Dvie Ciriello , Filomen Urno , Giuseppe Zmoni , Niol Pllino ,Frnes Bzzohi , Pol Prente

a Oncology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, Viale Cappuccini, San Giovanni Rotondo 71013, Italy

b Radiology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, Viale Cappuccini, San Giovanni Rotondo 71013, Italy

c Pathology Unit, Ospedale Sacro Cuore Don Calabria, vai Sempreboni, Negrar and University of Verona, Negrar 37024, VR, Italy

d Abdominal Surgical Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, Viale Cappuccini, San Giovanni Rotondo 71013, Italy

e Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, Viale Cappuccini, San Giovanni Rotondo 71013, Italy

Acinar cell carcinoma (ACC) is a rare malignant epithelial neoplasm accounting for 1%-2% of all pancreatic exocrine neoplasm,affecting more frequently man with an age between 50 and 70 years.Most patients present with nonspecific symptoms, which may give rise to difficulties in clinical diagnosis [1].ACC can manifest with diarrhea, weight loss, abdominal pain and, in up to 10%-15%, with lipase hypersecretion syndrome, characterized by elevated lipase production, diffuse subcutaneous fat necrosis and polyarthralgia [ 1 , 2 ].Biliary obstruction and jaundice are infrequent clinical manifestations, unlike ductal adenocarcinoma, due to pushing rather than infiltrating growth of ACC.This neoplasm may arise in any portion of the pancreas, with a decreasing frequency in the head, the tail, both the body and the tail/head,respectively [2].Among the 31 cases reported, only three cases involving the whole pancreas were described [ 3 , 4 ].Imaging is essential for detection and preoperative diagnosis in ACC management.Imaging features of ACC in computed tomography (CT) and magnetic resonance (MR) reveal an exophytic well-marginated mass originating from the pancreas, round to oval in shape, with a varied degree of cystic components that enhance homogeneously less than the surrounding normal pancreas [5].Here, we describe an unusual case of left abdominal mass, infiltrating the intestinal wall,without radiologically documented connection with the pancreas,with synchronous peritoneal carcinoma, histologically corresponding to ACC.

A 79-year-old woman was admitted to our institution for constipation and palpable swelling in the left-side abdominal wall,without previous oncological history and other systemic symptoms.Ultrasound documented an expansive neoplastic mass, adherent to intestinal wall, with peritoneal effusion.Liver, kidneys and pancreas were unremarkable.Colonoscopy revealed absence of mucosal lesion/mass, with diverticular disease in distal colon and a sub-occlusive stenosis in transverse.All serological exams were unremarkable.

On CT images, a well-circumscribed, lobulated, and encapsulated mass in left hemiabdomen, of 9 cm in maximum diameter,with thin, enhancing capsules, and a variable degree central hypodensity in the enhanced phase, was documented ( Fig.1 A).No calcification was identified.Pancreas was unremarkable, without any lesion or mass and with a regular profile, and had no connections with the main mass in any scansion.No alteration was documented in liver, kidneys, stomach and spleen.An inseparable adherence was documented with transverse colon, 5 cm in length,suggesting origin from intestinal wall.

Due to sub-occlusive disease, surgery was planned with laparoscopic approach.Macroscopically, abdominal mass was confirmed,infiltrating intestinal wall of transverse colon and strictly adherent to greater gastric curvature with omental cake association.Debulk surgery was performed with resection of transverse colon, omentum and abdominal mass.

Surgical resection was composed of a large bowel segment, 20 cm in length, indissociable from a large, well circumscribed, and at least partially encapsulated mass of 9 cm in maximum diameter, infiltrating the visceral wall.The cut surface of the mass appeared homogeneous pink to tan, fleshy, or even friable in consistency.Hemorrhage and necrosis were also observed.No adjacent parenchymatous component was found, even after a whole sampling of peripheral margins.The intestinal visceral serosa was,moreover, disseminated from small solid lesions, ranging from 0.5 to 1 cm in diameter.

Histologically, an acinar pattern of growth consisting of wellformed acini combined with a solid pattern characterized by sheets and cords of tumor cells in a fibrovascular stroma was documented( Fig.1 B).Cells were in a monolayer with basally located nuclei and had a moderate amount of granular eosinophilic cytoplasm.No desmoplastic stroma was found.To explore neoplastic histogenesis, immunohistochemistry was planned.Immunostaining for pancytokeratin (clone AE1-3), CK7, and EMA was detected in neoplastic cells; c-Kit, CD34, CK20 and CDX2 were negative.No positivity was documented for synaptophysin, chromogranin, MART/Melan-A,alfa 1-inhibin, Hep-Par andβ-catenin.Trypsin was diffusely positive ( Fig.1 C-D).Finally, a diagnosis of extra-pancreatic ACC according to WHO was confirmed.

Fig 1.A: CT imaging of extra-pancreatic mass.B: Acinar pattern of growth of cells forming structures resembling normal pancreatic acini, with small lumens (Hematoxylin and Eosin staining, on the right) and solid pattern characterized by large sheets of poorly differentiated cells without lumens (on the left side) (original magnification × 20).C: CK7 immunostaining (original magnification × 20).D: Trypsin immunostaining (original magnification × 20).CT: computed tomography.

We think this case has some unusual and interesting aspects.Developing from the acinar component, a signature for pancreatic origin, a connection with the pancreatic parenchyma is well awaited [ 1 , 2 ].In fact, on CT and MR images, ACCs are usually large, well circumscribed, round or oval, exophytic masses arising from the pancreas.The mean size is around 5-7 cm, with possible foci of hemorrhage and necrosis, leading central cystic component.Central foci of calcifications are also described [3].ACC typically enhances homogeneously or heterogeneously than surrounding pancreatic parenchyma [5].ACC diagnosis shares a wide range of disorders affecting the pancreas.Usually, ductal adenocarcinoma is an irregular intraparenchymal non-encapsulated mass,heterogeneously poorly enhancing on radiological imaging, infiltrating the surrounding fat, the main pancreatic duct and the common bile duct, leading the ‘double duct sign’ on CT imaging.Solid pseudopapillary tumor is not an usual entity to consider, due to its onset in young age and female sex.However, in ACC with predominant cystic component and an exophytic growing, a pancreatic neuroendocrine tumor, cystadenoma, or cystadenocarcinoma should be investigated [ 1 , 2 ].Radiologically, morphological imaging of our case was highly suggestive for ACC diagnosis.However, left-side abdominal localization without connection with the pancreas and the presence of infiltration of intestinal wall, raises up impossibility to define ACC diagnosis confidently.Histologically, neoplastic pattern of growth advances ACC diagnosis, which needs immunohistochemical characterization.Our case showed pancytokeratin, CK7, EMA, and trypsin immunostaining in neoplastic component.The monoclonal antibody directed against the COOH-terminal portion (pancreatic carboxyl ester lipase) of the BCL10 protein is highly specific and sensitive in detecting acinar differentiation [2]but the clone 331.3 is not available in clinical practice and we were not able to perform it.However,trypsin has the same specifity of BCL10, allowing us to confirm ACC diagnosis.

The only strain was the lack of connection with pancreatic parenchyma.An explanation for these findings could be ACC arising in heterotopic pancreas (HP), defined as pancreatic tissue constituted by ducts and acini, with or without islets of Langerhans, in an anatomic site lacking a connection to pancreas [6].HP usually occurs in the upper gastrointestinal (GI) tract, such as in the stomach, duodenum, and jejunum, although HP has been described anywhere along the GI tract, including the gallbladder, appendix, and bile ducts.Finally, HP has been reported in extra-GI sites such as abdominal wall, and rarely, in the lung, submandibular glands, and lymph nodes [6].In a literature review regarding malignancy arising from HP, 54 cases were described with some interesting clues:a) males predominate over females; b) middle-age is the most affected; c) stomach is the most common affected site; d) type I heterotopia according to Heinrich classification (HP composed from ducts, acini and endocrine islets) is the most recognized [7]; e) a submucosal localization is the most frequent finding; f) ductal adenocarcinoma is the most frequent histotype; g) these malignancies have better prognosis compared to the counterparts, the intrapancreatic neoplasms [8].ACC histotype in HP was documented only in 1 case, located in jejunum, with 8.5 cm in maximum diameter; conversely, among 13 cases of ACC in HP reviewed, stomach was the most common site, followed by small and large bowel and liver [9].Of interest, in preoperative biopsy, five cases were diagnosed as poorly differentiated adenocarcinoma; four cases were suggested as alternative histotypes; no case was diagnosed as ACC.Moreover, to define a carcinoma as arising from HP, three criteria should be respected: the main neoplastic lesion or mass must be within or near the HP; pancreatic normal tissue must be admixed but well distinguishable from carcinoma; the nonneoplastic pancreatic tissue must be formed by acini, epithelial and ductal structures [10].Intriguingly, our case showed no residual HP inside and/or at the periphery of neoplastic mass and has arisen in an old woman; moreover, our case has manifested as abdominal mass connected with intestinal wall without colonic submucosal/mucosal spreading but with synchronous peritoneal metastases.Finally, our patient died a few months after surgery, due to the advanced stage of the disease, showing an aggressive behavior of extra-pancreatic ACC.

In conclusion, we described the first case of extra-pancreatic and extra-GI ACC presenting as left abdominal mass with carcinoma and, beyond etiological unsolved queries, we think this report can help radiologists, surgeons, pathologists and oncologists in the best and timely management of this rare disease.

Acknowledgments

None.

CRediT authorship contribution statement

Davide Ciardiello:Conceptualization, Data curation, Formal analysis, Project administration, Resources, Writing - original draft,Writing - review & editing.Filomena Urbano:Data curation, Validation, Writing - review & editing.Giuseppe Zamboni:Data curation, Validation, Writing - review & editing.Nicola Palladino:Data curation, Validation, Writing - review & editing.Francesca Bazzocchi:Data curation, Validation, Writing - review & editing.Paola Parente:Conceptualization, Data curation, Formal analysis,Methodology, Project administration, Resources, Supervision, Writing - original draft, Writing - review & editing.

Funding

None.

Ethical approval

Written informed consent for publication was obtained from the patient.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.