Epithelial dysplasia [ie a non-mass forming intraepithelial neoplastic lesion] is considered the most widely accepted precursor lesion to gallbladder carcinoma [1–3]. Several lines of evidence support this hypothesis. First, demographic studies indicate that patients with low and high-grade dysplasia are respectively 15 and 5 years younger than patients with invasive adenocarcinoma, suggesting a linear progression . Second, dysplasia is more common in those portions of the gallbladder [body and fundus] where adenocarcinomas are most frequently localized (3). Third, the incidence of dysplasia is highest in those geographic areas with the highest incidence of invasive adenocarcinoma [5, 6]. Fourth, dysplasia is found in the epithelium adjacent to a high percentage of adenocarcinomas [1–3]. Finally, some dysplasias share molecular alterations with invasive adenocarcinomas of the gallbladder .
The incidence of dysplastic lesions in cholecystectomy specimens is largely related to the geographic location of the patient population being studied, with figures ranging from 0.4%–5% in North American studies [7, 8] to 13.5–13.6% in studies of the Chilean and Mexican populations [5, 6]. They are more commonly identified in females, with a female to male ratio of 3:1 [9, 10]. Dysplastic lesions are typically small, localized, grossly unrecognizable lesions. In one study, 68.6% of such lesions were <1 cm . As noted previously, these lesions are frequently present in the epithelium adjacent to up 79% of invasive adenocarcinomas [6, 11, 12].
Dysplastic lesions are classified into low grade and high grade [carcinoma-in-situ] based on the presence of abnormally polarized nuclei and other prominent nuclear abnormalities in the latter. Reported morphologic variants include flat, micropapillary, papillary and cribriform variants [1, 3]. In this report, we describe a morphologically distinctive and previously unreported variant that was characterized by abundant eosinophilic cytoplasm, nuclear pleomorphism and which was identified in association with a porcelain gallbladder.
The magnitude of the risk for malignancy conferred by diffuse gallbladder mural fibrosis and calcification (porcelain gallbladder) is controversial, with some studies showing an increased risk and others finding no such increase [13–15]. Therefore the gallbladder reported herein was extensively sampled [74 tissue sections], and the lesion described was identified only in one tissue section. However, other pathologic changes that have been suggested to play a role in the gallbladder carcinogenetic sequence, such as intestinal and gastric metaplasia, epithelial hyperplasia and cholecystitis, were present in many sections.
Given the aforementioned background of chronic inflammation, hyperplasia, fibrosis and calcification, the principal differential possibility that must be considered is that our lesion represents an unusual example of reactive atypia. Reactive atypia, in our experience, may show disorganized nuclei and increased eosinophilic cytoplasm. However, cells with reactive atypia will generally show prominent nucleoli, and only minimally enlarged nuclei. The exuberant eosinophilic cytoplasm noted herein will also be distinctly unusual for reactive atypia. The diffuse immunoreactivity for p53 in our lesion argues strongly in favor of its neoplastic nature. Wistuba et al  found overexpression of the p53 protein, as determined by immunohistochemistry, in 11 [32.4%] of 34 dysplasias. Neither normal epithelium nor metaplastic epithelium expressed p53 . Similarly, Wee et al . found that 28% of their dysplasias expressed p53. Normal epithelia in 38 gallbladders harboring various neoplastic, preneoplastic and nonneoplastic lesions were negative for p53, with the notable exception of one case associated with a gallbladder adenocarcinoma . Kamel et al  found overexpression of p53 in 2 of 8 dysplasias. It is our opinion that the strong and diffuse overexpression of the p53 protein, in combination with morphologic features, supports our contention that this lesion is dysplastic. Additionally, the high proliferative index [70%] in the lesion, notably distinct from the background epithelium, further bolsters this contention. The minute nature of the focus precluded any further investigation (e.g electron microscopic) into the precise etiology of the cytoplasmic eosinophilia (e.g cytoplasmic accumulation of mitochrondria, lysosomes, ribosomes, protein, secretory vesicles etc).
In summary, we described herein a morphologically distinctive intraepithelial proliferation of the gallbladder which we have designated eosinophilic dysplasia. Further studies are required to elucidate the true clinical significance of this lesion and whether or not its association with a porcelain gallbladder, as noted herein, is entirely fortuitous. Meanwhile, practitioners should be aware of this distinctive variant when evaluating cholecystectomy specimens.