Pancreatic acinar cell carcinoma: A comprehensive review

Table 1 Immunohistochemical profile from the differential diagnosis

Tumor type	PCK	Trypsin/chymotrypsin/BCL-10	BCL-10	B-Catenin	Synaptophysin	Chromogranin	Others
ACC	+	+	+	+/-	-/+	-/+	Amylase. Lipase. PAS
PDAC	+	-	-	-	-	-	P53, DPC4 loss
SPN	-/+	-	-	+1	-	-	PR, CD56, Alpha 1-antitrypsin
PanNET	+	-	-	-	+	+	CD56, PAX83, ISL13
PBL	+	+	-	+2	-	-	Alpha fetoprotein, CEA

¹Nuclear.

²Nuclear/Cytoplasmic and positive in squamous morules.

³PAX8 and ISL1 are specific markers for PanNETs.

ACC: Acinar cell carcinoma; PCK: Pancytokeratin; PanNET: Pancreatic neuroendocrine tumors; PBL: Pancreatoblastoma; SPN: Solid pseudopapillary neoplasm; PDAC: Pancreatic ductal carcinoma; PAS: Periodic acid-Schiff; ISL 1: Islet 1; CEA: Carcinoembryonic antigen.

Table 2 Summary of pertinent differential diagnostic features

Differential diagnoses	Age/sex	Imaging/gross findings	Histology	Prognosis
ACC	Predominant in males; mean age of 62 yr	Solid, well-circumscribed, bulky tumors; hemorrhage and necrosis are also frequent	Predominant acinar or solid architecture; uniform cells; basally located nuclei; eosinophilic granular cytoplasm; prominent single nucleoli. minimal stroma	Overall aggressive, with high rates of recurrence and metastasis
PDAC	Slightly higher in males; 6th-8th decade of life	Solid, poorly defined mass	Large, medium, or small malignant ducts with a tubular pattern; desmoplastic stroma. Processes of mitosis and necrosis	Poor survival rates
PanNET	Even distribution between the genders; more prevalent in adults; mean age of 40	Solid, well-circumscribed. 5% are cystic	Variable architectural patterns; uniform cells; oval or spherical nuclei; granular cytoplasm; undetected nucleoli; minimal stroma	Relatively languid, but with variable results
SPN	Almost exclusively female; average age of 28	Well-defined and encased with cystic degeneration	Pseudopapillae; cells with hyaline/myxoid stroma surrounding vessels; large cytoplasmic hyaline globules; nuclear groove	Overall low malignant potential: The majority are successfully treated surgically
PBL	First decade of life, mean age of 4; adults can be affected	Partially encapsulated, frequently lobulated, and substantial	Solid and acinar structure; cellular stroma; keratinization of squamoid nests; heterologous mesenchymal elements	Aggressive; better outcomes for children

ACC: Acinar cell carcinoma; PanNET: Pancreatic neuroendocrine tumors; PBL: Pancreatoblastoma; SPN: Solid pseudopapillary neoplasm; PDAC: Pancreatic ductal carcinoma

Table 3 American Joint Committee on Cancer 8^th Edition cancer staging for exocrine pancreatic tumor such as pancreatic acinar cell carcinoma

Stage	TNM	Description
0	Tis	Carcinoma in situ1
	N0	No regional lymph node metastases
	M0	No distant metastasis
IA	T1	T1 = Tumor is ≤ 2 cm in any direction
		T1a = Tumor is ≤ 0.5 cm in any direction
		T1b = Tumor is > 0.5 cm and < 1 cm in any direction
		T1c = Tumor is 1–2 cm in any direction
	N0	No regional lymph node metastases
	M0	No distant metastasis
IB	T2	Tumor is > 2 cm and ≤ 4 cm in any direction
	N0	No regional lymph node metastases
	M0	No distant metastasis
IIA	T3	Tumor is > 4 cm in any direction
	N0	No regional lymph node metastases
	M0	No distant metastasis
IIB	T1	T1 = Tumor is ≤ 2 cm in any direction
		T1a = Tumor is ≤ 0.5 cm in any direction
		T1b = Tumor is > 0.5 cm and < 1 cm in any direction
		T1c = Tumor is 1–2 cm in any direction
	N1	Metastasis in one to three regional lymph nodes
	M0	No distant metastasis
	T2	Tumor is > 2 cm and ≤ 4 cm in any direction
	N1	Metastasis in one to three regional lymph nodes
	M0	No distant metastasis
	T3	Tumor is > 4 cm in any direction
	N1	Metastasis in one to three regional lymph nodes
	M0	No distant metastasis
III	T1	T1 = Tumor is ≤ 2 cm in any direction
		T1a = Tumor is ≤ 0.5 cm in any direction
		T1b = Tumor is > 0.5 cm and < 1 cm in any direction
		T1c = Tumor is 1–2 cm in any direction
	N2	Metastasis in four or more regional lymph nodes
	M0	No distant metastasis
	T2	Tumor is > 2 cm and ≤ 4 cm in any direction
	N2	Metastasis in four or more regional lymph nodes
	M0	No distant metastasis
	T3	Tumor is > 4 cm in any direction
	N2	Metastasis in four or more regional lymph nodes
	M0	No distant metastasis
	T4	Regardless of tumor size, the cancer has grown outside the pancreas, into the nearby large blood vessels2
	Any N	NX = Regional lymph nodes cannot be assessed
		N0 = No regional lymph node metastases
		N1 = Metastasis in one to three regional lymph nodes
		N2 = Metastasis in four or more regional lymph nodes
	M0	No distant metastasis
IV	Any T	TX = Primary tumor cannot be assessed
		T0 = No evidence of primary tumor
		Tis = Carcinoma in situ1
		T1 = Tumor is ≤ 2 cm in any direction
		T1a = Tumor is ≤ 0.5 cm in any direction
		T1b = Tumor is > 0.5 cm and < 1 cm in any direction
		T1c = Tumor is 1–2 cm in any direction
		T2 = Tumor is > 2 cm and ≤ 4 cm in any direction
		T3 = Tumor is > 4 cm in any direction
		T4 = Regardless of tumor size, the cancer has grown outside the pancreas, into the nearby large blood vessels2
	Any N	NX = Regional lymph nodes cannot be assessed
		N0 = No regional lymph node metastases
		N1 = Metastasis in one to three regional lymph nodes
		N2 = Metastasis in four or more regional lymph nodes
	M1	Distant metastasis

¹Included in this category are high-grade pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm with high-grade dysplasia, intraductal tubulopapillary neoplasm with high-grade dysplasia, and mucinous cystic neoplasm with high-grade dysplasia.

²Celiac axis, superior mesenteric artery, and/or common hepatic artery are involved.

T: Primary tumor; N: Regional lymph node; M: Distant metastasis.

Table 4 Acinar cell carcinoma treatment options

Clinical stage	Treatment options
Resectable or borderline resectable	Neoadjuvant therapy1
	Surgery
	Postoperative chemotherapy
	Postoperative chemoradiation therapy
Locally advance	Chemotherapy2
	Chemoradiation therapy
	Surgery
	Palliative surgery
Recurrent or metastatic	Chemotherapy2

¹Chemotherapy with or without chemoradiation therapy given before surgery.

²With or without target therapy.

Table 5 Characteristics of studies on various acinar cell carcinoma treatment regimes

Ref.	Year of publication	ACC sample size	Type of treatment	No. of patients	Conclusion
Holen et al[8]	2002	39	Resection	9	A high recurrence rate following complete surgical resection suggests that micrometastases are present even in localized disease, and that adjuvant therapies may be indicated. Chemotherapy and radiation are ineffective, however, and novel treatments are required
			RT alone	22
			Fluoropyrimidine-based chemotherapy and RT	1
			Fluoropyrimidine-based chemotherapy	7
Kitagami et al[65]	2007	115	Resection	88	To improve prognosis, surgical resection should be pursued if possible. If ACC cannot be resected or recurs, chemotherapy is likely to be beneficial. A multidisciplinary treatment centered on the role of surgery must be developed
			Palliative operation	12
			Exploratory laparotomy	4
			Other treatment1	11
Seth et al[11]	2008	14	Resection	10	When feasible, surgical resection is the optimal first-line treatment for resectable ACC due to its superior survival, which can be further improved by the addition of a planned neoadjuvant and/or adjuvant chemoradiation regimen
			Resection, mixed chemotherapy2 and RT	4
Wisnoski et al[64]	2008	672	Resection	266	ACC surgical resection appears to improve survival, and the findings support an aggressive strategy for resectable disease. In order to define the role of chemoradiation in the palliative, adjuvant, and neoadjuvant settings, additional research is required
			Other treatment1	406
Schmidt et al[5]	2008	865	Resection	190	In these favorable pancreatic cancers, aggressive surgical resection with negative margins is associated with long-term survival. Second, cancer registries lack certain information, such as the specific type of chemotherapy administered and radiation therapy details. Consequently, institutional and multi-institutional reports of ACC continue to be essential for performing a more comprehensive analysis of the presentation, pathology, natural history, and treatment-related outcomes of ACC
			Resection and chemotherapy	33
			Resection and RT	10
			Resection and chemoradiation	100
			Other treatment1	532
Matos et al[75]	2009	17	Resection	12	ACC requires aggressive surgical resection. Importantly, some patients with locally advanced ACC have responded to a neoadjuvant approach allowing resection of a downstaged tumor; therefore, a combined modality approach should be considered for these patients
			Mixed chemotherapy2	3
			Mixed chemotherapy2 and RT	2
Seki et al[76]	2009	4	Gemcitabine-based chemotherapy	1	A partial response suggested that fluoropyrimidine-based chemotherapy may have some activity against this tumor. To confirm the efficacy of fluoropyrimidine in treating pancreatic ACC, prospective clinical trials are required
			Fluoropyrimidine-/gemcitabine-based chemotherapy	3
Lee et al[78]	2010	29	Resection	12	In Korea, the clinical characteristics of ACC include a young age, a large size, a location in the tail, and nonspecific tumour markers. ACC should always be actively treated with surgery, regardless of its size
			Resection, mixed chemotherapy2 and RT	10
			Mixed chemotherapy2 and RT	1
			Other treatment1	6
Butturini et al[73]	2011	9	Resection	2	Using multiple chemotherapy regimens and regional treatments sequentially for recurrent disease allowed for 45-, 85-, and 52-mo post-primary survival. Long-term survival and clinical benefit may be possible with repeated surgery, neoadjuvant and adjuvant chemoradiation therapies, and locoregional therapy
			Resection and gemcitabine-based chemotherapy	7
Hartwig et al[79]	2011	17	Resection	13	ACC of the pancreas is a relatively uncommon tumor entity for which resection may lead to long-term survival, even in the presence of limited metastatic disease. Optimized adjuvant treatment protocols are required to improve the long-term survival of ACC patients
			Resection and gemcitabine-based chemotherapy	4
Lowery et al[77]	2011	20	Gemcitabine-based chemotherapy	20	Observed efficacy of combination chemotherapy in metastatic patients. ACC supports the use of combination therapies based on gemcitabine or 5-fluorouracil and incorporating irinotecan, a platinum analog, or docetaxel in patients with advanced disease. A potential association between germline mutations in DNA mismatch repair genes and ACC warrants further evaluation
Zheng et al[80]	2015	15	Resection	12	Clinicians generally regard pancreatic acinar cell carcinoma as a low-grade malignancy due to its unique clinical features. Positive sentiments towards ACC should be held
			Resection and gemcitabine-based chemotherapy	3
Kruger et al[81]	2016	15	Resection	3	In contrast to PDAC, gemcitabine alone does not appear to have significant activity in ACC. Based on the findings, advanced ACC should be treated with chemotherapy regimens containing 5-FU and/or a platinum compound (such as oxaliplatin). Undetermined is whether this observation also applies to adjuvant chemotherapy administered after surgical resection of ACC
			Resection and gemcitabine-based chemotherapy	8
			Chemoradiation	1
			Mixed chemotherapy2	3
Seo et al[82]	2017	20	Resection	9	Compared to PDAC, patients with resectable pancreatic ACC had a favorable prognosis after curative resection. Although adjuvant chemotherapy was not associated with improved survival in this study, it is unknown whether this was due to a selection bias or the ineffectiveness of 5-FU monotherapy in pancreatic ACC. On the basis of molecular analysis utilizing innovative genetic analytic tools, additional research on effective adjuvant chemotherapy is required
			Resection and 5-fluorouracil-based chemotherapy	9
			Resection and gemcitabine-based chemotherapy	1
			Resection and etoposide plus cisplatin-based chemotherapy	1
Pishvaian et al[83]	2020	12	Mixed chemotherapy2	12	Molecularly guided treatments targeting oncogenic drivers and the DNA damage response and repair pathway require further prospective evaluation, based on these real-world findings
Zong et al[84]	2020	11	Resection	4	For pancreatic acinar cell carcinoma, surgery is a potentially curative treatment contributing to long-term survival. It has been confirmed that adjuvant systemic therapy, including chemotherapy and chemoradiotherapy, significantly improves survival compared to surgery alone for resectable ACC. To investigate the role and protocol of perioperative and palliative treatments, additional research with a large sample size is required
			Resection and gemcitabine-based chemotherapy	4
			Resection and capecitabine	1
			Resection and mixed chemotherapy2	2
Xu et al[85]	2022	22	Resection	6	Although the value of adjuvant chemotherapy remains obscure, fluoropyrimidine-based chemotherapy merits consideration. Fluorouracil-based chemotherapy, such as FOLFIRINOX, may be the preferred treatment for patients with metastasis, but additional research is required due to the small sample size in this study
			Resection and S1- based chemotherapy	3
			Resection and SOX- based chemotherapy	2
			Resection and fluoropyrimidine-based chemotherapy	3
			Resection and AG- based chemotherapy	1
			Resection and gemcitabine-based chemotherapy	7
Chen et al[86]	2022	26	Resection	11	After radical resection, patients with ACC had a longer overall survival than those with PDAC. ACC is also an aggressive tumor with a similar recurrence-free survival trend to PDAC, necessitating multidisciplinary treatment for resectable ACC disease
			Resection and adjuvant chemotherapy	15

¹Not specified in manuscript.

²Treatment using more than one anticancer drug including FOLFIRNOX (5-FU + oxaliplatin + leucovorin + irinotecan), CAPOX (oxaliplatin + capecitabine), and S1 (tegafur/gimeracil/potassium).

ACC: Acinar cell carcinoma; PDAC: Pancreatic ductal adenocarcinoma; RT: Radiotherapy; 5-FU: 5-fluorouracil; SOX: S1 + Oxaliplatin; AG: Albumin-bound paclitaxel + gemcitabine; FOLFIRNOX: 5-FU + oxaliplatin + leucovorin + irinotecan.