• A 55-year-old woman with a history of orthotopic lung transplantation due to pulmonary fibrosis secondary to scleroderma was on multiple medications, including Immuran, Prednisone, Prilosec, Bactrim, Lasix, Aspirin, folate, and ferrous sulfate, among others. During follow-up, she developed acute mid-abdominal pain, nausea, belching and episodes of emesis. Esophago-gastro-duodenoscopy was performed which showed acute esophagitis, gastritis and ulceration of the distal esophagus.

YOUR DIFFERENTIAL DIAGNOSIS ?

Choose the correct diagnosis:

b. Gastroesophageal reflux diseasec. Thermal injury to the esophagusd. Fungal esophagitis

a. Pill-associated esophagitis

• The diagnosis is pill-associated esophagitis, most probably secondary to ferrous sulfate. The esophageal mucosa shows a tan-brown discoloration and encrustration of the squamous cells with a refractile light brown pigment that neatly outlines and encases the squamous epithelial cells. A minor degree of acute esophagitis is also present. There is no evidence of necrosis of the superficial cells in a laminar pattern. A brightly positive Prussian blue reaction indicates the brown pigment to be iron.

Medication-associated injury to the esophageal mucosa is usually a consequence of swallowing pills at bedtime without sufficient fluid to wash them down. This is particularly prone to occur in elderly patients and those who are somewhat obtunded. Prolonged contact of the pill or medication seems to facilitate the local injury. Ferrous sulfate is among the medications known to cause esophagitis. Some of the more common medications associated with esophagitis are tetracycline, quinidine, corticosteroids, NSAIDs, oral contraceptives, alendronate, and antibiotics.

• Typically the injury is localized and produces an ulcer in the mid or distal esophagus. The diagnosis is made with a careful history and clinico-pathological correlation, although in this case the medication itself serves as a diagnostic marker of the injurious agent. The epithelial cellular encrustation and crystalline nature of the pigment seen in this case is most likely of exogenous origin (iron pill) and the likely cause of esophageal injury.

• A 34-year-old male patient with a history of gastroesophageal reflux disease was incidentally found to have a 1x0.5 cm broad-based, smooth nodule at 37 cm from the incisors during esophagoscopy. The nodule was endoscopically resected.

YOUR DIFFERENTIAL DIAGNOSIS ?

Choose the correct diagnosis:

a. Squamous cell carcinomab. Spindle cell type squamous carcinomac. Gastrointestinal stromal tumor (GIST)d. Leiomyomae. Granular cell tumor

• The diagnosis in this case is granular cell tumor, with pseudo-epitheliomatous hyperplasia. The plump spindled and epitheloid tumor cells have an eosinophilic granular cytoplasm and are filled with coarse red granules and occasional large globules. The tumor cells are arranged in broad fasicles and occasionally in small nests. The tumor involves the superficial lamina propria of the esophagus, where the overlying epithelium shows proliferation. The proliferating squamous epithelial nests interdigitate with the underlying connective tissue of the lamina propria as well as the granular cell tumor. The squamous epithelium is mature, showing narrow bands of downward growth, as well as disjointed islands of squamous epithelium with intercellular bridges and no evidence of cellular atypia.

• Pseudo-epitheliomatous hyperplasia is often observed overlying granular cell tumors. A misdiagnosis of squamous cell carcinoma is a classic pitfall in diagnostic surgical pathology. A superficial biopsy that contains little or no granular tumor cells is a typical trap for the unwary surgical pathologist. Once the granular cell tumor is recognized in the H&E section and confirmed by an S-100 protein or PAS stain, the benign and pseudo-epitheliomatous nature of the squamous proliferation becomes obvious. The tumor cells, which at one time were thought to be myogenic in origin are typically S-100 protein positive and are currently thought to be of schwannian derivation.

In the esophagus these tumors can be single or multiple, superficial or deep-seated, and can occur anywhere along the length of the esophagus. Within the gastrointestinal tract, the esophagus appears to be a relatively common site for the occurrence of granular cell tumors

54-year-old male with a liver mass.

YOUR DIFFERENTIAL DIAGNOSIS ?

Choose the correct diagnosis:

• a. Hepatocellular carcinoma• b. Metastatic adenocarcinoma• c. Metastatic carcinoid tumor• d. Cholangiocarcinoma

• The tumor is composed of nests and cords of cells with uniform round to oval nuclei. The nuclear chromatin is fine and has a "salt and pepper" quality. Numerous mitotic figures can be identified within the tumor.

• The tumor cells show neuroendocrine chromatin with salt and pepper nuclei. The nuclear features favor a diagnosis of a neuroendocrine tumor. However, immunohistochemical stains for neuroendocrine markers such as chromogranin and synaptophysin can be performed to confirm a neuroendocrine tumor and to rule out metastatic or primary adenocarcinoma. Although primary carcinoid tumor can occur in the liver, the majority of cases are metastatic from another primary site. In this particular case, the patient had a history of a lung carcinoid. In the absence of a clinical history, immunohistochemical stains may be helpful in identifying the source of the primary carcinoid tumor. Thyroid transcription factor-1 (TTF-1) is a nuclear protein expressed in thyroid, lung and forebrain. TTF-1 is expressed in 70 to 80% of pulmonary carcinoid tumors, and in 0 to 2% of gastrointestinal carcinoid tumors and pancreatic endocrine tumors.

A young female with right upper quadrant pain and a discrete liver lesion

YOUR DIFFERENTIAL DIAGNOSIS ?

Choose the correct diagnosis:

• a. Focal nodular hyperplasia• b. Cirrhosis• c. Nodular regenrative hyperplasia• d. Congenital hepatic fibrosis

• Histology:This lesion is characterized by bridging fibrosis and regenerative nodules of hepatocytes. There is a central scar in which abnormally structured blood vessels are present.

• Discussion:The process is histologically identical to cirrhosis; however, we are told that the process is focal. Therefore, the diagnosis is "focal cirrhosis" , also known as focal nodular hyperplasia. Cirrhosis requires that the liver diffusely demonstrate bridging fibrosis and nodular regenerative hyperplasia of hepatocytes. Nodular regenerative hyperplasia characterized by diffuse micronodular transformation of the liver in the absence of bridging fibrosis. Congenital hepatic fibrosis is characterized by diffuse fibrosis within the liver bridging portal tracts, but regenerative nodules of hepatocytes are not found. The bile ducts have a hamartomatous appearance consistent with the hypothesis that this lesion represents a ductal malformation. Focal nodular hyperplasia is thought by many to be a reactive process in response to alteration in hepatic blood flow. The presence of dysplastic arterioles within the central scar of the lesion as seen in the current case, supports this theory.

A 54 year-old male is found to have an incidental gastric mass on imaging

YOUR DIFFERENTIAL DIAGNOSIS ?

Choose the correct diagnosis:

• a. Schwannoma• b. Leiomyoma• c. Gastrointestinal stromal tumor (GIST)• d. Inflammatory fibroid polyp• e. Inflammatory myofibroblastic tumor

• The lesion is a well-circumscribed, non-infiltrative spindle cell tumor centered in the gastric sub-serosa. Focal lymphoid aggregates are seen at the periphery of the lesion. The individual spindle cells have elongated nuclei with blunt to pointed ends and occasional perinuclear vacuoles. The nuclei are focally palisaded. There is no necrosis and no mitotic figures. Immunohistochemical stains show the lesional cells to be positive for c-kit (CD117), CD34, and DOG-1, but negative for the S100-protein.

DOG-1

• Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that arise from the interstitial cells of Cajal, or their derivatives, which are driven primarily by KIT and to a lesser degree PDGFRA mutations. The presence of mutations in KIT is pertinent, because it enables GISTs to be treated with targeted tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec). Most KIT mutations occur in exon 11, while a subset occur in exon 9; this is also pertinent, because the tumors with exon 9 mutations do not respond as well to the tyrosine kinase inhibitors. GISTs can arise anywhere along the GI tract, either sporadically or syndromically. Syndromic GISTs are associated with neurofibromatosis type 1, which is characterized predominantly by multiple neurofibromas (solitary or plexiform) café-au-lait skin pigmentation, pigmented iris hamartomas (Lisch nodules), and an increased incidence of MPNST and other soft tissue tumors. Familial GISTs also arise in the setting of hereditary KIT/PDGFRA mutations, loss of succinate dehydrogenase subunit B (SDHB), Carney triad, and Carney-Stratakis syndrome. The prognostication of GISTs depends upon the tumor site, size and mitotic rate. In general, gastric GISTs do well even with large size or moderate mitotic rate, while small intestinal (particularly jejunal/ileal) and rectal GISTs do worse.

• The morphology of GISTs is classically spindled but the tumors can also display epithelioid, hypercellular, or sarcomatoid morphologies. Extracellular collagen globules called skeinoid fibers may be seen, particularly in the small intestinal tumors. Hyalinized vessels, nuclear palisading, and lymphocytic cuffing may also be seen, mimicking gastrointestinal schwannomas. GISTs can also cytologically malignant, recur, or metastasize. The differential diagnosis of low grade, spindled GISTs includes schwannoma, leiomyoma, inflammatory myofibroblastic tumor, inflammatory fibroid polyp, and desmoid fibromatosis. Most GISTs are diffusely positive for c-KIT, CD34, and DOG-1, and some can display focal smooth muscle markers; schwannomas are diffusely positive for the S-100 protein; and leiomyomas are diffusely positive for smooth muscle actin.

This elderly woman with anemia was found to have a 2 cm gastric mass on endoscopy.

YOUR DIFFERENTIAL DIAGNOSIS ?

Choose the correct diagnosis:

• a. A. Brunner’s gland hyperplasia• b. B. Ectopic pancreas• c. C. Metastatic acinar cell carcinoma• d. Carcinoid tumor

• Histology:This well-defined nodule is composed of mature pancreatic parenchyma including ducts, acini, and islets of Langerhans.

• Discussion:• Ectopic pancreata can mimic a neoplasm. In

addition, they can occasionally lead to local bleeding, which may lead to anemia. The entity is readily diagnosed if one keeps it in mind. While many cases, such as this case, are composed of both mature endocrine and exocrine components, some cases are composed entirely of acinar and ductal cells.

This is a 67 year old male with a 13cm small bowel wall mass.

YOUR DIFFERENTIAL DIAGNOSIS ?

• a. Gastrointestinal stromal tumor (GIST)• b. Leiomyoma• c. Leiomyosarcoma• d. Schwannoma

• Histology: This is a neoplasm form of fascicles of eosinophilic spindled cells. The cells have dense eosinophilic neoplasm and the nuclei have a rectangular, “box-car” shape. The lesion ulcerates the overlying small bowel mucosa. Mitotic activity and cytologic atypia are absent. The neoplastic cells label for desmin and actin, but not for S100 protein or CD117. These are the typical features of a leiomyoma

• Discussion: Gastrointestinal stromal tumor would label for CD117, and would have less eosinophilic cytoplasm than the current lesion. Leiomyosarcomas would demonstrate atypia and/or mitotic activity. Schwannomas would label for S100 protein. True smooth muscle tumors of the small bowel very rare. They occur approximately at 3% the frequency of GIST. Leiomyosarcoma of the small bowel is more common than leiomyoma

52 year old man with jejunal polypoid mass. Grossly, it appeared to be composed of fronds attached to a stalk

YOUR DIFFERENTIAL DIAGNOSIS ?

Choose the correct diagnosis:

• a. Peutz-Jeghers polyp• b. Adenoma with pseudoinvasion• c. Hyperplastic polyp• d. Juvenile-type polyp

• Peutz-Jeghers polyps are the most common Hamartomatous polyps of the small intestine. They are composed of an admixture of epithelial elements and smooth muscle fibers that arise from an abnormally thickened muscularis mucosa. The epithelial cells are composed of intestinal absorptive cells, goblet cells, endocrine cells and Paneth cells. Recurrent acute abdominal pain secondary to intussusceptions is the most frequent complaint associated with this polyp. It is in general associated with Peutz-Jeghers syndrome (Hamartomatous polyps, mucocutaneous pigmentation, tumors of the ovary and testis). In this case patients with a polyp are at an increased risk for the development of dysplasia and carcinoma in the polyp and in the adjacent mucosa

This is a 51 year old female with a strictured colonic mass.

YOUR DIFFERENTIAL DIAGNOSIS ?

Choose the correct diagnosis:

• a. Endometriosis• b. Adenocarcinoma• c. Adenomatous Polyp with Pseudoinvasion• d. Mesothelial cyst

• Histology: Within the strictured area, characterized by smooth muscle thickening, there are bland glands with columnar nuclei set in a hypocellular, edematous, bland stroma. Intracellular mucin is not identified within the epithelium in this lesion. These are the typical features of endometriosis.

• Discussion: Adenocarcinoma would demonstrate greater cytologic atypia than the current lesion, and would lack the characteristic endometrial stroma. Adenomatous polyps may demonstrate pseudoinvasion; however, this is typically associated with hemosiderin deposition and the stroma is that of the lamina propria, which is different from the endometrial stroma seen in the current lesion. Mesothelial cysts are composed of bland cuboidal epithelium which may be flat and attenuated, and is not associated with endometrial stroma.

an 8 year old male with diarrhea

YOUR DIFFERENTIAL DIAGNOSIS ?

Choose the correct diagnosis:

• a. Pseudolipomatosis• b. Pneumatosis cystoides intestinalis• c. Cystic adenomatoid tumor• d. Lymphangioma

• Histology: Within the wall of the colon there are large cystic spaces. No epithelial lining is identified, but focally one can identify multinucleate giant cells. This represents a foreign body type giant cell reaction to air which has penetrated into the wall of the bowel.

• Discussion: Pseudolipomatosis results from excessive insufflations of air into the bowel during colonoscopy. One does not see a giant cell reaction in response to the air. Adenomatoid tumors may be cystic, but should be lined by mesothelial cells. Lymphangioma would be lined by endothelial cells. Pneumatosis cystoides intestinalis may present in a fulminant fashion, typically in patients with bowel necrosis which permits gas forming bacteria to grow within the dead bowel, or in benign fashion, typically associated with areas of ulceration.

This >50 year old man was found to have a colon polyp on routine screening. A polpectomy was performed.

YOUR DIFFERENTIAL DIAGNOSIS ?

Choose the correct diagnosis:

• a. Tubular adenoma• b. Tubular adenoma with pseudoinvasion• c. Infiltrating adenocarcinoma arising in a

tubular adenoma• d. Peutz-Jegers polyp

• Histology: The surface epithelium of this polyp is lined by the cells of a tubular adenoma. The polyp is remarkable for several large dilated glands in the stalk of the polyp. On close inspection, these glands lack significant atypia and they have “brought” their lamina propria down with them

• Discussion: Pseudoinvasion is a common mimicker of true invasion in colon polyps. Pseudoinvasion occurs when adenomatous epithelium is displaced into the submucosa of the polyp. Pseudoinvasion occurs most frequently in polyps in the rectum and sigmoid colon. Features which can be used to identify pseudoinvasion include the absence of a desmoplastic reaction, and the presence of lamina propria with associated hemorrhage. The glands of pseudoinvasion are often dilated and can be ruptured.

This is a 61 year old female with a pancreatic mass and a history of prior surgery.

YOUR DIFFERENTIAL DIAGNOSIS ?

Choose the correct diagnosis:

• a. Malignant lymphoma• b. Small cell carcinoma• c. Pancreatoblastoma• d. Metastatic Merkel cell carcinoma

• Histology: The pancreas is involved by high cellular small blue cell tumor. The nuclei are generally uniform, and have very fine, delicate chromatin. The cells demonstrate nuclear molding where they contact each other. Mitotic activity is high. This patient was later known to have had a Merkel cell carcinoma resected from her skin several years back.

• Discussion: Malignant lymphoma would feature less cohesive cells with thicker nuclear membranes and irregular nuclear contours. Small cell carcinoma of the pancreas is extremely uncommon. In general, visceral small cell carcinomas demonstrate greater cytologic atypia and have more coarse chromatin than merkel cell carcinoma. Pancreatoblastoma typically has areas of acinar differentiation, along with characteristic squamoid corpuscles. Pancreatoblastomas typically demonstrate acinar differentiation and show nuclear labeling for â-catenin. Merkel cell carcinomas typically label for cytokeratin 20 in a perinuclear fashion, and also label for neurofilament. These two markers can help distinguish Merkel cell carcinoma from visceral small cell carcinomas. Merkel cell carcinoma has now been shown to be associated with a specific polyomavirus, which promises to be the basis of a distinctive assay for these neoplasms.

64 year old male with an enlarged gallbladder suspicious for carcinoma

YOUR DIFFERENTIAL DIAGNOSIS ?

Choose the correct diagnosis:

• a. Metastatic renal cell carcinoma• b. Adenocarcinoma of the gallbladder, clear

cell type• c. Xanthogranulomatous cholecystitis• d. Gallbladder typical of primary sclerosing

cholangitis

• Histology: The gallbladder wall is markedly distorted by an infiltrate of clear cells with foamy cytoplasm. The residual gallbladder epithelium is reactive. The clear cells have finely granular cytoplasm with small areas of bile pigment deposition. They lack mitotic activity or cytologic atypia.

• Discussion: Metastatic renal cell carcinoma would be composed of cells with clearer cytoplasm and increased vasculature. These cells would label for epithelial markers. Clear cell adenocarcinoma of the gallbladder would feature greater cytologic atypia and mitotic activity. In primary sclerosing cholangitis, the gallbladder typically demonstrates a superficial, diffuse lymphoplasmacytic cholecystitis. The prominent histiocytes seen in the current lesion would not be typical of that condition. Xanthogranulomatous cholecystitis is thought to result from rupture of Rokitansky-Aschoff sinuses with bile extravasation inciting a florid histiocytic reaction. Clinically, the lesion simulates malignancy by adherence to and invasion of adjacent organs

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