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Page 8 of 26 Skorupan et al. J Cancer Metastasis Treat 2023;9:5 https://dx.doi.org/10.20517/2394-4722.2022.106

consequent activation of TP63 and upregulation of MYC.

Epidemiology and prognosis
ASCP comprises 0.38%-10% of exocrine pancreatic cancers and appears to have a slight male
predominance [49,60,77] . ASCP is typically considered more aggressive than standard PDAC. Multiple registry
studies that have evaluated large cohorts of patients concur that ASCP patients have similar demographic
characteristics to PDAC patients, but present with larger and more poorly differentiated tumors [78-81] .
Median survival in the unselected population is similar between ASCP and PDAC patients and is ~4-6
months [Table 2]. In patients who undergo resection for local or locoregional disease, those with ASCP have
a lower median overall survival (OS), but similar long-term outcomes, with less than 20% of patients
surviving 5 years or more [Table 3]. Adjusting for the more aggressive clinical characteristics of ASCP at
diagnosis did not change the poorer outcome in two studies [79,80] , but matching ASCP patients to similar
PDAC patients using a nested case-control design did find that survival differences in resected patients
[78]
resolved .
Recently, a nomogram utilizing 9 independent clinical and demographic risk factors was found to be
[82]
predictive of overall survival and cancer-specific survival in ASCP patients . Protective factors for
increased overall survival included resection, radiotherapy, chemotherapy, negative lymph node
involvement, smaller tumor size, multiple tumors, localized tumors, and being married. Female sex was also
associated with prolonged cancer-specific survival. In the metastatic/recurrent disease setting, presence of
lung or peritoneal metastases, anemia, high serum C-reactive protein, and CA 19-9 ≥ 1,000 conferred poorer
prognosis in patients receiving chemotherapy . These factors are largely consistent with those identified as
[83]
pro-survival determinants in other studies.

Diagnosis and imaging
Pathological diagnosis of ASCP is most straightforward in resected patients where the large quantity of
tissue available allows for more conclusive determination of the percentage of squamous component in the
tumor. Unfortunately, the majority of patients with ASCP do not present with resectable disease and
diagnosis must be made from fine needle aspiration (FNA) or core needle biopsy. Diagnosis using these
methods is possible ; however, definitive ASCP diagnosis is more difficult as patients with some squamous
[84]
component noted in the sample may be diagnosed with PDAC due to the pathologist’s inability to
conclusively quantitate a ≥ 30% percentage of squamous component. Note in Table 3 that ASCP constitutes
at least 1% of diagnoses in resected patients, while Table 2 shows that this percentage is much lower in the
full populations which include non-resected patients, although the incidence of metastatic ASCP is
anticipated to be higher given its more aggressive behavior. These data suggest that the percentage of
patients with ASCP in the metastatic exocrine pancreatic cancer population is likely underestimated and
may be due to limitations of diagnosing ASCP from non-surgical samples.

On CT imaging, ASCP is more likely to be round or lobulated than PDAC, to have extensive central
necrosis and to have more frequent accompanying portal vein thrombosis . Indeed, central necrosis may
[85]
be a predominant feature, with at least 75% of cases exhibiting this characteristic , although others have
[86]
found more evidence of ring enhancement than widespread necrosis [87,88] . MRI was found to be more
sensitive and specific than CT for detecting ring enhancement and necrosis, and concurrence of both
[88]
findings is indicative of ASCP . Ren et al. have developed a novel radiomics signature that can
preoperatively differentiate between ASCP and PDAC with a positive predictive value of 92% and a negative
predictive value of 98% . If this signature could be accurately applied in the non-operative setting, it might
[89]
increase diagnostic accuracy for ASCP when used in conjunction with pathologic review of needle biopsy
specimens.