A current knowledge of the undifferentiated carcinoma of the pancreas with osteoclast-like giant cells: a narrative review

Introduction

Ranked as the sixth most common cause of cancer-related deaths, pancreatic cancer (PC) was a cause of 467,005 deaths worldwide in 2022 (1). The current relative survival rate of PC including all races and ethnicities is 13% in the USA, which places it last in the list of cancers with the lowest survival rates (2). The mortality rate of PC in the USA is estimated to surpass that of breast and colorectal cancer by 2030 (3).

About 90% of pancreatic tumors are of exocrine origin, with pancreatic ductal adenocarcinoma (PDAC), an infiltrating neoplasm harboring glandular differentiation being the most common subtype (4,5). There is also a subset of PC with largely opposite features, an undifferentiated PC, which lacks glandular differentiation and comprises prominent histiocyte and osteoclast-like giant cell infiltration (6). Undifferentiated PC demonstrates poor cohesion as well as hypercellularity with sparse stroma (7). According to the World Health Organization (WHO), there is a further division within the group of undifferentiated PCs, covering undifferentiated osteoclast-like giant cell (OGC) [undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC)], rhabdoid, and sarcomatoid types, and their combinations (8).

UCOGC is an uncommon PC subtype representing less than 1% of all PCs (9). The main feature of this rare variant comprises pleomorphic neoplastic mononuclear cells mixed with large non-neoplastic multinucleated giant cells. This histological category contains three subtypes within itself: osteoclastic, pleomorphic, and a mixture of the two (4). The latest classification of the malignant epithelial tumors of the pancreas by the WHO is summarized in Figure 1 (10). The UCOGC is more frequently diagnosed within the 6^th and 7^th decades of life, and appears to affect males and females equally (11,12). In this paper, we will focus on the genetic background, histology, immunohistochemistry, possible treatment options, and the clinical course of the UCOGC. We will describe the current knowledge of this very rare specific subtype of PC as a narrative review. We present this article in accordance with the Narrative Review reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-780/rc).

Figure 1 Malignant epithelial tumors of the pancreas according to the latest classification by WHO (10). NOS, not otherwise specified; WHO, World Health Organization.

Methodology

All the studies referred for this review have been searched via the National Library of Medicine (NIH), PubMed, with the keywords “undifferentiated carcinoma of the pancreas with osteoclast-like giant cells”, “genetic background of UCOGC”, “histopathology of UCOGC”, “immunohistochemistry of UCOGC”, “treatment of UCOGC”, and “clinical course of UCOGC”. A visual tool Connected Papers (www.connectedpapers.com) and reference manager software Mendeley (www.mendeley.com) served for proper citation and access to the studies regarding the abovementioned aspects of UCOGC. For this review, we did not specify the time range of studies referred due to insufficiency in number. Our inclusion criteria comprised previous studies, which specifically focused on the rare UCOGC subtype of PC as a confirmed histopathology, either pure or present together with other subtypes. We disregarded the studies involving any other PC subtype but not UCOGC, including undifferentiated and anaplastic carcinomas without OGC component. The search strategy is summarized in Table 1.

The genetic background of UCOGC

Luchini et al. demonstrated a remarkable similarity between the PDAC and UCOGC regarding their genetic alterations (6). By the whole exome sequencing of the UCOGC specimens, they found mutations in tumor suppressor genes or oncogenes KRAS, CDKN2A, TP53, and SMAD4 with already demonstrated roles in formation of conventional PDAC. Their findings about genetic alterations suggest the classification of the UCOGC as a PDAC variant (6). This suggestion is further supported by Hrudka et al. (13). After the next generation panel sequencing of the histologically confirmed 13 UCOGC samples, they also detected a spectrum of mutations in KRAS, TP53, CDKN2A, and SMAD4 similar to those observed in sequenced PDAC specimens (13).

KRAS mutations have also been reported by the other studies involving UCOGC (Table 2) (6,15-17). One of these studies demonstrated a mutational analysis for microdissected UCOGC samples, showing that they harbor KRAS mutations. They suggested the presence of KRAS mutations in the osteoclast-like giant cells of these microdissections as a reflection of their propensity for phagocytosis of surrounding tumor cells. They further suggested ductal epithelium as an origin of UCOGC by documenting the base changes at codon 12 of KRAS, which were the same as those detected in the corresponding ductal epithelial proliferation (16). This contradicts the findings of Lewandrowski et al. from the previous century, who showed the absence of epithelial features in both mononuclear and osteoclast-like giant cells under the electron microscope (18).

Programmed cell death ligand-1 (PD-L1) expression is another important point worth mentioning, as it seems to negatively affect the clinical course of patients with UCOGC, which will be discussed later in the treatment clinical course section. Luchini et al. demonstrated the expression of PD-L1 in numerous UCOGC tumor cells in 17 of 27 cases in total (Table 2) (14).

Histopathology and immunohistochemistry of UCOGC

The preferential location of UCOGC includes the tail and the head of the pancreas (19). UCOGC can be present pure or together with other PC subtypes, such as cystadenocarcinoma, pancreatic mucinous cystic neoplasm, adenosquamous carcinoma, and PDAC (6,20-22). The growth pattern of the UCOGC has been microscopically observed as endoluminal/polypoid with pushing border (23). The histopathological examination reveals the UCOGC as a combination of osteoid and glandular elements, resembling the giant cell tumors of bone with benign appearance, and containing the osteoclast-like eosinophilic multinucleated cells with 5 to 20 nuclei located centrally with ovoid or spindle mononuclear cells (11,23). The mononuclear cells demonstrate varying degrees of cytological atypia, together with the true osteoclasts lacking significant mitotic activity or pleomorphism (16). Manduch et al. microscopically observed the foci of osteochondroid differentiation predominantly consisting of chondroid differentiation with some peripheric osteoid formation with remarkable OGC rimming. Their immunohistochemical results suggest the origins as epithelial and histiocytic for mononuclear and osteoclast-like giant cells, respectively (24). Areas of chondromyxoid differentiation, irregular calcifications, and numerous foamy macrophages, which resemble lipoblasts, have also been evident in some cases (25,26). Studies involving the immunohistochemistry of UCOGC specimens for mononuclear cells, associated malignant epithelial cells, and OGC are summarized in Table 3 (23,26-33).

Treatment options and the clinical course of UCOGC

The treatment strategy for the UCGOC has never been standardized due to the scarcity of this PC subtype. Such a challenge also applies to confirming a diagnosis, complicated by the lack of specific symptoms and accurate biomarkers in blood (34,35). The definitive role of EUS for PC remains incompletely characterized by currently available guidelines (36). The primary treatment for localized UCOGC is radical R0 resection with lymphadenectomy when possible (37,38). While the efficacy of chemotherapy for UCOGC remains under investigation, established chemotherapeutic regimens for PC, including FOLFIRINOX and gemcitabine have been adopted for UCOGC due to its classification as a variant of ductal adenocarcinoma of the pancreas (39). In a randomized phase II–III trial of patients with PDAC, FOLFIRINOX therapy was associated with a median increase in overall survival of 4.3 months (40). In a phase III trial of patients with resected PC, the median overall survival for the gemcitabine plus capecitabine group was 28 months [95% confidence interval (CI): 23.5–31.5], compared with 25.5 months (95% CI: 22.7–27.9) in the gemcitabine alone group (P=0.032) (41). The combination of gemcitabine and albumin-bound paclitaxel has also been approved for treating metastatic cases of PC (42). Randomly designed phase III study of the efficacy and safety of this combination versus gemcitabine monotherapy revealed the median overall survival of 8.5 months in the nab-paclitaxel-gemcitabine group, versus 6.7 months in the gemcitabine group (P<0.001) (43). Similarly, as in PDAC cases, FOLFIRINOX neoadjuvant chemotherapy followed by conversion surgery is reserved for borderline and advanced tumors in patients with good performance status (44,45).

A comprehensive meta-analysis of survival rates of UCOGC cases was conducted by Mylonakis et al. The analysis revealed that surgical resection was the predominant treatment strategy, employed in 88.4% of patients. Following surgical resection, 19 patients received adjuvant chemotherapy, consisting of either gemcitabine or FOLFIRINOX. The 1-, 3-, and 5-year survival rates were determined to be 58%, 44.7%, and 37.3%, respectively. The study revealed that the administration of adjuvant chemotherapy, either gemcitabine or FOLFIRINOX, did not significantly improve survival outcomes for patients with UDOGC (46). A comparison of survival rates between patients who underwent surgery alone and those who received both surgery and adjuvant treatment demonstrated no statistically significant difference (P=0.518). Furthermore, the limited use of neoadjuvant chemotherapy in only three out of 67 cases (4.4%) precluded a definitive assessment of its impact on survival (46).

Igarashi et al. presented a case of UCOGC that underwent conversion surgery after receiving neoadjuvant FOLFIRINOX chemotherapy. Notably, the patient exhibited a 6-month disease-free survival period following the surgery (47). A comprehensive review of the existing literature revealed no prior reports of conversion surgery for UCOGC performed after neoadjuvant FOLFIRINOX therapy. Consequently, the efficacy of neoadjuvant chemotherapy followed by conversion surgery in UCOGC warrants further clinical investigation.

A multicenter retrospective cohort study involving 17 institutions in Japan was undertaken to compare the outcomes of different chemotherapeutic approaches for unresectable cases of undifferentiated carcinoma (UC) of the pancreas, including UCOGC (48). The study retrospectively collected clinical and treatment data from patients with unresectable UC. The results demonstrated a significant improvement in overall survival (OS) for patients receiving a paclitaxel-containing first-line regimen compared to those treated with non-paclitaxel-based regimens (6.94 vs. 3.75 months; P=0.041). Notably, the positive association between paclitaxel-containing regimens and OS persisted even after adjusting for potential confounding factors (P=0.006). Based on these findings, the utilization of a paclitaxel-containing regimen was considered a reasonable therapeutic strategy for patients with unresectable UC by Imaoka et al. (48).

The lack of treatment standardization also applies to the metastatic cases of UCOGC. However, pembrolizumab, a humanized monoclonal antibody against programmed cell death protein 1 (PD-1) has been effective against the lung metastases of UCOGC in the case of a 66-year-old man, presented by Obayashi et al. The patient demonstrated no cancer recurrence 6 months postoperatively, without adjuvant treatment (49). A marked response to pembrolizumab monotherapy has also been demonstrated in another case report of UCOGC distantly spreading to lungs and brain. In total, 46 cycles of pembrolizumab resulted in a continuous reduction of UCOGC lesions in pancreas and brain, as well as a complete elimination of lung metastases (Table 4) (50).

Various studies reported a significantly better prognosis for cases involving UCOGC versus those with PDAC (Table 4) (6,27). A large study with 38 patients has been done involving the comparison between the survival rates of patients with UCOGC versus PDAC. A 5-year overall survival rate in patients suffering from UCOGC was 59.1% with a median survival period of 7.67 years, which was significantly better than for those with PDAC, 15.7% with 1.59 years of median survival period (P=0.0009) (27). Luchini et al. also compared the survival rates of patients suffering from either pure or PDAC-associated UCOGC. They demonstrated a significantly longer survival period for patients having pure UCOGC with median overall survival being 36 months versus 15 months for UCOGC with associated PDAC (P=0.04) (6). Another case report of pure UCOGC demonstrated a >7-year disease-free survival after curative surgery, suggesting a significantly better prognosis for UCOGC lacking ductal adenocarcinoma component (52). Another case of a 71-year-old patient with UCOGC, who underwent curative surgery and four cycles of adjuvant gemcitabine, showed 10-year period without metastasis or any other signs of tumor recurrence (53).

A meta-analysis conducted by Kobayashi et al. identified several other patient characteristics associated with shorter-term survival in UCOGC. These factors include older age, male gender, and positive lymph node metastasis (54). On the other hand, the presence of osteoclast-like giant cells, small tumor size and encapsulation have been associated with increased survival period for UCOGC cases (55). The presence of PD-L1 expression is another important factor for the clinical course according to the study done by Luchini et al., demonstrating a worse prognosis for patients with PD-L1-positive UCOGCs compared to PD-L1-negative ones (14). Hrudka et al. also observed a significantly shorter median survival period of 9 months in patients with PD-L1 expression (P=0.0042) (Table 4) (51).

Conclusions & discussion

In the clinical setting, we encounter UCOGC very rarely. However, due to better prognosis, different histological and molecular characteristics, and possible targeted treatment options, it is important to be aware of this rare subtype with the goal of personalized medicine.

Histological reports from multiple cases demonstrate the UCOGC as a combination of pleomorphic neoplastic mononuclear cells with large non-neoplastic multinucleated giant cells. The mononuclear cells exhibit cytological atypia with varying degrees. On the other hand, true osteoclasts show the absence of significant mitotic activity and pleomorphism.

A spectrum of mutations in KRAS, TP53, CDKN2A, and SMAD4 reminds of the genetic similarity to PDAC specimens in two different studies discussed before. Considering the expression and mutational analysis, ductal epithelium seems to be the most probable origin of this rare subtype, which is also in accordance with the current classification by the WHO. This similarity, coupled with a better prognosis, may give researchers hope for more effective treatment for PDAC. In other words, while the mutations are similar, the prognoses differ. This can be revealed by omics cross-match analyses of whole genome, exome, and RNA sequencing data of common PDAC and rare subtypes of PC.

So far there is no standardized treatment for UCOGC. The primary treatment of choice is surgical resection. The limited available data precludes a definitive assessment of the efficacy of both neoadjuvant and adjuvant chemotherapy in the treatment of UCOGC, necessitating further clinical investigation. While the efficacy of chemotherapy remains unclear, established chemotherapeutic regimens for PC, including FOLFIRINOX, have been adopted for UCOGC due to its classification as a PDAC subtype. For unresectable cases, the utilization of a paclitaxel-containing regimen has been considered a reasonable therapeutic option. Pembrolizumab seems to be effective in metastatic cases of UCOGC. In one particular case, it significantly reduced the size of UCOGC lesions in the pancreas and brain and eliminated metastases in lung. Multiple cases demonstrate a better overall survival rate for patients with pure UCOGC versus those having simultaneously a PDAC component or solely PDAC. Furthermore, PD-L1 expression has been shown to be an important determinant, which shortens the overall survival period of patients diagnosed with UCOGC. As our understanding of the molecular drivers of UCOGC deepens, personalized medicine approaches, such as targeted therapies and immunotherapy, hold the potential to revolutionize the treatment landscape for this rare and aggressive disease.

Our review provides a fair overview of current knowledge about UCOGC. However, due to limited available data, our conclusions may be broad. Nonetheless, this review contributes to the field and informs future research. The rarity of UCOGC limits data for clinical courses and treatment plans. We need more data to better understand the relationship between pathogenic mutations, histological subtypes, and prognosis in PC, including UCOGC. Clinical research will collect more cases and long-term follow-up data, refining our approach. Understanding UCOGC’s molecular, clinical, radiological, and pathological characteristics can lead to earlier, more accurate diagnoses and better management.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-780/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-780/prf

Funding: The work was supported by the Czech Medical Council (No. AZV NW24-03-00024 to M.O.) and the European Union, Programme EXCELES (No. LX22NPO5102 to P.S.). Study sponsors had no role in the study design, in the collection, analysis and interpretation of data, in the writing of the manuscript and in the decision to submit the manuscript for publication.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-24-780/coif). T.S. reports financial support from the Charles University, and serves as an unpaid president of Young Surgeon Board of Czech Surgical Society. P.S. reports financial support was provided by the European Union, Programme EXCELES, ID project (No. LX22NPO5102). M.O. reports financial support was provided by the Czech Medical Council (No. AZV NW24-03-00024). The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63. [Crossref] [PubMed]
2. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin 2024;74:12-49. [Crossref] [PubMed]
3. Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-21. [Crossref] [PubMed]
4. Bosman FT, Carneiro F, Hruban RH, et al. WHO Classification of Tumours of the Digestive System. 4th ed. World Health Organization; 2010.
5. Moini J, Badolato C, Raheleh Ahangari. Pancreatic Tumors. Elsevier eBooks. 2020 Jan 1;335–58.
6. Luchini C, Pea A, Lionheart G, et al. Pancreatic undifferentiated carcinoma with osteoclast-like giant cells is genetically similar to, but clinically distinct from, conventional ductal adenocarcinoma. J Pathol 2017;243:148-54. [Crossref] [PubMed]
7. Luchini C, Grillo F, Fassan M, et al. Malignant epithelial/exocrine tumors of the pancreas. Pathologica 2020;112:210-26. [Crossref] [PubMed]
8. Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology 2020;76:182-8. [Crossref] [PubMed]
9. Maksymov V, Khalifa MA, Bussey A, et al. Undifferentiated (anaplastic) carcinoma of the pancreas with osteoclast-like giant cells showing various degree of pancreas duct involvement. A case report and literature review. JOP 2011;12:170-6. [PubMed]
10. Gonzalez RS. WHO classification [Internet]. www.pathologyoutlines.com. Available online: https://www.pathologyoutlines.com/topic/pancreaswho.html
11. Temesgen WM, Wachtel M, Dissanaike S. Osteoclastic giant cell tumor of the pancreas. Int J Surg Case Rep 2014;5:175-9. [Crossref] [PubMed]
12. Guo YL, Ruan LT, Wang QP, et al. Undifferentiated carcinoma with osteoclast-like giant cells of pancreas: A case report with review of the computed tomography findings. Medicine (Baltimore) 2018;97:e13516. [Crossref] [PubMed]
13. Hrudka J, Kalinová M, Ciprová V, et al. Undifferentiated Carcinoma with Osteoclast-like Giant Cells of the Pancreas: Molecular Genetic Analysis of 13 Cases. Int J Mol Sci 2024;25:3285. [Crossref] [PubMed]
14. Luchini C, Cros J, Pea A, et al. PD-1, PD-L1, and CD163 in pancreatic undifferentiated carcinoma with osteoclast-like giant cells: expression patterns and clinical implications. Hum Pathol 2018;81:157-65. [Crossref] [PubMed]
15. Imai Y, Morishita S, Ikeda Y, et al. Immunohistochemical and molecular analysis of giant cell carcinoma of the pancreas: a report of three cases. Pancreas 1999;18:308-15. [Crossref] [PubMed]
16. Westra WH, Sturm P, Drillenburg P, et al. K-ras oncogene mutations in osteoclast-like giant cell tumors of the pancreas and liver: genetic evidence to support origin from the duct epithelium. Am J Surg Pathol 1998;22:1247-54. [Crossref] [PubMed]
17. Koorstra JB, Maitra A, Morsink FH, et al. Undifferentiated carcinoma with osteoclastic giant cells (UCOCGC) of the pancreas associated with the familial atypical multiple mole melanoma syndrome (FAMMM). Am J Surg Pathol 2008;32:1905-9. [Crossref] [PubMed]
18. Lewandrowski KB, Weston L, Dickersin GR, et al. Giant cell tumor of the pancreas of mixed osteoclastic and pleomorphic cell type: evidence for a histogenetic relationship and mesenchymal differentiation. Hum Pathol 1990;21:1184-7. [Crossref] [PubMed]
19. Pop RM, Diaconu CI, Rimbaş M, et al. EUS-guided fine needle biopsy is able to provide diagnosis in rare osteoclast-like giant cells undifferentiated carcinoma of the pancreas: report of two cases. Rom J Intern Med 2023;61:116-24. [Crossref] [PubMed]
20. Sedivy R, Kalipciyan M, Mazal PR, et al. Osteoclast-like giant cell tumor in mucinous cystadenocarcinoma of the pancreas: an immunohistochemical and molecular analysis. Cancer Detect Prev 2005;29:8-14. [Crossref] [PubMed]
21. Hirano H, Morita K, Tachibana S, et al. Undifferentiated carcinoma with osteoclast-like giant cells arising in a mucinous cystic neoplasm of the pancreas. Pathol Int 2008;58:383-9. [Crossref] [PubMed]
22. Alwaheeb S, Chetty R. Adenosquamous carcinoma of the pancreas with an acantholytic pattern together with osteoclast-like and pleomorphic giant cells. J Clin Pathol 2005;58:987-90. [Crossref] [PubMed]
23. Rusu A, Giuşcă SE, Apostol DGC, et al. Cephalic undifferentiated carcinoma with osteoclast-like giant cells arising from the main pancreatic duct: case report and literature review. Arch Clin Cases 2021;6:6-21. [Crossref] [PubMed]
24. Manduch M, Dexter DF, Jalink DW, et al. Undifferentiated pancreatic carcinoma with osteoclast-like giant cells: report of a case with osteochondroid differentiation. Pathol Res Pract 2009;205:353-9. [Crossref] [PubMed]
25. Molberg KH, Heffess C, Delgado R, et al. Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas and periampullary region. Cancer 1998;82:1279-87. [Crossref] [PubMed]
26. Sakhi R, Hamza A, Khurram MS, et al. Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells reported in an asymptomatic patient: a rare case and literature review. Autops Case Rep 2017;7:51-7. [Crossref] [PubMed]
27. Muraki T, Reid MD, Basturk O, et al. Undifferentiated Carcinoma With Osteoclastic Giant Cells of the Pancreas: Clinicopathologic Analysis of 38 Cases Highlights a More Protracted Clinical Course Than Currently Appreciated. Am J Surg Pathol 2016;40:1203-16. [Crossref] [PubMed]
28. Dhall D, Klimstra DS. The cellular composition of osteoclastlike giant cell-containing tumors of the pancreatobiliary tree. Am J Surg Pathol 2008;32:335-7; author response 337.
29. Chen CH, Li HN. Undifferentiated Carcinoma with Osteoclast-Like Giant Cells of the Common Bile Duct: A Case Report of a Rare Entity at an Unusual Location. Diagnostics (Basel) 2022;12:1517. [Crossref] [PubMed]
30. Deckard-Janatpour K, Kragel S, Teplitz RL, et al. Tumors of the pancreas with osteoclast-like and pleomorphic giant cells: an immunohistochemical and ploidy study. Arch Pathol Lab Med 1998;122:266-72. [PubMed]
31. Joo YE, Heo T, Park CH, et al. A case of osteoclast-like giant cell tumor of the pancreas with ductal adenocarcinoma: histopathological, immunohistochemical, ultrastructural and molecular biological studies. J Korean Med Sci 2005;20:516-20. [Crossref] [PubMed]
32. Nai GA, Amico E, Gimenez VR, et al. Osteoclast-like giant cell tumor of the pancreas associated with mucus-secreting adenocarcinoma. Case report and discussion of the histogenesis. Pancreatology 2005;5:279-84. [Crossref] [PubMed]
33. Sakai Y, Kupelioglu AA, Yanagisawa A, et al. Origin of giant cells in osteoclast-like giant cell tumors of the pancreas. Hum Pathol 2000;31:1223-9. [Crossref] [PubMed]
34. Mills K, Birt L, Emery JD, et al. Understanding symptom appraisal and help-seeking in people with symptoms suggestive of pancreatic cancer: a qualitative study. BMJ Open 2017;7:e015682. [Crossref] [PubMed]
35. Kane LE, Mellotte GS, Mylod E, et al. Diagnostic Accuracy of Blood-based Biomarkers for Pancreatic Cancer: A Systematic Review and Meta-analysis. Cancer Res Commun 2022;2:1229-43. [Crossref] [PubMed]
36. Rogers HK, Shah SL. Role of Endoscopic Ultrasound in Pancreatic Cancer Diagnosis and Management. Diagnostics (Basel) 2024;14:1156. [Crossref] [PubMed]
37. Pancreatic Cancer Treatment (Adult) (PDQ®)–Health Professional Version [Internet]. National Cancer Institute. Cancer.gov; 2020. Available online: https://www.cancer.gov/types/pancreatic/hp/pancreatic-treatment-pdq
38. Bassi C, Salvia R, Butturini G, et al. Value of regional lymphadenectomy in pancreatic cancer. HPB (Oxford) 2005;7:87-92. [Crossref] [PubMed]
39. Demetter P, Maréchal R, Puleo F, et al. Undifferentiated Pancreatic Carcinoma With Osteoclast-Like Giant Cells: What Do We Know So Far? Front Oncol 2021;11:630086. [Crossref] [PubMed]
40. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. [Crossref] [PubMed]
41. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet 2017;389:1011-24. [Crossref] [PubMed]
42. Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26:v56-68. [Crossref] [PubMed]
43. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703. [Crossref] [PubMed]
44. Springfeld C, Ferrone CR, Katz MHG, et al. Neoadjuvant therapy for pancreatic cancer. Nat Rev Clin Oncol 2023;20:318-37. [Crossref] [PubMed]
45. Janssen QP, Buettner S, Suker M, et al. Neoadjuvant FOLFIRINOX in Patients With Borderline Resectable Pancreatic Cancer: A Systematic Review and Patient-Level Meta-Analysis. J Natl Cancer Inst 2019;111:782-94. [Crossref] [PubMed]
46. Mylonakis A, Driva TS, Lykoudis P, et al. Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas: An individual participant data meta-analysis. Ann Hepatobiliary Pancreat Surg 2024;28:125-33. [Crossref] [PubMed]
47. Igarashi Y, Gocho T, Taniai T, et al. Conversion surgery for undifferentiated carcinoma with osteoclast-like giant cells of the pancreas: a case report. Surg Case Rep 2022;8:42. [Crossref] [PubMed]
48. Imaoka H, Ikeda M, Maehara K, et al. Clinical outcomes of chemotherapy in patients with undifferentiated carcinoma of the pancreas: a retrospective multicenter cohort study. BMC Cancer 2020;20:946. [Crossref] [PubMed]
49. Obayashi M, Shibasaki Y, Koakutsu T, et al. Pancreatic undifferentiated carcinoma with osteoclast-like giant cells curatively resected after pembrolizumab therapy for lung metastases: a case report. BMC Gastroenterol 2020;20:220. [Crossref] [PubMed]
50. Besaw RJ, Terra AR, Malvar GL, et al. Durable Response to PD-1 Blockade in a Patient With Metastatic Pancreatic Undifferentiated Carcinoma With Osteoclast-Like Giant Cells. J Natl Compr Canc Netw 2021;19:247-52. [Crossref] [PubMed]
51. Hrudka J, Lawrie K, Waldauf P, et al. Negative prognostic impact of PD-L1 expression in tumor cells of undifferentiated (anaplastic) carcinoma with osteoclast-like giant cells of the pancreas: study of 13 cases comparing ductal pancreatic carcinoma and review of the literature. Virchows Arch 2020;477:687-96. [Crossref] [PubMed]
52. Cai Y, Chen Y, Wu X, et al. Seven-year disease-free survival in a patient with osteoclast-like giant cell-containing pancreatic undifferentiated carcinoma: a case report and literature review. Int J Clin Exp Pathol 2020;13:3200-5. [PubMed]
53. Gao HQ, Yang YM, Zhuang Y, et al. Locally advanced undifferentiated carcinoma with osteoclast-like giant cells of the pancreas. World J Gastroenterol 2015;21:694-8. [Crossref] [PubMed]
54. Kobayashi S, Nakano H, Ooike N, et al. Long-term survivor of a resected undifferentiated pancreatic carcinoma with osteoclast-like giant cells who underwent a second curative resection: A case report and review of the literature. Oncol Lett 2014;8:1499-504. [Crossref] [PubMed]
55. Strobel O, Hartwig W, Bergmann F, et al. Anaplastic pancreatic cancer: Presentation, surgical management, and outcome. Surgery 2011;149:200-8. [Crossref] [PubMed]