Morphologic repertoire of pancreatobiliary-type adenocarcinoma originating in the pancreas (invasive ductal adeno-carcinoma, PDCA) includes a hitherto unrecognized distinctive pattern characterized by infiltrating cribriform clusters of cells with microcystic formations. In this variant, the microcysts appear to result from the fusion of intracellular lumenae, many of which contain CA19-9 positive secretory material admixed with nuclear debris and mucin. These spaces compress the cytoplasmic organelles to the periphery of the cell, forming a thin bridging membrane. The nuclei are often compressed and indented, creating a picture reminiscent of signet-ring cells or adipocytes, to an extent that these tumor cells have been mistaken for lipogranulomas or sinusoidal fat, both of which are common findings in peripancreatic lymph nodes. They may also be mistaken for fat necrosis in biopsies from peripancreatic tissue or peritoneal surfaces to which PDCA often disseminates.
It is important to recognize this pattern because it may be diagnostically important in limited specimens or in biopsies from metastatic foci, especially since many PDCA patients present with distant tumor and an unsuspected primary in the pancreas. The authors have seen several examples in the liver and other sites including bone marrow, in which this pattern led to the correct diagnosis of otherwise unsuspected PDCA. Differential diagnosis include signet-ring cell carcinoma, tumors with lipoblast-like or signet-ring cells from other primary sites, specifically breast and stomach, and liposar- coma (alone or as part of sarcomatoid carcinoma). All these distinctions have significant therapeutic implications.
Although uncommon, this pattern may also be encountered in tumors from other sites, especially in surface epithelial organs. The presence of distinctive large vacuoles that compress the nucleus forming a cribriform architecture is a typical finding in adenomatoid tumors (the so-called localized mesothelioma of gynecologic tract) [6
], but may also be rarely seen in mesotheliomas [8
]. This pattern is also well recognized as a variant of meningioma in the meninges [9
], another site with a highly specialized “lining” properties, similar in that sense to mesothelium. The authors have also encountered this pattern in laryngeal and GE-junction carcinomas, both of which are sites with transition from a glandular to squamous epithelium, raising the question of this pattern being a result of lumen forming cells that are also showing immature squamous properties. The positivity of CK34βE12, a marker of squamous differentiation in the pancreas, in 6 of 11 cases reported here may lend further support to this possibility. On the other hand, in none of these cases was frank evidence of squamous differentiation such as keratin formation, squamous pearls, or histologic evidence of desmosomal junctions identified. Therefore, it appears that the process is likely to be recapitulating attenuated “lining” cells akin to those seen in adenomatoid tumors or mesotheliomas, rather than true squamous differentiation.
A pattern similar to the one described here may also be rarely seen in solid glandular organs including the salivary glands [10
], and we have noted it occasionally even in the colon. In the ovary, it has been documented as a rare variant that was reported as “mixed-epithelial carcinoma with microcystic pattern and signet ring cells” [12
], a term that has been coined for this pattern in the meninges [9
]. Since ovarian involvement in disseminated PDCA is not uncommon [13
] (and vice versa is also true [16
]), it is important to be aware that this pattern may be exhibited by the tumors from both organs. A similar tumor type has been also noted in the urinary bladder under the same heading (microcystic transitional cell carcinomas) [5
] along with the lipid cell variant of urothelial carcinoma with histologic appearance similar to lipoblasts [19
The term microcystic, in the pancreas, however, is used specifically for serous cystadenomas (and its look-alikes) that are characterized by macroscopically visible small cysts (only a few millimeters in diameter) that form a distinctive sieve-like arrangement. Therefore, although “microcystic” is probably the best descriptive term for this pattern, it ought to be avoided for this variant of PDCA since it is already fully identified with a benign and distinctive tumor in this organ. Also, although the cells in this pattern have “signet-ring” appearance; we, as many others, are of the opinion that the term “signet ring” ought to be avoided outside the setting of diffuse infiltrative-type (E-cadherin related) carcinoma that is characterized by individual cell infiltration. In the void of the liberty to use these terms, the best descriptive names to designate this pattern are felt to be vacuolated or cribriform adenocarcinoma. The latter has been associated with a distinctive and well-differentiated tumor in the breast and may be misleading as well.
Fortunately, the name one chooses to describe this variant may not be that important because the findings in this study suggest that this is a morphologic variant of pancreatobiliary-type adenocarcinoma, not a separate tumor type. Its clinical characteristics are not too different from PDCA, with the exception of higher incidence of smoking history. The association with smoking may be of interest because studies in other organs are now revealing that smoking triggers different pathways of carcinogenesis [23
] and may have closer association with certain glandular subtypes [25
]. Along the same lines, although it did not reach statistical significance, the incidence of K-ras
mutation appeared to be higher in vacuolated carcinomas in our population. Whether this has a role in the development of this distinctive secretory/ vacuolated pattern needs further scrutiny because it is becoming increasingly clear that K-ras
is an oncogene commonly involved in glandular neoplasia of various organs [26
], and different types of K-ras
mutation may be responsible for different patterns and degrees of secretory properties.
The clinical course of vacuolated variant appears to be slightly more aggressive than the average PDCA, putting it in the more poorly differentiated category. Breast carcinomas with similar pattern also reported to have worse prognosis, particularly in elderly patients [27
]. While this may be surprising based on the degree of glandular secretory differentiation, it is not at all if the nuclear grade is taken into consideration because this variant is often associated with high nuclear grade; despite their compressed (attenuated) appearance, the nuclei are often very atypical, hyperchromatic, and irregular, an important clue for the diagnosis of this pattern.
In conclusion, the morphologic spectrum of PDCA includes a vacuolated (cribriform) pattern that ought to be recognized because it may be important in the often challenging differential diagnosis of this tumor type both in limited specimens from the pancreas and metastatic sites.