Answer: C. Nephrogenic adenoma

Histology: The bladder biopsies show partially denuded benign urothelium that where intact displays small uniform nuclei with overlying umbrella cells. The lamina propria contains chronic inflammatory cells including eosinophils. One tissue fragments contains irregular glands/tubule-like structures located in the lamina propria immediately underneath benign surface urothelium. The glands are lined by hobnail cells with bland cytology. By immunohistochemistry, the glands are positive for Pax8 and negative for GATA3.

Discussion: The bladder biopsy contains a nephrogenic adenoma, a benign proliferation which is believed to be derived from renal tubule epithelium. Evidence supporting renal derivation of nephrogenic adenoma comes from both immunohistochemistry (positivity for PAX8 and PAX2), but also based on studies of nephrogenic adenomas in patients with renal transplants. In these studies, the X-chromosome status of the nephrogenic adenoma mirrored the gender of the kidney donor and not the host patient. Nephrogenic adenomas most commonly occur in the bladder but can also be seen elsewhere in the urinary tract such as the urethra, ureter or renal pelvis, and typically occur in patients with a history of prior genitourinary instrumentation (e.g., renal transplant, genitourinary surgery). Nephrogenic adenomas can have variable histologic appearances: the spaces may appear more tubular, glandular or vascular-like; the individual cells may be cuboidal, eosinophilic, mucinous or signet-ring like. Nephrogenic adenomas are typically bland with minimal mitotic activity, but they can show degenerative-type atypia. One primary diagnostic pitfall with nephrogenic adenoma is prostatic adenocarcinoma, but they can also mimic urothelial carcinoma with glandular differentiation, vascular lesions, and clear cell adenocarcinoma. By immunohistochemistry, nephrogenic adenomas are positive for PAX8, PAX2, and AMACR/Racemase; may be positive for PSA; and are negative for vascular markers (CD34, ERG, CD31) and urothelial markers (p63, GATA3). (Notice that nephrogenic adenomas may be PSA+, Racemase+ and p63-, thus mimicking the staining pattern of prostatic adenocarcinoma on a PIN4 stain!)

References:
1. Oliva E, Young RH. Nephrogenic adenoma of the urinary tract: a review of the microscopic appearance of 80 cases with emphasis on unusual features. Mod Pathol. 1995 Sep;8(7):722-30.
2. Mazal PR, Schaufler R, Altenhuber-Müller R, et al. Derivation of nephrogenic adenomas from renal tubular cells in kidney-transplant recipients. N Engl J Med. 2002 Aug 29;347(9):653-9.
3. Netto GJ, Epstein JI. Benign Mimickers of Prostate Adenocarcinoma on Needle Biopsy and Transurethral Resection. Surg Pathol Clin. 2008 Dec;1(1):1-41.

Answer: E. Pancreatic heterotopia with intraepithelial neoplasia

Histology: The mass is comprised of pancreatic parenchyma with all components of the normal pancreatic gland—acini, islets, and ducts. The pancreatic ducts are lined by columnar type cells with pseudostratified nuclei, hyperchromatic nuclei, and micropapillary architecture.

Discussion: This is an example of heterotopic pancreas with pancreatic intraepithelial neoplasia (PanIN). Heterotopic pancreas is a relatively uncommon lesion that can occur anywhere throughout the gastrointestinal tract; it can be detected as an incidental mass or can cause symptoms such as obstruction. Normal pancreatic ducts are lined by bland cuboidal or low-columnar cells. In contrast, ducts that contain PanIN are lined by columnar epithelial cells displaying a spectrum of nuclear atypia and micropapillary architecture. PanIN has traditionally be classified as PanIN-1A, -1B, -2 and -3 on the basis of increasing micropapillary architecture and cytologic atypia from grades 1 to 3. However, the recommended classification scheme for PanIN has recently shifted from a 3-tiered system to a 2-tiered system (low grade and high grade), wherein PanIN 1 and 2 are grouped into “low grade” and PanIN 3 is “high grade” (Basturk O, et al.). PanIN lesions are precursor lesions to pancreatic ductal adenocarcinoma, and interestingly, PanIN and even intraductal papillary mucinous neoplasms (IPMN) have been described in heterotopic pancreas, including in patients with no evidence of pancreatic adenocarcinoma in the main pancreatic gland.

References:
1. Armstrong CP, King PM, Dixon JM, and Macleod IB. The clinical significance of heterotopic pancreas in the gastrointestinal tract. Br J Surg 1981. 68:384–387
2. Zhang L, Sanderson SO, Lloyd RV, Smyrk TC. Pancreatic intraepithelial neoplasia in heterotopic pancreas: evidence for the progression model of pancreatic ductal adenocarcinoma. Am J Surg Pathol. 2007 Aug;31(8):1191-5.
3. Basturk O, Hong SM, Wood LD, et al. A Revised Classification System and Recommendations From the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas. Am J Surg Pathol. 2015 Dec;39(12):1730-41.
4. Ma C, Gocke CD, Hruban RH, Belchis DA. Mutational spectrum of intraepithelial neoplasia in pancreatic heterotopia. Hum Pathol. 2016 Feb;48:117-21.

Answer: D. Pseudomembranous colitis

Histology: The specimen received is a total colectomy. The entire mucosal surface is grossly remarkable grossly for a thin, yellow-green membranous film. Histologic sections show regions of the colonic mucosa to be entirely necrotic with alternative areas of residual viable epithelium. The luminal surface of the bowel has a layer of fibrin and acute inflammatory cells corresponding to the grossly apparent pseudomembrane. There is submucosal edema, but the underlying muscularis propria and subserosal soft tissue are fairly unremarkable with no evidence of vasculitis. There are no granulomata or viral cytopathic changes. The patient’s stool was tested by the molecular microbiology lab and was positive for Clostridium difficile toxin B gene by nucleic acid testing.

Discussion: The clinical presentation, laboratory results, and pathologic findings are diagnostic of pseudomembranous colitis due to Clostridium difficile infection in the setting of prior antibiotic use. C. difficile is an anaerobin, gram-positive, spore-forming, bacillus that produces pathogenic exotoxins A and B. C. difficile is not part of the normal gut flora, but rather will colonize the intestines after the normal flora is disrupted by prior antibiotic treatment. C. difficile colitis is a leading nosocomial infection and can result in fulminant colitis, toxic megacolon, bowel perforation, and sepsis with high mortality. The damage to the intestine is due to the effects of the toxin, not due to actual bacterial invasion or overgrowth within the mucosa. Gross and histologic examination of the tissue often reveals the classic “pseudomembranous colitis” with diffuse necrosis of the mucosa and an overlying “pseudomembrane” of necrotic tissue, mucus, fibrin and inflammatory cells. Diagnosis of C. difficile can be done in several ways including enzyme immunoassay and DNA based assays such as RT-PCR for the toxins; although the histologic presence of diffuse pseudomembranous colitis raises the possibility of C. difficile infection, the diagnosis should be made in conjunction with the laboratory results.

References:
1. Svensson AM, LaSala PR; Education Committee of the Academy of Clinical Laboratory Physicians and Scientists. Pathology consultation on detection of Clostridium difficile. Am J Clin Pathol. 2012 Jan;137(1):10-5.
2. Leffler DA, Lamont JT. Clostridium difficile Infection. N Engl J Med. 2015 Jul 16;373(3):287-8