatic pathology consultation service. Clinical information was obtained through the institutional and/or shared electronic medical records. Hematoxylin and eosin (H&E) stained slides and immunohistochemistry were reviewed by the authors. Next generation sequencing (NGS) was performed on one case using our standard clinical solid tumor panel. Briefly, a multiplex polymerase chain reaction was performed using the Ion Oncomine Comprehensive Panel Plus (OCAPlus). Amplified library was sequenced on an Ion Torrent GeneStudio S5 Prime Sequencer. The reads were aligned to hg19 and variant calls identified through the Ion Reporter Software v5.18.2. Additional variant filtering was performed by an in-house pipeline (Z  +  v2.3).

Results

Patient 1

An 80-year-old man with a recent history of acute cholecystitis status post cholecystectomy who presented with elevated lipase post-operatively and concern for retained biliary calculi. His past medical history was otherwise significant for hypertension, hyperlipidemia, and remote history of urinary bladder cancer. Magnetic resonance imaging and cholangiopancreatography (MRI/MRCP) revealed a 1.9  ×  1.8 cm hypoenhancing T2 hypointense lesion in the pancreatic tail with upstream dilatation of the main pancreatic duct.

The patient was referred for endoscopic ultrasound (EUS) and biopsy. EUS highlighted a solid mass in the pancreatic body measuring 2.7  ×  2.2 cm with irregular outer margins, features suggestive of splenic artery invasion, and upstream dilatation of the main pancreatic duct. Fine needle core biopsy produced a cellular neoplasm with predominantly acinar differentiation, including cells with prominent eosinophilic cytoplasmic granules and formation of acinar structures. Many of the nuclei of the neoplastic cells contained single prominent nucleoli. Diffuse positive immunolabeling with BCL10 confirmed acinar differentiation (Figure 1). Trypsin and chymotrypsin were focally positive. Squamoid nests were present and had variable morphology ranging from foci of subtle epithelioid cells to rare foci with overt squamoid morphology. CDX2 antibodies immunolabeled the nuclei of the squamoid nests (Figure 1). Immunolabeling for beta-catenin produced a mixed pattern with patchy nuclear and cytoplasmic labeling accentuated in the squamoid nests admixed with intact membranous labeling (Figure 1). There was focal positive expression of INSM1 and chromogranin, markers of neuroendocrine differentiation. Synaptophysin was negative. SMAD4 (DPC4) expression was lost in the neoplastic cells (Figure 1). Additional immunolabeling showed focal labeling for CD10 and focal weak positive expression of p40. The Ki-67 proliferation index was 30-40%.

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Figure 1.

Patient 1 fine needle biopsy showed a solid cellular neoplasm with acinar differentiation and squamoid nests (A and B). Diffuse BCL10 immunolabeling confirms acinar differentiation (C). Beta-catenin showed a mixed pattern nuclear and/or cytoplasmic immunolabeling with accentuation of nuclear staining in squamoid nests (D). CDX2 immunolabeling highlighted squamoid nests (E). SMAD4 (DPC4) immunolabeling showed complete loss of nuclear and cytoplasmic staining in neoplastic cells (F). All images at 400x magnification.

Additional radiographic evaluation with positron emission tomography–computed tomography (PET/CT) showed no evidence of metastatic disease. The patient subsequently underwent robotic subtotal distal pancreatectomy.

The resection specimen showed a 2.5 cm well-circumscribed solid pancreatic mass with extension of the neoplastic cells into the lumina of large ducts (Figure 2). Microscopically the neoplastic cells had a lobular growth pattern with broad sheets of cells separated by fibrous bands. Extensive acinar pattern of growth was present with patchy admixed solid areas and numerous squamoid nests (Figure 2). No other morphologically distinct components were identified. Perineural invasion was present. No lymphovascular invasion was identified. Three lymph nodes were present and were negative for tumor.

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Figure 2.

Patient 1 resection specimen showed a solid, well-circumscribed and lobulated mass with extension into large ducts (arrow) (A). The neoplasm showed acinar differentiation with numerous squamoid nests (B), including very rare nests with focal keratinization (C), and growth into and along the ductal system (D). Image B and D at 100X magnification. Image C at 400x magnification.

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Figure 3.

Patient 2 fine needle biopsy showed a solid cellular neoplasm with acinar differentiation and squamoid nests (A). Acinar differentiation was confirmed by diffuse BCL10 and patchy chymotrypsin immunolabeling (B and C, respectively). β-catenin showed mixed pattern of nuclear and/or cytoplasmic immunolabeling with accentuation of nuclear staining in squamoid nests (D). CDX2 immunolabeling highlighted the squamoid nests (E). DPC4 immunolabeling showed loss of nuclear and cytoplasmic staining in neoplastic cells (F). All images at 400x magnification.

Next generation sequencing (NGS) was performed on the resected tumor. Pathogenic or likely pathogenic variants were detected in APC (missense), SMAD4 (two separate nonsense), and PIK3CA (gain of function), as well as copy number losses of 11p.15.5 and 9p21 (CDKN2A/B). Interestingly, alterations in APC and SMAD4 were present at allele frequencies suggestive of germline pathogenic variants and germline testing and genetic counseling is being pursued.

The patient is alive and has no evidence of disease at the time of this writing, six months after initial diagnosis.

Discussion

Pancreatoblastomas are rare neoplasms in adults with approximately 74 previously reported cases to date. ¹ Pancreatoblastoma is defined by neoplastic cells with acinar differentiation and squamoid nests, though minor neuroendocrine or rarely even ductal or mesenchymal components may be variably present.^2,3 The primary differential diagnosis includes other solid cellular neoplasms of the pancreas, including acinar cell carcinoma, neuroendocrine neoplasms, and solid pseudopapillary neoplasm. Acinar cell carcinoma and pancreatoblastoma both have neoplastic cells with acinar differentiation, but pancreatoblastoma is distinguished by the presence of squamoid nests, which are absent in acinar cell carcinoma. Pancreatoblastoma may show neuroendocrine differentiation by immunohistochemistry, however, this will only be present in a minority of neoplastic cells, whereas pancreatic neuroendocrine neoplasms typically show diffuse immunolabeling with neuroendocrine markers. Solid pseudopapillary neoplasms are exceedingly rare in elderly adults, and most commonly occur in young women. Solid pseudopapillary neoplasms can be distinguished from pancreatoblastoma morphologically by the presence of degenerative pseudopapillae, foamy macrophages, cholesterol clefts, and nuclear grooves and the absence of acinar differentiation and squamoid nests. Both solid pseudopapillary neoplasm and pancreatoblastoma may show abnormal nuclear immunolabeling with beta-catenin, however, this labeling is limited to squamoid nests in pancreatoblastoma, whereas it is typically diffuse in solid pseudopapillary neoplasms.

We present two elderly patients (aged 80 and 81), one at initial presentation and one with a history of pancreaticoduodenectomy for an unknown neoplasm presenting with metastatic disease. Compared to pancreatoblastoma occurring in pediatric patients, those occurring in adults may show less characteristic histologic appearance in some cases with rare and/or subtle squamoid nests or only focal acinar differentiation.^13,14 However, this was not the case in our patients, as both had neoplasms that demonstrated classic histomorphologic features, including prominent acinar differentiation (confirmed by diffuse positive immunolabeling for BCL10) and abundant squamoid nests. Interestingly, the resection specimen showed extension of neoplastic cells in the lumina of large ducts, which is a feature previously reported in pancreatoblastomas, as well as in acinar cell carcinomas^15–17. Additionally, CDX2 immunolabeling highlighted the nuclei in the squamoid nests, which has previously been reported in endometrioid proliferations as well as a variety of other neoplasms containing squamous nests/morules, though the mechanism of this is unknown.^18,19

Both neoplasms showed diffuse loss of SMAD4 (DPC4) by immunolabeling. Though most characteristically lost in pancreatic ductal adenocarcinomas, SMAD4 (DPC4) loss has been reported in a subset of pancreatoblastomas. ⁸ NGS performed on one tumor confirmed two pathogenic SMAD4 alterations, including one at allele frequencies suggestive of germline mutation. This tumor showed copy number loss at 11p.15.5 and a likely pathogenic APC mutation in keeping with the most common genetic alterations previously described in pancreatoblastoma.^1,6,8,12 CTNNB1 mutations are the most common somatic alteration in the wnt pathway, whereas APC mutations have been predominantly detected in patients with familial adenomatous polyposis (FAP).^6,8,20–22 Pathogenic alterations either of these genes may result in upregulation of the wnt/β-catenin pathway and abnormal beta-catenin immunolabeling. ²² Interestingly, the APC variant in our patient was at an allele frequency suggestive of a germline mutation, which raises the possibility that this patient may have FAP. Other findings included somatic PIK3CA gain of function mutation and copy number loss of 9p21 (CDKN2A/B), the latter of which has been reported in one other published case of pancreatoblastoma. ²²

In summary, pancreatoblastomas are rare and typically thought of as neoplasms that occur in children. Though in fact, there is a bimodal age distribution with one peak in children, and a second smaller peak occurring in adults. We present two patients that extend the upper age limit for reported pancreatoblastomas, including one with NGS findings suggestive of an inherited cancer predisposition syndrome. The latter finding highlights the importance of considering inherited cancer predisposition syndromes even in the elderly.