Comprehensive review of pancreatic acinar cell carcinoma: epidemiology, diagnosis, molecular features and treatment

Abstract

Pancreatic acinar cell carcinoma is a rare form (0.2–4.3%) of pancreatic neoplasm with unique clinical and molecular characteristics, which largely differ from pancreatic ductal adenocarcinoma. Pancreatic acinar cell carcinoma occurs more frequently in males and can occur in children. Serum lipase is elevated in 24–58% of patients with pancreatic acinar cell carcinoma. Pancreatic acinar cell carcinomas tend to be large at diagnosis (median tumour size: ~5 cm) and are frequently located in the pancreas head. Radiologically, pancreatic acinar cell carcinoma generally exhibits a solid appearance; however, necrosis, cystic changes and intratumoral haemorrhage can occur in larger lesions. Immunostaining is essential for the definitive diagnosis of pancreatic acinar cell carcinoma. Compared with pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma has a more favourable prognosis. Although radical surgery is recommended for patients with pancreatic acinar cell carcinoma who do not have distant metastases, the recurrence rate is high. The effectiveness of adjuvant therapy for pancreatic acinar cell carcinoma is unclear. The response to FOLFIRINOX is generally favourable, and some patients achieve a complete response. Pancreatic acinar cell carcinoma has a different genomic profile compared with pancreatic ductal adenocarcinoma. Although genomic analyses have shown that pancreatic acinar cell carcinoma rarely has KRAS, TP53 and CDKN2A mutations, it has a higher prevalence of homologous recombination-related genes, including BRCA1/2 and ATM, than pancreatic ductal adenocarcinoma, suggesting high sensitivity to platinum-containing regimens and PARP inhibitors. Targeted therapies for genomic alternations are beneficial. Therefore, genetic testing is important for patients with pancreatic acinar cell carcinoma to choose the optimal therapeutic strategy.

Pancreatic acinar cell carcinoma is a rare form of pancreatic neoplasm with unique clinical and molecular characteristics, which influence the response to chemotherapeutic agents and targeted, gene-matched therapies.

Introduction

Most cases of pancreatic cancer are pancreatic ductal adenocarcinoma (PDAC). Although acinar cells are present in more than 80% of the pancreas, pancreatic acinar cell carcinoma (PACC) is a rare form of pancreatic cancer with unique clinical and molecular characteristics distinct from those of PDAC. The molecular characteristics influence the response to chemotherapeutic agents. This review provides a review of the current state of knowledge regarding PACC, including the epidemiology, pathological diagnosis, role of surgery and (neo)adjuvant treatment, molecular features and treatment options for patients with unresectable PACC.

Epidemiology, clinical features, diagnosis, molecular features and treatment

Epidemiology

PACC is a rare pancreatic epithelial malignancy arising mainly from pancreatic acinar cells, accounting for 0.2–4.3% of all pancreatic carcinomas (Table 1) (1–8). PACC occurs more frequently in males, with a male-to-female ratio of 1.9–3.1:1 (9–14). The peak age at diagnosis of PACC is 60 years (10–12). In a multicenter retrospective analysis of chemotherapy in 58 patients with advanced PACC, 69% were male, and the median age was 60.5 years (11). In the United States, a national cancer database analysis (593 patients with PACC) showed that 72.8% of the patients were male, and the mean age was 64.4 years (13). In a retrospective analysis of German cancer registry group (233 patients with PACC), the median age was significantly lower, and the percentage of males was significantly higher in patients with PACC than in those with PDAC (14). PACC can occur in children and comprises 15% of paediatric pancreatic tumours (15,16).

Table 1.

Overview of PACC

Epidemiology   • Incidence: 0.2–4.3% of all pancreatic carcinomas • Incidence is higher in males (male-to-female ratio: 1.9–3.1:1) • Peak age: 60 years, but can occur in children

Symptoms, laboratory data and tumour markers   • PACC presents with a range of nonspecific symptoms • Elevation of lipase 24–58%; CEA 15–24%; CA19–9 33–45%

Radiological features and pathologic examination   • Most frequently located in the head of the pancreas • Large mass with an ovoid shape and well-circumscribed margin • Necrosis, cystic changes and intratumoral haemorrhage can occur in larger lesions • Immunostaining is essential for confirmation of cell differentiation • EUS-TA is required, not only for pathological diagnosis but also for genetic analysis

Prognosis and surgical treatment   • Prognosis of PACC: more favourable than that of PDAC, with a 5-year survival rate of 21.5–42.8% • Radical surgery is recommended for PACC without metastasis • The efficacy of adjuvant treatment remains unclear

Molecular features and treatment for patients with unresectable PACC   • Favourable treatment responses to fluoropyrimidine, platinum and irinotecan • FOLFIRINOX showed more favourable treatment outcomes than GnP • Rare KRAS, TP53, CDKN2A and SMAD4 mutations • Higher prevalence of homologous recombination-related genes, including BRCA1/2 • Targetable alterations in more than 30% of patients with PACC • Gene-matched therapy can improve the prognosis of PACC, but data are limited

EUS-TA, endoscopic ultrasound-guided tissue acquisition; FFX, FOLFIRINOX, GnP, gemcitabine plus nab-paclitaxel combination therapy; PACC, pancreatic acinar cell carcinoma; PDAC, pancreatic ductal adenocarcinoma.

Symptoms, laboratory data and tumour markers

Similar to other pancreatic neoplasms, PACC presents with many nonspecific symptoms, including abdominal pain, back pain, weight loss, gastrointestinal bleeding, nausea and diarrhoea (11,17). Owing to their growth pattern, jaundice is less common in PACC than in PDAC (2). The serum lipase level is elevated in 24–58% of patients with PACC (11,18–20). Owing to its specificity, an elevated serum lipase level is useful for differentiating PACC from other pancreatic malignancies. Excessive lipase expression can cause lipase hypersecretion syndrome. A minority of patients with PACC (0–15%) display signs of lipase hypersecretion syndrome, including fever, polyarthritis, subcutaneous fat nodular necrosis and eosinophilia, which is associated with poor prognosis (2,8,11,20–23). Although α-fetoprotein (AFP) has been proposed as a serum marker to differentiate PACC from PDAC, the prevalence of elevated AFP varies widely from 7.5 to 47% (10–12,24). The frequency of elevation of other tumour markers, including serum carcinoembryonic antigen (CEA) and CA19–9 levels, was previously thought to be low; however, recent studies have found a relatively high prevalence of CEA (15–24%) and CA19–9 (33–45%) elevation (10,11).

Radiological features

In PACC, the tumour is most frequently located in the pancreas head (24–28). The tumour is frequently large at the time of diagnosis (12,29–31), with a median tumour size of 45–54 mm in cases of resected PACC (25,26,32). PACC frequently presents as a large mass with an ovoid shape and well-circumscribed margin (Fig. 1) (30,33). Local invasion of the surrounding organs, including the duodenum, stomach, kidney, peritoneum and spleen, is observed in ~45% of PACC cases (23). Moreover, ~10% of patients with PACC have pancreatic ductal ingrowth, which can be observed in intraductal papillary mucinous neoplasm and pancreatic neuroendocrine neoplasm (pNEN) (34–38). Calcifications are detected in 0–50% of PACC cases (24,30,33,39). PACC usually has a solid appearance; however, necrosis, cystic changes and intratumoral haemorrhage can occur in larger lesions (24,30,40). Computed tomography (CT) is more sensitive for detecting calcifications, whereas magnetic resonance imaging is more effective for detecting intratumoral haemorrhage, tissue invasion and pancreatic duct dilation (24,40). Approximately 30–50% of patients with PACC have metastatic disease at the time of presentation (4,13,14). Takahashi et al. (11) reported that the most common metastatic sites are the liver (68%), peritoneum (19%) and distant lymph nodes (14%).

Figure 1.

Case presentation of pancreatic acinar cell carcinoma (PACC). (A) Contrast-enhanced computed tomographic (CECT) image showing 6-cm heterogenous mass located in the pancreatic tail. (B) Endoscopic ultrasound image showing a hypoechoic mass with irregular contours, invading the gastric wall. (C) CECT image showing pancreatic tail tumour shrinkage 7 months after initiating modified FOLFIRINOX. (D–I) Pathologic findings of surgically resected PACC (distal pancreatectomy). (D) A surgically resected tumour localized in the body of the pancreas, formalin fixed, showing an expansive and partially encapsulated growth. (E) A lobular or confluent nodular cut-surface of tumour with an adjacent lymph-node metastasis (*). (F) A low-power microphotograph demonstrating hypercellular tumour in nests with scant fibrous stroma and necrosis (haematoxylin and eosin stain, ×20). (G) The acinar pattern characterized by small lumina and non-mucinous cells with stratified nuclei, occasionally with conspicuous nucleoli (haematoxylin and eosin stain, ×400). (H, I) Immunohistochemical positivity for trypsin (H) and Bcl-10 (I) (immunostaining, ×200).

Important differential diagnoses of PACC include solid pseudopapillary neoplasm (SPN), pNEN, PDAC and (in children), pancreatoblastoma. The clinical presentation of SPN is quite different from that of PACC. SPN is more common in young and middle-aged women and is frequently located in the tail of the pancreas (41–44). Calcification is also a prominent characteristic of SPN (45). Recently, it was reported that PACC and SPN can be differentiated based on imaging findings (tumour location, maximum diameter, boundary, intratumoral vessels and distant metastasis) (42). Furthermore, PACC is often misdiagnosed as pNEN. PACC is usually hypercellular with scant fibrous stroma, characterized by a lobular pattern of growth and frequent necrosis. Some cases of pNEN show a similar histologic architecture, although necrosis is uncommon (46). The appearance of pNEN on CT is very variable and includes heterogeneous density with haemorrhage, cystic changes, necrosis and calcification (45,47). In children, PACC needs to be distinguished from pancreatoblastoma, a rare type of malignant pancreatic tumour that arises from the exocrine cells of the pancreas and is rare in adults (15,16,48–50). Pancreatoblastoma is also immunoreactive to trypsin and Bcl-10 but can be differentiated from PACC by the presence of squamoid nests on histopathology (48,49).

Pathologic examination with immunohistochemistry

Macroscopically, PACC tumours are typically large and generally well-circumscribed with at least a partial fibrous capsule and a homogenous tan to reddish cut surface, commonly accompanied by haemorrhage and central necrosis (51). Cytohistologic differentiation between PACC and pNEN is occasionally difficult because these neoplasms share similar monomorphic, round, medium-sized cells and some architectural variations such as solid and glandular patterns (41). Ancillary immunostaining on tissue specimens is essential for confirmation of cell differentiation, especially when examining fragmented or crushed cell samples. The sensitivity of immunostaining for lipase and amylase was 30 and 8%, respectively (23). For the definitive diagnosis of PACC, immunostaining with antibodies to identify acinar cell differentiation (trypsin and Bcl-10) (Fig. 1), in addition to the use of general neuroendocrine markers (synaptophysin and Chromogranin A) to exclude pNEN, is important (16,44,52,53). Scattered neuroendocrine cells positive for synaptophysin and/or Chromogranin A can be observed in PACC, and a small subset of pNEN shows focal acinar differentiation (2,54). A recent study showed high sensitivity and specificity of carboxypeptidase A1 immunostaining for acinar differentiation in the pancreas (55–57). Immunostaining with chymotrypsin-like elastase family member 3B, a pancreatic enzyme with digestive function in the intestine, also shows high sensitivity (75%) and specificity (99.9%) (58).

Pancreatic mixed acinar carcinomas include mixed acinar-neuroendocrine carcinoma (MANEC), mixed acinar-ductal carcinoma and mixed acinar-neuroendocrine-ductal carcinoma, which are rare subtypes of pancreatic tumour (59–63). They contain a significant proportion (>30%) of each cellular component (64). MANEC immunohistochemically expresses both neuroendocrine and exocrine markers (23,65,66). The clinicopathological behaviour of MANEC is similar to that of PACC (23,64,67).

Tissue acquisition for pathological diagnosis and creation of patient-derived organoids

Endoscopic ultrasound-guided fine-needle tissue acquisition (EUS-TA) is recommended for the pathological diagnosis of mass lesions in the pancreas and used for the pathological diagnosis of PACC (68–70). EUS-TA is generally successful in obtaining tissue for diagnosis, and the incidence of adverse events is low in patients with pancreatic tumours (71,72). Because genetic analysis using histological specimens is needed in patients with unresectable pancreatic cancer, including PACC, large-gauge biopsy needles should be used, and multiple biopsy specimens should be obtained (73–77). Patient-derived organoids (PDOs) can be created from surgically resected specimens, EUS-TA specimens and residual samples from saline flushes during EUS-TA (78–80). PDOs are useful for determining the sensitivity to chemotherapy and the preclinical evaluation of novel therapies in patients with pancreatic cancer (81–84). Recently, a PACC cell line was established using PDOs (85). The development of PDOs from patients with PACC could help provide new insights into the biological characteristics of PACC and useful data for personalized medicine and drug discovery.

Surgical resection and (neo)adjuvant treatment

PACC differs from PDAC in its clinical and molecular features; PACC also has a more favourable prognosis, with a 5-year survival rate of 21.5–42.8% (7,14,86,89). Tumour size was not associated with overall survival (OS) (25,26,87), whereas surgical resection was identified as an independent prognostic factor (14). Although radical surgery is recommended for patients with PACC who do not have distant metastases, the recurrence rate is high (12,19,88–90). The 5-year survival rate of Stage IV patients was not significantly different between patients who underwent surgery and those who did not (13). Evidence is accumulating regarding the effectiveness of surgical resection for oligometastasis in patients with PDAC (91–95). In patients with PACC, surgical resection for limited metastatic disease may provide a survival benefit (96).

The results of two multicenter studies on radical resection of PACC were recently reported (Table 2) (25,26). In a multicenter European study of 59 patients who underwent radical resection of PACC, the 5-year OS was 60.9%, and the median disease-free survival (DFS) was 30 months (25). The R0 resection rate was 84.7%. Compared with patients with N1 or N0 PACC, patients with N2 PACC had significantly shorter OS and DFS. N2 status was identified as the only significant negative prognostic factor. Eight patients (six with locally advanced disease and two with synchronous distant metastases) underwent neoadjuvant treatment, primarily with FOLFOX and FOLFIRINOX (FFX). Of the 59 patients, 37 (62.7%) underwent adjuvant treatment, primarily with gemcitabine (GEM)-based regimens. The recurrence rate after radical surgery was 52.5% (31/59) (local recurrence 7; local and systemic 6; systemic 18). The OS and DFS did not differ significantly based on whether the patients received adjuvant therapy (P = 0.542 and P = 0.159, respectively).

Table 2.

Multicenter studies on radically resected patients with PACC

Patient characteristics	European study (25) (59 patients)	Korean study (26) (59 patients)
Age	Median: 64 years	Mean: 59.2 years
Male	74.6%	83.1%
Tumour size	Median: 45.0 mm	Mean: 46.0 mm
Tumour location (%)
Head	44.1	55.9
Body	30.5	5.1
Tail	20.3	37.3
Overlapping	5.1	1.7
Surgery (%)
PD or PPPD	44.0	50.8
DP	40.7	35.6
TP	13.6	5.1
Others	1.7	8.5
Staging (%) (AJCC 8th edition)
0	1.7	0
IA	8.5	13.6
IB	6.8	27.1
IIA	42.3	33.9
IIB	18.6	18.6
III	11.9	6.8
IV	10.2	0
R0 resection rate (%)	84.7	93.2
5-year OS (%)	60.9	57.4
Median OS (months)	NA	78.8
5-year DFS (%)	38.3	38.5
Median DFS (months)	30	30.9
Independent prognostic factors affecting OS	Nodal status (N2)	Nodal status (N2); CA19–9 level; chemotherapy; intraductal and papillary variant
Proportion of patients who underwent neoadjuvant treatment (%)	15.3	0
Proportion of patients who underwent adjuvant treatment (%)	62.7	52.5
Effectiveness of adjuvant therapy	No significant differences in OS and DFS in relation to adjuvant therapy	No significant differences in OS between patients who received no adjuvant therapy, chemotherapy or concurrent chemoradiotherapy
Recurrence rate (%)	52.5	NA

AJCC, American Joint Committee on Cancer; DFS, disease-free survival; DP, distal pancreatectomy; NA, not available; OS, overall survival; PD, pancreaticoduodenectomy; PPPD, pylorus-preserving pancreaticoduodenectomy; TP, total pancreatectomy.

In a multicenter Korean study of 59 patients who underwent radical resection, the 5-year OS was 57.4%, and the median OS was 78.8 months (26). The 5-year DFS was 38.5%, and the median DFS was 30.9 months. The R0 resection rate was 93.2%. Patients with N2 nodal status had a significantly poorer prognosis than those with N0 status (P = 0.011). Of the 59 patients, 31 (52.5%) underwent adjuvant therapy (chemotherapy n = 22, chemoradiation n = 9). No significant differences were observed in survival based on the type of adjuvant therapy. Multivariable analysis identified CA19–9 level, nodal status (N2), 5-fluorouracil-containing chemotherapy and intraductal and papillary variants as independent prognostic factors.

Although the benefit of adjuvant treatment has been demonstrated in patients with PDAC (97–99), the benefit of adjuvant treatment in patients with PACC is unclear (1,13,14,27,32,100–102). Two recent multicenter studies demonstrated that 52.5–62.7% of patients who underwent adjuvant treatment did not show any survival benefit of adjuvant treatment, and more than 50% of the patients experienced recurrence after surgery (25,26). Thus, effective treatment strategies for preventing recurrence are urgently required.

A neoadjuvant treatment strategy has been developed for resectable and borderline-resectable PDAC (103–105). Treatment primarily with combination chemotherapy for unresectable PDAC enables conversion surgery (106–108). In a multicenter European study on patients with PACC who underwent radical resection, 15% (9/59) of patients underwent conversion surgery (25). Moreover, several recent case reports on conversion surgery after chemotherapy (primarily FFX) in patients with unresectable PACC have shown favourable treatment outcomes (Table 3) (69,109–116). Further research is needed to determine the effectiveness of treatment prior to radical resection and the chemotherapeutic regimens that are most appropriate.

Table 3.

Cases of patients with unresectable PACC who underwent conversion surgery following chemotherapy

Authors, year [ref. no.]	Age	Sex	Tumour location	Tumour size (mm)	Reason for unresectable status	Chemotherapy	Treatment period	Effect	Procedure of conversion surgery	Adjuvant chemotherapy	Treatment outcomes after surgery
Distler, et al. 2009 [109]	65	Male	Head	40	Locally advanced disease	5-FU	12 months	PR	PD with combined resection of PV	None	Alive for 18 months without recurrence
Yamamoto et al. 2012 [110]	71	Male	Body	35	Peritoneal dissemination	S1	6 months	PR	DP	S1	Alive for 24 months without recurrence
Jimbo et al. 2016 [111]	56	Male	Body	60	Locally advanced disease	FFX →FOLFOX	6 months	PR	DP	NA	NA
Kida et al. 2017 [112]	59	Male	Body	45	Locally advanced disease	GEM and S-1	8 months	PR	DP	S1	Alive for 60 months without recurrence
Villano et al. 2020 [113]	71	Male	Tail	36	Liver metastasis	FFX	6 cycles	PR	DP and partial right hepatectomy	None	Alive for 6 months without recurrence
Izumo et al. 2022 [69]	65	Male	Head	40	PV tumour thrombosis	FFX	14 cycles	PR	PD with combined resection of PV	None	Alive for 33 months without recurrence
Sunami et al. 2022 [114]	37	Male	Tail	150	Liver metastasis	FFX	12 cycles	PR	DP	S1	Alive for 36 months without recurrence
Uemura et al. 2022 [115]	67	Male	Body and tail	67	Peritoneal dissemination	FFX	12 months	PR	TP	S1	Alive for 32 months without recurrence
Yamada et al. 2023 [116]	60	Male	Tail	70	Liver metastasis	FFX	3 cycles	PR	DP and extended right hemi-hepatectomy	S1	Alive for 36 months without recurrence

GEM, gemcitabine; PR, partial response; PV, portal vein.

Molecular features and optimal treatment for patients with unresectable PACC

Owing to the rarity of PACC, data regarding PACC-specific treatment outcomes is limited. Because the standard treatment of unresectable PACC has not been established, systemic chemotherapy for PACC is derived from the treatment of PDAC, including FFX and GEM plus nab-paclitaxel combination therapy (GnP) (11,12,100,117–119). In previous studies on patients with advanced PACC, GEM-containing regimens have shown poorer treatment outcomes than fluoropyrimidine-containing regimens (11,12,118). OS tended to be better in patients who received a platinum-containing or irinotecan-containing regimen than in patients who did not (11). PACC generally responds favourably to FFX, and some patients achieve a complete response (57,116,119–122). Currently, limited data are available regarding the effectiveness of concurrent chemoradiotherapy for PACC; therefore, further studies are warranted (17,101,118,123–125).

Genomic analysis of pancreatobiliary malignancies has become easier in recent years (126–130). Targeted gene-matched therapies can provide survival benefits for patients with pancreatic cancer who harbour mutations sensitive to chemotherapeutic agents (131). Accumulating evidence indicates that PACC has a different genomic profile compared with PDAC (29,121,125,132–135). Genomic analyses have demonstrated that PACC rarely has KRAS, TP53 or CDKN2A mutations, which are frequently observed in PDAC. The results of two recent large studies that compared the genomic profiles of patients with PACC and PDAC are summarized in Table 4 (121,125).

Table 4.

Studies on genomic analysis, including PACC and PDAC

Characteristics	Study from the United States (125) (PACC: 51 patients; PDAC: 4205 patients)	Study from Japan (121) (PACC: 44 patients; PDAC: 2568 patients)
Age	Median: PACC 60 years; PDAC 68 years	Mean: PACC 60.6 years; PDAC 63.9 years
Male	PACC 74.5%; PDAC 53.4%	PACC 70.5%; PDAC 56.7%
Genomic alteration
KRAS	PACC 3.8%; PDAC 90.7%	PACC 13.6%; PDAC 85.1%
TP53	PACC 13.7%; PDAC 77.7%	PACC 15.9%; PDAC 69.1%
CDKN2A	PACC 11.6%; PDAC 23.8%	PACC 25.0%; PDAC 35.4%
SMAD4	PACC 15.1%; PDAC 19.9%	PACC 29.6%; PDAC 19.4%
BRCA1	PACC 2.0%; PDAC 0.9%	PACC 2.3%; PDAC 0.9%
BRCA2	PACC 17.3%; PDAC 2.7%	PACC 13.6%; PDAC 2.9%
PALB2	PACC 3.8%; PDAC 0.6%	PACC 0%; PDAC 0.9%
ARID1A	PACC 11.1%; PDAC 9.6%	PACC 9.1%; PDAC 7.1%
BRAF	PACC 3.8% (V600E); PDAC 1.2%	PACC 15.9%; PDAC 1.7%
IDH1	PACC 3.8%; PDAC 0.2%	PACC 0%; PDAC 0.1%
dMMR/MSI-High	PACC 2.1%; PDAC 0.9%	PACC 2.6%; PDAC 0.3%
TMB-high	PACC 2.0%; PDAC 0.9%	PACC 7.9%; PDAC 1.8%
Time to treatment failure (FFX vs. GnP)	—	PACC 42.3 vs. 21.0 weeks (P = 0.004) PDAC 28.1 vs. 28.0 weeks (P = 0.47)
Overall response rate	—	PACC 61.5 vs. 23.5% (P = 0.06) PDAC 24.1 vs. 25.2% (P = 0.61)

dMMR, mismatch repair-deficient; MSI, microsatellite instability; TMB, tumour mutational burden.

A comprehensive genomic profiling study conducted in the United States (including 51 patients with PACC and 4205 patients with PDAC) revealed that 90.7% of patients with PDAC, but only 3.8% of patients with PACC, harboured KRAS mutations (125). TP53, CDKN2A and SMAD4 mutations were present in 13.7, 11.6 and 15.1% of patients with PACC, respectively. Approximately 20% (10/51) of patients with PACC, but only 3.6% of patients with PDAC, had BRCA1/2 mutations. In patients with PACC, the frequency of PALB2, BRAF (V600E) and IDH1 mutations and loss-of-function mutations in FBXW7 was 3.8, 3.8, 3.8 and 3.8%, respectively. Genomic characterization revealed targetable alterations in more than 30% of patients with PACC.

A retrospective study from Japan using Center for Cancer Genomics and Advanced Therapeutics data (including 44 patients with PACC and 2568 patients with PDAC) revealed that the frequency of homologous recombination-related genes, including BRCA1/2 and ATM, was significantly higher in patients with PACC (11.4/15.9%) than in patients with PDAC (2.5/3.7%) (121). Importantly, patients with PACC showed a higher objective response rate with FFX than with GnP (61.5 vs. 23.5%, P = 0.06) and significantly longer time to treatment failure (median: 42.3 vs. 21.0 weeks, P = 0.004).

Platinum-containing regimens and PARP inhibitors show favourable treatment outcomes in patients with germline PDAC with BRCA mutations and have become the standard of care for these patients (136–143). Germline PACC with BRCA mutations has been reported to respond to PARP inhibitors such as olaparib (144). Homologous recombination deficiency (HRD) in advanced pancreatic cancer is a putative biomarker of therapeutic response to platinum-containing regimens (145–147). In a large pan-cancer cohort, patients with PACC showed a high prevalence of germline BRCA2 mutations (pure PACC, 35.5%; PDAC, 3.1%), suggesting that PACC should be considered as a part of the BRCA-related cancers spectrum (135). Genomic features of HRD were observed in 7 of 12 patients with PACC undergoing whole-genome sequencing. More than half (54.8%) of the pure PACC cases were observed to have germline pathogenic variants in homologous recombination or DNA damage-response genes.

Immune checkpoint inhibitor therapy is effective for microsatellite instability (MSI)/mismatch repair-deficient and high tumour mutational burden (TMB) PDAC (148–150). In 236 patients with PACC, the prevalence of high TMB and high MSI was 6.8 and 1.3%, respectively (150); thus, immune checkpoint inhibitors are a promising option for this population (151). BRAF/MEK inhibition achieved a complete response in patients with PACC harbouring the BRAF V600E mutation (125,152,153). In patients with PACC, tumours with ALK-KANK4 gene fusion respond favourably to treatment with alectinib, and tumours with NTRK gene fusion respond favourably to treatment with larotrectinib (154,155). Because targeted therapies have been demonstrated to be beneficial, genetic testing should be performed on patients with PACC to guide the choice of therapy. PACC-specific prospective treatment studies are limited (NCT05286827 and jRCTs031220099); therefore, further studies are required to determine the optimal treatment for PACC.

Conclusion

Although PACC is a rare subtype of pancreatic cancer, recent studies have clarified its genomic profile and potential treatment strategies. A combination of chemotherapy and gene-matched therapies improves treatment outcomes, with an increase in the number of patients who undergo conversion surgery. The high frequency of postoperative recurrence is one of the major unresolved problems, and the effectiveness of adjuvant therapy for PACC has not been established. Further studies, including studies of targeted gene-matched therapies, are needed to determine the optimal treatment strategy.

Funding

None declared.

Conflict of interest statement

Kenji Ikezawa reports honoraria for lectures from Taiho Pharmaceutical, Yakult Honsha, Ono Pharmaceutical, MSD, Myriad Genetics, Asahi Kasei Pharma, Nihon Servier and Incyte Biosciences Japan, and research funding from ASKA Pharmaceutical. Ryoji Takada reports honoraria for lectures from Hisamitsu Pharmaceutical, Novartis and Teijin Pharma. Kazuyoshi Ohkawa reports honoraria for lectures from Eisai, Chugai Pharmaceutical, Yakult Honsha, Incyte Biosciences Japan, Takeda, Gilead and Hisamitsu, and research grants from Towa Pharmaceutical and Sumitomo Chemical. The other authors have no conflict of interest.