Harris JT, Gurley S, Borazanci E. Adult pancreatoblastoma: Systematic review of the literature and case report of a young adult patient. World J Gastrointest Oncol 2025; 17(7): 106701 [DOI: 10.4251/wjgo.v17.i7.106701]
Corresponding Author of This Article
Jacob T Harris, MD, Internal Medicine, HonorHealth Thompson Peak Medical Center, 7400 E Thompson Peak Parkway, Scottsdale, AZ 85255, United States. jacharris@honorhealth.com
Research Domain of This Article
Oncology
Article-Type of This Article
Systematic Reviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Harris JT performed the research and wrote the manuscript; Harris JT and Borazanci E designed the research; Harris JT, Gurley S, and Borazanci E analyzed the data and edited the manuscript; and all authors thoroughly reviewed and endorsed the final manuscript.
Supported by the Honor Health Foundation, Michael and Mary Ellen Francis; and the Seena Magowitz Foundation.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jacob T Harris, MD, Internal Medicine, HonorHealth Thompson Peak Medical Center, 7400 E Thompson Peak Parkway, Scottsdale, AZ 85255, United States. jacharris@honorhealth.com
Received: March 5, 2025 Revised: April 30, 2025 Accepted: June 16, 2025 Published online: July 15, 2025 Processing time: 131 Days and 12.1 Hours
Abstract
BACKGROUND
Adolescent/adult pancreatoblastoma (PB) is an uncommon malignant pancreatic tumor. The paucity of data stemming from the rarity of this disease leads to minimal generalized guidelines regarding its diagnosis and treatment. There is a limited number of case reports in the literature and there has been no recent analysis of the literature to consolidate their common features. The purpose of the featured study is to review the available cases of adolescent/adult PB and analyze the common genetic features, histologic features, treatment regimens, tumor sizes, tumor locations, and areas of metastasis to advance ongoing research and better understand and treat this rare condition.
AIM
To present a patient case and systematically review all available cases in the literature to consolidate the common physical, genetic, and histologic features of PB.
METHODS
This is a systematic review of the literature with a case study. A total of 89 patient cases were discovered in the literature database for adolescent/adult PB, all of which were reviewed and are included in our research. Patients aged 16-18 were considered adolescent and patients aged greater than 18 were considered adult. Adolescents and adults were grouped together for the purpose of this study. The patient from the case report was seen in a community hospital setting.
RESULTS
The 89 cases analyzed from the literature were found in 51 references (our case report included), which were consolidated into the six categories mentioned above. A plurality of references reports PB in the head of the pancreas, 4.0-10.0 cm in size, and with the most common site of metastasis to the liver. Histology studies most commonly included acinar groups, squamous corpuscles/nests, cytokeratin, chromogranin, trypsin, chymotrypsin, and synaptophysin. Genetic studies most commonly included adenomatous polyposis coli, B-cell lymphoma/leukemia 10, catenin beta 1, and Wnt/beta-catenin mutations. The mainstay of treatment was surgery with chemotherapy typically including cisplatin, carboplatin, doxorubicin, 5 fluorouracil, mitomycin, bleomycin, gemcitabine, and vindesine. Radiation was also often used.
CONCLUSION
Common pancreatoblastoma features include acinar groups, chromogranin, chymotrypsin, squamous corpuscles, synaptophysin and trypsin on histology and adenomatous polyposis coli, B-cell lymphoma/leukemia 10, catenin beta 1, and Wnt/beta-catenin genetic mutations.
Core Tip: Pancreatoblastoma is exceedingly rare in the adolescent/adult population. This is a systematic review of all the 89 available cases in the literature as well as a case presentation. Notable results of this study include: (1) Common histologic features of acinar groups, squamous corpuscles/nests, cytokeratin, chromogranin, trypsin, chymotrypsin, and synaptophysin; (2) Common genetic features of adenomatous polyposis coli, B-cell lymphoma/leukemia 10, catenin beta 1, and Wnt/beta-catenin mutations; and (3) Chemotherapeutic regimens including cisplatin, carboplatin, doxorubicin, 5 fluorouracil, mitomycin, bleomycin, gemcitabine, and vindesine. Future therapies should focus on targeting the Wnt pathway.
Citation: Harris JT, Gurley S, Borazanci E. Adult pancreatoblastoma: Systematic review of the literature and case report of a young adult patient. World J Gastrointest Oncol 2025; 17(7): 106701
Pancreatoblastoma (PB) is a rare malignant epithelial tumor that can occur anywhere in the pancreas. While it is rare in children, its occurrence in adolescents/adults is exceedingly uncommon. For the purposes of the current study, adolescent PB is defined as patients aged 16-18 years old. PB has an annual incidence in all age groups of roughly 4 in 100000000[1]. The five-year overall survival of patients aged less than 10 years of age is 70%-77%[2,3]. With increased age, these numbers dramatically decrease, with a five-year overall survival of adolescent and adult patients dropping to approximately 50%[1]. When just considering adult patients, the survival rates drop precipitously more, with a median survival time of just 18.5 months[4]. The rarity of the disease leads to a sparsity of data in the literature, which explains the few generalized guidelines available for this condition. Reasons for the poor prognosis of PB are plentiful but include: The diagnostic difficulty that accompanies exceptionally rare malignancies; the delayed diagnosis often associated with diagnostic difficulty of pancreas lesions, lack of specific symptoms, and non-characteristic imaging findings; difficult surgical treatment options and incomplete resections due to the invasive nature of the tumor; and the lack of standardized regimens for systemic therapy due to the rarity of this disease. Some of these factors, particularly the aggressive nature of PB, are heightened with increased age and are therefore implicated in the worse prognosis of adolescent/adult patients compared to pediatric patients. However, there are features that help distinguish PB from other pancreatic neoplasms.
Given the rarity of PB, there is no standardized treatment protocol. This is apparent through analysis of international treatment guideline databases and through our own thorough literature review. In 2021, a review was published that mentioned 70 cases in the literature[5]. While this article discussed in detail the differential diagnosis of PB because it can mimic other neoplasms, it did not provide as thorough of an analysis for the histology and genetics common to the different cases of PB. Since then, there has been no analysis of the literature to thoroughly consolidate their common features. We therefore reviewed all the available cases of PB in the literature to date, which totaled 89 cases. We analyzed the different genetic features, histological features, treatment regimens, tumor sizes, tumor locations, and areas of metastasis. We also provided a case report of PB in an adolescent female. It is anticipated that these results will advance ongoing research and better understand and treat this rare disease.
MATERIALS AND METHODS
Literature search
We performed a database search on PubMed to find all relevant cases of adolescent/adult PB. Inclusion criteria included patients at least 16 years old. Some case series and reviews of the literature were discovered and used in our data, though the case reports included in these publications were considered individually and cross referenced to other publications to ensure no duplicates were analyzed. The following keywords were used in the PubMed search: “(1) Adolescent Pancreatoblastoma; (2) Adult Pancreatoblastoma; (3) Case Report; and (4) Case Series”.
A total of 50 publications were identified, which together included a total of 88 cases of adolescent/adult PB. When also including our own case report of PB, the total number of cases included in our results is 89 cases. No cases were excluded that met the PubMed search criteria. It is worth noting that not all of the cases included contained information in each of our six categories of analysis. For example, some did not include histology data, treatment regimens, etc. However, every case had data in at least one of our six categories. The results of our analysis are best represented in six tables: Genetic features, histological features, treatment regimens, tumor sizes, tumor locations, and areas of metastasis. In each table, numbers are included to identify which references included cases of PB that exemplified each given feature. These reference numbers are included in the far right column of each table. These reference numbers correlate to the reference article in the bibliography at the end of the manuscript. Of note, the numbers correlate to publications and not individual cases. Some publications/numbers, therefore, may appear multiple times in a single table because these publications discussed multiple cases. Some publications/numbers may also have multiple cases with a given table category (e.g., multiple cases with acinar cell groups on histology), but that reference number will only be included in that category row one time. This was done for the ease of reading the charts.
Case presentation
The patient is a 17-year-old female with a history of Gardner syndrome with a 2004delC adenomatous polyposis coli (APC) mutation who required regular esophagogastroduodenoscopies and colonoscopies as a result. After multiple years of such screening and occasional polyp removal, the patient developed diffuse abdominal pain. She had no associated symptoms. Physical exam was significant for diffuse abdominal discomfort to palpation but was otherwise unremarkable. esophagogastroduodenoscopies and colonoscopy around that time were unremarkable. A computed tomography (CT) scan of the abdomen was obtained and showed a 5.8 cm × 4.2 cm × 4.3 cm mass in the pancreatic body with chronic occlusion of the splenic vein and a large pancreatic duct, as seen in Figure 1A. An magnetic resonance imaging confirmed a lobulated mass occluding the splenic vein and multiple perisplenic and mesenteric collateral vessels, as seen in Figure 1B. Labs showed white blood count of 11000/μL (ref: 4000-10500 μL), hemoglobin of 11.1 gm/dL (ref: 12-16 gm/dL), complete blood count with differential within normal limits, prothrombin time/International Normalized Ratio/partial thromboplastin times within normal limits, lipase 68 IU/L (ref: 16-63 IU/L), carcinoembryonic antigen within normal limits, alpha-fetoprotein 37.3 ng/mL (ref: < 8.7 ng/mL), albumin 4.6 g/dL (ref: 3.2-4.5 g/dL), and complete metabolic panel within normal limits.
The patient underwent a spleen sparing distal pancreatectomy with resection of the tumor. While the mass was originally thought to be a pseudo papillary tumor, biopsy pathology confirmed PB with lymph node involvement (12 of the 42 lymph nodes biopsied). She was diagnosed with PB stage II. Histology demonstrated positivity for beta-catenin, squamoid corpuscle formation, trypsin, acinar cell differentiation, chromogranin, and synaptophysin. Estrogen and progesterone receptors were negative on immunohistochemistry. Grossly, the tumor was pale yellow to gray, soft to firm, friable, and had vocal areas of yellow necrosis. Histological slides from her tumor can be appreciated in Figure 2. Pathology results were confirmed by a second opinion obtained at an academic center hospital.
Figure 2 Histological slides from her tumor can be appreciated.
A: Hematoxylin and eosin stain demonstrating the interface between tumor (right) and a pancreatic islet with adjacent duct (left). Tumor has suggestion of rosette formation; B: Hematoxylin and eosin stain demonstrating the immature small round blue cell component (lower right) and acinar component on (upper left); C: Immunohistochemistry stain for synaptophysin; D: Immunohistochemistry stain for CD10.
The patient developed post-operative portal vein thrombosis and Budd-Chiari syndrome. Repeat positron emission tomography/CT and chest CT showed no evidence of additional metastatic disease. She was started on multi-agent chemotherapy with cisplatin, 5-fluorouracil (5FU), vincristine, and doxorubicin. Unfortunately, the patient developed Fanconi Syndrome due to cisplatin use. She completed six of six cycles, the last of which included the ICE regimen (ifosfamide, carboplatin, and etoposide) in place of the C5VD regimen (cisplatin, 5-flourouracil, vincristine, and doxorubicin). Overall, she did not tolerate treatment well and experienced recurrent hospitalizations due to electrolyte disturbances, arrhythmias, migraines, peripheral neuropathy, nausea, vomiting, constipation, diarrhea, chest pain, etc. She continued to have intermittent abdominal pain. She developed esophagitis, esophageal varices, and internal hemorrhoids. Mental strain associated with her diagnosis and treatment presented as anxiety, depression, and panic attacks. After chemotherapy treatment completion, she was placed on observation and monitored clinically and with recurrent CT scans of her chest, abdomen, and pelvis. Three years after her initial PB diagnosis, the patient developed an ovarian mass found to be serous borderline tumor and underwent a total hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and appendectomy. She continued to have various gastrointestinal complications and was diagnosed with cirrhosis. Tumor markers cancer antigen 125, cancer antigen 199, and carcinofembryonic antigen remained within normal limits.
About 3.5 years after her original PB diagnosis, the patient developed an omental nodularity that was 4.0 cm × 3.7 cm × 1.5 cm in size. An excisional biopsy was performed and pathology showed recurrent metastatic PB. CD10, chromogranin, and pancytokeratin were positive and vimentin was negative. Genetic testing also showed a TP53 (Ter394 Lext) mutation. No further treatment was provided because after excision there was no evidence of disease on imaging. Continued monitoring demonstrated skull osteomas from Gardner’s syndrome, periodic gastrointestinal bleeds, and positive lupus anticoagulant. Five years after the original PB diagnosis, CT imaging showed another peritoneal lesion. Endoscopic ultrasound was performed and pathology revealed recurrent PB. Radiation therapy was undertaken. However, seven years after the original PB diagnosis, a CT scan revealed peritoneal carcinomatosis, intrahepatic lesion measuring 6.3 cm × 3.7 cm, and intra-abdominal lymphadenopathy, as seen in Figure 3. The patient was therefore enrolled in a phase 1 clinical trial involving combined immunotherapy. She continued to have upper gastrointestinal bleeding and underwent variceal banding. At this point, the patient had also developed ascites from her liver disease. 7.5 years after original PB diagnosis, repeat imaging showed progression of disease with new liver metastases and worsening peritoneal carcinomatosis. The patient’s quality of life continued to deteriorate and was enrolled in hospice care. She ultimately succumbed to her disease at the age of 25.
Figure 3 Computed tomography axial views of omental and peritoneal metastatic disease.
A: Computed tomography axial view showing left omental mass with liver metastases; B: Computed tomography axial view demonstrating peritoneal disease.
RESULTS
Outlined below are the results of our data analysis in each of the six categories of study.
Tumor location
The review of the literature revealed cases of PB in the pancreatic head, body, and tail, as well as in the ampulla. The results can be seen in Table 1[4,6-51]. About half of the cases had PB in the pancreatic head, with about a third of cases with PB in the pancreatic tail. There were 23 publications, 12 publications, 22 publications, and 2 publications with cases of PB in the pancreatic head, body, tail, and ampulla respectively. A frequency of occurrence is included for this set of data. The frequency is a measurement of the number of actual cases with the given feature, instead of the number of publications. In this set of data, there were 79 total cases that provided the location of the PB tumor. The relative frequency of PB in the pancreatic head, body, tail, and ampulla is 47% (37 cases), 16% (13 cases), 34% (27 cases), and 3% (2 cases) respectively.
The variability of tumor size in the reviewed literature is wide. Our data have been separated into tumors 1.0-3.9 cm, 4.0-9.9 cm, and ≥ 10.0 cm. The results can be seen in Table 2[4,7-38,40,42-53]. Tumors in the 4.0-9.9 cm range were by far the most common. A total of 47 publications had cases that included tumor size in their data. 10 publications had cases with tumors size 1.0-3.9 cm, 31 publications had cases with tumors size 4.0-9.9 cm, and 13 publications had cases with tumor size ≥ 10.0 cm.
In the data reviewed, the areas to which PB had spread beyond the pancreas included adrenal, bone, breast, brain, colon/small bowel, kidney, liver, lung, peritoneal carcinomatosis, spleen, and stomach. The results can be seen in Table 3[6-12,14-18,20,24,25,28,29,32,33,36,38-41,43,44,46,49,50]. The most common area of metastasis is the liver. It is also worth noting that stomach involvement was entirely due to local invasion instead of metastasis. The splenic involvement was a combination of both local invasion and metastasis. And the colon/small bowel was a combination of both local invasion and metastasis. The rare sites of PB metastasis to the brain and bone cannot be overlooked.
There were many different histological features present in the data reviewed. The results can be seen in Table 4[6-14,17,26-31,37-43,49,50,52-54]. The most common features included acinar cell groups/differentiation, anti-epithelial antigen (AE) 1/AE3 (cytokeratin), chromogranin, chymotrypsin, squamous corpuscles/nests, synaptophysin, and trypsin. Other features that had a lower incidence among the references reviewed are also included in Table 4. Many histological features are known to be present in PB and others are more novel findings. In addition, not every tumor demonstrated the typical quintessential features of PB. As mentioned above, the histological slides of our patient case can be seen in Figure 2.
There were also a wide variety of genetic features present in the cases reviewed. The results can be seen in Table 5[6-8,12,14,17,28,29,31,37,39-43,49,50,52,54]. The most common features included APC, B-cell lymphoma 10 (BCL 10), catenin beta 1 (CTNNB1), and Wnt/beta-catenin pathway mutations. In this set of data there are both genetic features that are more commonly associated with PB and features not previously identified with the disease. Two of these are the suppressor of mothers against decapentaplegic 4 (SMAD4) and cyclin-dependent kinase inhibitor 2A and 2B (CDKN2A/B) mutations.
Finally, the treatment results of our data analysis can be seen in Table 6[4,6,8-37,39-53]. The mainstay of PB treatment is surgery. This is most commonly supplemented with chemotherapy regimens containing cisplatin, carboplatin, doxorubicin, 5FU, mitomycin, bleomycin, gemcitabine, and vindesine. Among these chemotherapeutic agents, the variability of different regimens was incredibly plentiful, with different cases involving almost every possible combination of these different agents. We therefore included in our data only the list of chemotherapy agents and did not differentiate between different combinations of therapies. Radiation was commonly utilized with or without chemotherapy. The rare use of stem cell transplant and chemoembolization/ablation should also not be overlooked.
The presentation of our case report of a patient with PB will hopefully aid in the continued effort to better understand, diagnose, and treat this rare malignancy in adolescents and adults. Our systematic review of all the available cases of adolescent/adult PB demonstrates the common features of PB within the different categories discussed. It also brings to light various principles worth further discussion.
Genetic features
There is surprising variability in the genetic mutations in PB. As mentioned in the Results section, the most common genetic features from our analyzed cases were APC, BCL 10, CTNNB1, and Wnt/beta-catenin mutations. The APC mutation is often related to familial adenomatous polyposis-associated tumors. These include colorectal, duodenal, gastric, desmoid, thyroid, hepatoblastomas, pancreatic, and CNS tumors[55,56]. It is the most common genetic alteration in colorectal cancer. APC has been reported to occur in up to 67% of PB[57]. There were seven references in our data, including our own case report, that had APC mutations. This gene encodes a tumor suppressor protein that regulates the breakdown of beta-catenin. Therefore, APC mutations result in dysfunctional proteins, leading to increased tumorigenesis from activated Wnt target genes.
CTNNB1 is a gene that encodes beta-catenin, which is a component of the Wnt/beta-catenin pathway. Beta-catenin mutations typically occur in exon 3, which contains phosphorylation sites that are crucial for beta-catenin degradation. Mutations therefore prevent beta-catenin degradation and result in its nuclear accumulation, where it activates Wnt target genes. Wnt mutations in general refer to alterations in the many different components of the Wnt signaling pathway. These mutations can be ligand-dependent (requiring Wnt ligands for activation) or ligand-independent (where downstream components such as APC or beta-catenin lead to pathway activation). Beta-catenin mutations are seen in colorectal, hepatocellular, endometrial, ovarian, thyroid, medulloblastoma, and skin cancers[58-66]. Colorectal cancer is the predominant malignancy with both APC and beta-catenin mutations. Wnt mutations are a known feature of PB, with some reports claiming their presence in 90% of PB cases[67]. Of note, some cases in our analysis reported Wnt/beta-catenin pathway mutations in general instead of naming specific component mutations such as CTNNB1. While CTNNB1 encodes a portion of the Wnt/beta-catenin pathway, there are many other proteins that contribute, and therefore other genes that may be mutated. There were six publications with cases demonstrating CTNNB1 mutations and eight publications with cases demonstrating Wnt/beta-catenin pathway mutations. There was minimal overlap between these publications. Further research would be necessary to delineate the different Wnt/beta-catenin pathway mutations outside of the already established CTNNB1 mutation.
The BCL 10 mutation is less commonly associated with PB. This mutation typically accompanies MALT lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. While not historically associated with PB, there were five publications with cases exhibiting the BCL 10 mutation. In our data, this is just as frequent as the CTNNB1 mutation seen and almost as frequent as both the APC mutation and the Wnt/beta-catenin pathway mutation, all of which are historically linked with PB. Further research is required to understand the extent to which BCL 10 plays a role in PB pathogenesis. At this juncture, however, it appears that its role is not insignificant.
In addition to the BCL 10 mutation, there are other mutations found in our analysis that, though with a lower incidence of occurrence in our data, may have significance in PB pathogenesis. These include SMAD4, CDKN2A/B (9p21), B72.3, insulinoma-associated protein 1 (INSM1), and neuron-specific enolase (NSE). The SMAD4 gene modulates the transforming growth factor-beta signaling pathway, which plays a role in regulating cellular activities such as apoptosis, growth, and differentiation. Inactivation of SMAD4 therefore contributes to malignant development. It is common in pancreatic malignancies in general, typically including pancreatic ductal adenocarcinoma but also some PB. SMAD4 mutations have been associated with more aggressive tumors and poorer prognoses[68,69]. CDKN2A/B (9p21) encodes a tumor suppressor protein that inhibits cyclin-dependent kinases active during the cell cycle. Mutations, therefore, lead to uncontrolled cellular growth. This mutation is also commonly seen in pancreatic malignancies, including PB. Like SMAD4, CDKN2A/B (9p21) portends poor prognosis due to increased cancer aggressiveness and progression[68,69]. B72.3 and INSM1 gene mutations are both mostly related to insulinomas. B72.3 has historically not been associated with PB but has been related to metastatic/aggressive forms of insulinoma[70]. INSM1 is a transcription factor whose mutation has been strongly linked to neuroendocrine tumors and is associated with poorer prognoses. Importantly, it also helps regulate other signaling pathways such as Sonic Hedgehog, phosphoinositide 3-kinases/protein kinase B, p53, and Wnt[71,72]. Given these associations, especially to Wnt, it is less surprising that it has been linked with PB. Finally, NSE is a marker indicating neuroendocrine differentiation. Its activity is linked with other genes such as VEGF, NM23, and E-cadherin. It has historically been associated with small cell lung cancer and has no clear connection with PB in the literature[73]. SMAD4, CDKN2A/B (9p21), B72.3, INSM1, and NSE individually only had 1-3 publications with cases mentioning their mutation in the literature we reviewed. However, due to their clinical relevance and likely contribution to PB pathogenesis, future research in these areas would likely be fruitful.
The following is a list of the remaining genetic features we discovered through out literature review: 11p.15.5, 13q14.2 (RB1), 6p22, cyclin D1, DDR2, EWSR1-FLI1 fusion, FANCD2, FGF3, FGF4, FEFR1 c1081+1G>T (somatic), FGFR2, FGFR20INA fusion, KMT2C, LAMP1, MEN1, MLH1, MLH6, MSH2, NSD3/WHSc1 L1, PIK3CA, PMS2, RB1. Loss of exons 18-27, SMARCA4, SMARCB1, and SSTR2. These individual genetic mutations were only mentioned in one reference each. The sparsity of genetic PB data in general limits our inferences regarding these mutations. It cannot be asserted that they have special relevance in the pathogenesis and treatment of PB based on our analysis, though further research and a larger sample size are needed to make any substantial claim regarding their significance.
Histological features
There is surprising variability in the histological features of PB. As mentioned above, the most common features were acinar cell groups/differentiation, AE1/AE3 (cytokeratin), chromogranin, chymotrypsin, squamous corpuscles/nests, synaptophysin, and trypsin. Interestingly, not every tumor demonstrated the more quintessential histological findings such as acinar cell differentiation and squamous corpuscles. Squamous corpuscles are historically a defining characteristic of PB. Acinar cell differentiation is typically characterized by granular cytoplasm and zymogen-like granules. Cytokeratin is strongly related to epithelial cells and carcinomas. There has been some mention in the literature of it being associated with PB, but this is less common, and it is more often related to PB with SMAD4, CDKN2A/B, B72.3, INSM1, and NSE gene mutations[74].
Chromogranin, trypsin, and chymotrypsin are already established in the diagnosis of PB. Chromogranin indicates neuroendocrine differentiation and can therefore be used in conjunction with INSM1 and NSE mutations to help diagnose PB. Trypsin and chymotrypsin are both related to pancreatic cells and indicate acinar differentiation. They have been associated with PB with SMAD4 and CDKN2A/B gene mutations[75]. Synaptophysin is also already established in the diagnosis of neuroendocrine tumors, but it is less commonly associated with PB.
Other histological features that occurred with less frequency within our case review were eosinophilic cytoplasmic granules, epithelioid cells, Ki-67, nested/trabecular growth, and rosette-like formations. Overall, each of these can be associated with PB but is not unique to it. Eosinophilic cytoplasmic granules can help identify acinar cell differentiation. Epithelioid cells can help distinguish squamoid corpuscles. Ki-67 is a proliferation index that is used to determine the aggressiveness of a tumor and is often more relevant when SMAD4 and CDKN2A/B mutations are present[76]. Nested/trabeculated growth are typical of PB. Rosette-like formations are used to identify neuroendocrine components and are therefore relevant for tumors with INSM1 and NSE gene mutations[77]. In summary, many of the histological findings in the cases we reviewed were typical or often associated with PB. Some, like synaptophysin, are less commonly associated with PB. Many can be used in combination with genetic results to clinch certain elements of the diagnosis (e.g., neuroendocrine in nature) or severity of the disease. While squamoid corpuscles are often claimed as the diagnostic standard of PB, many publications that we reviewed mentioned other histological findings without mentioning any squamoid corpuscles. This leads us to believe that there is a wide variety of histology in this rare malignancy.
There were many histological features that were analyzed in our data that had lower frequency and undetermined significance for the pathophysiology of PB. Some of these features were reported in 2-3 references and others were only reported in one reference. Those that were reported in more than one reference include sheets of cells separated by fibrous bands, epithelioid cells, granular appearance, grooved nuclei, high nuclear to cytoplasmic ratio, INSM1 staining, neuroendocrine components/differentiation, NSE staining, pancytokeratin, prominent nucleoli, and undifferentiated cells. Those that were reported in only one reference include A-hematoxylin, alpha-1-antitrypsin, alpha-1-chymotrypsin, basophilic cells, bland nuclei cells, blast-like cells, cyclin-D1, epithelial membrane antigen squamoid corpuscles squamoid corpuscles, fine chromatin, focal nuclear molding, papillae with rare stromal fragments, polarization and granular cytoplasm, polygonal/spindled cells, and pseudopapillae. It is assumed that there may be variation pathologist reading of biopsy slides. Therefore, the inclusion or exclusion of histological features in both of these low frequency groups mentioned above may be attributed to the discretion of the pathologist and what she/he deems relevant. Furthermore, these low frequency features may also be different ways to describe similar histological findings. It should be noted, however, that our sample size appears to be sufficient to claim the infrequency of these features. Whether any one of them is actually relevant in the pathogenesis and characterization of PB remains the discussion of future research.
Treatment regimens
Treatment regimens do not appear to be standardized. As mentioned, the rarity of PB has resulted in no standardized treatment protocol but regimens include a variety of chemotherapy agents including cisplatin, carboplatin, doxorubicin, 5FU, mitomycin, bleomycin, gemcitabine, and vindesine (Table 6). Radiation is often also used. And surgery is the historical mainstay of treatment. Our set of data had incredible variation in the combinations of chemotherapy used. It was so variable, in fact, that to attempt to outline all the different regimens would have been futile. A consolidation of what chemotherapeutic agents were used was therefore determined to be most realistic and helpful. Childhood PB is more established in the literature and most commonly treated with cisplatin and doxorubicin[78]. However, even childhood PB has treatment variability and cyclophosphamide, vincristine, pirarubicin, and etoposide are also periodically used[78-81]. It is anticipated that with increased experience treating adolescent/adult PB, more standardized guidelines will emerge regarding treatment regimens. Also, ongoing research will likely also elucidate the effectiveness of rare treatment modalities such as chemoembolization/ablation and stem cell transplant. There were two references that reported stem cell transplant and seven references that reported chemoembolization/ablation. Further research may also focus on the effect that various treatments - different chemotherapy regimens, stem cell transplant, ablation, radiation, etc. - have on overall mortality.
Tumor location
Almost half of the reported cases of PB had tumor in the head of the pancreas and about a third of cases had tumor in the pancreatic tail. Many fewer cases had tumor in the pancreatic body and only two cases of PB had tumor in the ampulla. These data can help guide further efforts to improve timely and accurate diagnosis of PB because of the improved understanding of which area of the pancreas in which PB typically presents. While this data set fulfills our original purpose to consolidate features of PB, there are elements that future research could further elucidate. For example, future research could analyze whether the location of the primary tumor in the pancreas is correlated with areas of metastasis. Future research could also focus on correlation with aggressiveness of disease.
Tumor size
There is high variability in the size of PB tumors. For the sake readability, our data were separated into tumors 1.0-3.9 cm, 4.0-9.9 cm, and ≥ 10.0 cm. Tumors with size 4.0-9.9 cm were undoubtedly the most common. This is important because it can provide insight into the size of tumor at which symptoms become more prevalent. It is already known that the poor prognosis of PB is in part due to its diagnostic difficulty and lack of specific symptoms. It is not therefore unreasonable to infer that perhaps tumors of size 1.0-3.9 cm have fewer symptoms. However, this is a field of PB that requires further research. Additionally, future research could focus on efficacy of chemotherapy and radiation on the different sizes of PB tumor.
Areas of metastasis
PB most commonly metastasizes to the liver. Other areas of metastasis can be appreciated in Table 3. Notably, some areas such as the stomach, spleen, colon, and small bowel were either entirely or at least partially involved through local invasion instead of metastasis. This may be related to the location of the tumor in the pancreas (pancreatic head, tail, etc.) or the size of the pancreatic tumor. Surely, it is also related to the genetic features and aggressiveness of the tumor. However, the correlation of these features is beyond the scope of this manuscript and fodder for future research. It would also be important to determine in future research if different areas of metastasis respond better to different chemotherapy regimens. Finally, it cannot be overlooked that PB has been reported to metastasize to brain and bone. These results become important as clinicians work to determine the stage of cancer for their patients with PB.
CONCLUSION
PB is an exceedingly uncommon adolescent/adult pancreatic cancer. Review of our patient’s case and the results of our literature review will be helpful in better understanding the disease and will hopefully prompt more work in the six areas of study described here: Genetic features, histological features, treatment regimens, tumor sizes, tumor locations, and areas of metastasis. Specifically, understanding the genetic features of PB will better enable clinicians to effectively treat this uncommon disease. APC and Wnt are historically linked with PB (reported to be seen in 67% and 90% of PB cases respectively), which is further supported by our data. Our results also support the association of SMAD4, CDKN2A/B, and INSM1 with PB, which mutations were previously seen in some cases of PB but were not so prevalent as APC and Wnt. Previously unrelated genetic mutations including BCL 10, B72.3, and NSE are likely not insignificant mutations based on our results and further research is warranted in these fields. We are hopeful in future research that focuses on furthering our knowledge of the roles of various genetic mutations, both known and newly investigated, in the pathogenesis and treatment of PB.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Corresponding Author’s Membership in Professional Societies: American College of Physicians.
Specialty type: Oncology
Country of origin: United States
Peer-review report’s classification
Scientific Quality: Grade B
Novelty: Grade A
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Scientific Significance: Grade A
P-Reviewer: Zhao SR S-Editor: Bai Y L-Editor: A P-Editor: Yu HG
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