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Page 14 of 26 Skorupan et al. J Cancer Metastasis Treat 2023;9:5 https://dx.doi.org/10.20517/2394-4722.2022.106

[143]
in females with PACC . Retrospective population-based studies suggest that 32%-54% of patients present
with distant metastatic disease [142-145] . The most frequent site of metastasis is the liver. While this proportion
is similar (in some studies) to that for PDAC, PACC patients have improved median survival compared to
[145]
PDAC at every disease stage . This is particularly notable in patients with PACC who undergo resection,
where median OS can exceed 70 months, but rarely reaches 36 months in PDAC patients. PACC tumors are
typically larger at diagnosis than those seen in PDAC. Interestingly, primary tumor size did not correlate
with the time to onset of metastatic disease or with the presence of metastatic lesions . Those with mixed
[141]
acinar-neuroendocrine and acinar-ductal pathologies appear to have similar prognosis and tumor
characteristics . PACC is still an aggressive tumor, but prognosis is superior to PDAC. PACC
[146]
retrospective case series examining clinical outcomes are summarized in Table 5 [142-148] .

PACC has been seen in kindreds with familial adenomatous polyposis , Lynch syndrome , and BRCA
[149]
[150]
mutation [134,151] , but it is difficult to determine how influential these genetic syndromes are in this disease
given the small number of cases overall. Specific clinical or environmental risk factors for PACC remain
unknown.

PACC diagnosis and imaging
Diagnosis of PACC is by pathology. Tumor samples can be obtained through surgical resection or needle
aspiration. Diagnosing PACC from a fine needle aspiration can present a challenge as cytologic samples can
be easily confused with normal acinar cells or sampling from a neuroendocrine tumor. Labate et al. were the
first to describe the cytopathology of PACC in detail and were able to correctly diagnose PACC from a
cytology specimen in just 2 of 7 cases . Subsequently, the diagnostic yield has not appeared to improve, as
[152]
only 2 of 7 cases reported since could be definitively diagnosed as PACC based on cytology alone [153-156] .

CT is the standard and first line choice for imaging studies of PACC. Visible lymph nodes were noted to be
more frequent in PACC than PDAC. Tumor hypoattenuation in arterial phase compared to the uninvolved
pancreas was much less frequent in PACC and PACC was much more likely to have well-defined margins
than PDAC. Lack of bile duct dilatation was also much more common in PACC than PDAC . MRI
[157]
characteristics of PACC were investigated in a small study of 5 patients, and it was concluded that PACC
presents as a round, encapsulated tumor with moderate and heterogeneous enhancement after gadolinium
[158]
administration . Either CT or MRI can adequately detect PACC.
Clinical manifestations of PACC
The most common symptoms in newly diagnosed PACC patients are generally non-specific: abdominal
pain and weight loss occur most frequently . Jaundice is an infrequent symptom even when PACC
[141]
presents in the pancreatic head. Jaundice is very common in PDAC and PACC tumors are typically larger at
diagnosis [141,148,159] , so the rarity of jaundice in PACC has been difficult to understand. It has been suggested
that the more encapsulated biology of PACC is less susceptible to causing jaundice than the more infiltrative
biology of PDAC.

Lipase hypersecretion syndrome (LHS) is a paraneoplastic syndrome uniquely observed with PACC. Many
PACCs produce lipase and excessive release of this enzyme into the circulation occurs in about 10%-15% of
PACC patients, leading to accumulation of pancreatic enzymes in peripheral tissues and subsequent
enzymatic digestion. Very elevated blood lipase levels can cause eosinophilia and panniculitis that most
often manifests as painful subcutaneous nodules that resemble erythema nodosum. Panniculitis of LHS has
a predilection for pressure points in the lower extremities, especially on the shins [160,161] . Another common
feature of LHS is painful and inflammatory polyarthritis that resembles rheumatic fever or gout. It is
thought to be secondary to periarticular fat necrosis. Joint aspirates are typically sterile but occasionally