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Background Precursor colonic polyps of varied subtypes correlate with the known neoplastic pathways. When patients present with synchronous pre-malignant polyps of multiple histologies, multiple genetic mechanisms are likely to be active, potentially resulting in a more unstable, tumourigenic mucosa. Methods We hypothesized that patients with a combination of sessile serrated adenomas/polyps (SSA/Ps), hyperplastic (HP) polyps and adenomas would be at highest risk of developing dysplasia/cancer compared to SSA/Ps alone, due to the synergistic effect of multiple active carcinogenic pathways. A prospective colonoscopy database was examined for patients with a history of SSA/P. Patients were placed into four groups based on patterns of polyp histology as follows: (i) only SSA/Ps; (ii) SSA/P + HP; (iii) SSA/Ps + adenomas; and (iv) SSA/Ps + HP + adenomas. These groups were compared in terms of the numbers, size, location and histology of polyps and personal or family history of colorectal cancer. Results A total of 374 patients were included. The average age was 70 years (range 21-88), and 43% were male. There was a trend towards the most aggressive neoplastic pattern in group 4, associated with a tendency to larger SSA/Ps, more villous architecture in the adenomas and more high-grade dysplasia in both types of polyps. It was also associated with multiplicity of both SSA/Ps and adenomas. No SSA/Ps existing in the absence of adenomas had cytological dysplasia. Conclusion The combination of SSA/Ps, HP and adenomas in the colorectal epithelium seems to be a marker for aggressive carcinogenesis and suggests that accurate and effective surveillance is important to manage this risk.

The incidence of colorectal cancer (CRC) among young adults has been dramatically rising, with guidelines for screening recently adjusted to start at age 45. However, knowledge of the precursor lesions is limited. We recently reported that 83% of CRC diagnosed under age 50 are left sided. Our aim was to analyze the location and histology of benign colorectal lesions found in a cohort of patients younger than 50, documenting the presence of advanced histology. We used the database in the Department of Pathology to retrospectively review the location and histology of all benign colorectal neoplasms in patients under age 50 submitted to pathology examination during 2006–2016. A total of 8364 lesions were examined from 4773 patients, and 3534 (65.5%) of the patients had only one polyp and the rest had multiple. Mean age was 41.9 years (range 16–49) while 3843 (72.8%) of the patients were between the ages of 40 and 49. In total, 4570/8364 lesions (54.6%) were distal to the splenic flexure. The most common pathology was tubular adenoma (63.7%), then hyperplastic polyps (16.6%), sessile serrated lesions (SSLs) (13.1%), and tubulovillous adenomas (6.3%). Tubulovillous adenomas, villous lesions, advanced adenomas, and adenomas with high-grade dysplasia were all predominantly left sided (left colon and rectum = 77.6%, 85%, 78.3%, and 87.6% respectively). Of the SSLs, 71.5% were in the right colon while 16.6% of hyperplastic lesions were right sided. High-risk advanced adenomas are predominantly left sided. This focuses attention on the rectum and left colon where carcinogenesis is strong in the young.

Metastatic invasive lobular carcinoma (mILC) may masquerade as primary diffuse gastric adenocarcinoma (PDGA) by demonstrating significant clinical and pathologic overlap. Accurate distinction is of therapeutic and prognostic significance. On the basis of anecdotal cases of mILC that lacked estrogen receptor and/or GATA3 expression, we analyzed the cytoarchitectural features of 28 mILC and 44 PDGA specimens obtained from women to assess features that would help in this distinction and prompt ancillary work-up. In addition to performing an interobserver agreement analysis among 3 pathologists, we also evaluated SATB2 expression in this setting. Eighteen of 20 (90%) patients had a history of ILC. The mean interval between initial diagnosis of breast cancer and metastasis was 7.3 years (range: 1 to 36 y). Compared with mILC, PDGA was significantly associated with full-thickness mucosal involvement (47% vs. 80%; P=0.015), a nested/sheet-like growth pattern (32% vs. 68%; P=0.004), anastomosing cords (0% vs. 100%; P=0.001), multivacuolated cells (0% vs. 61%; P0.0001), pleomorphic nuclei (4% vs. 70%; P0.0001) and enlarged nuclei (4% vs. 70%; P0.0001). Single file growth pattern (P0.0001) and superficial lamina propria involvement (P=0.009) were more common in mILC. Estrogen receptor and GATA3 were expressed in all but 5 mILC cases; SATB2 was only seen in 30% of PDGA cases. Our results demonstrate that in a biopsy specimen, careful morphologic assessment can be extremely helpful in distinguishing mILC from PDGA and guiding ancillary work-up, especially when a history of breast cancer may not be readily available or when the neoplasm lacks expression of conventional breast markers.

Purpose: Histologic correlation of clinical patterns of recurrent choroidal melanoma following I-125 plaque brachytherapy was performed to identify pathologic mechanisms of recurrence. Methods: We reviewed 7 cases of recurrent choroidal melanoma following I-125 plaque brachytherapy managed with enucleation. Clinical characteristics included tumor dimensions, radiation dose, time to local recurrence, and clinical pattern of recurrence. Histopathology (hematoxylin and eosin and periodic acid – Schiff) and immunohistochemistry (Ki-67, CD-163, HMB45, and SOX10) were performed. Results: Mean follow-up time and time to local recurrence were 42 and 21 months after brachytherapy, respectively. Tumor recurrences were described clinically as marginal in 43%, diffuse in 29%, and extraocular extension (EOE) in 29%. Eighty-six percent were classified as mixed cell type and 14% were epithelioid type. Tumor zonation (histologic demarcation between zones of recurrent and nonrecurrent tumor cells by immunohistochemistry) was present in marginal and EOE cases (n = 6) and absent in the diffuse cases (n = 2). Ki-67 proliferative index was higher in marginal and EOE recurrences, while diffuse cases showed uniform ­Ki-67 staining. CD-163 staining was found to be greater in nonrecurrent tumor. HMB45 correlated with SOX10 with a greater staining in recurrent tumor. Conclusion: Our observations provide a correlation between histopathologic and clinical patterns of local recurrence of choroidal melanoma after brachytherapy.

Autoimmune enteropathy is an extremely rare condition characterized by an abnormal intestinal immune response which typically manifests within the first 6 months of life as severe, intractable diarrhea that does not respond to dietary modification. Affected individuals frequently present with other signs of autoimmunity. The diagnosis is made based on a characteristic combination of clinical symptoms, laboratory studies, and histological features on small bowel biopsy. Autoimmune enteropathy is associated with a number of other conditions and syndromes, most notably immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome and autoimmune polyglandular syndrome type 1 (APS-1). Diagnosis and treatment is challenging, and further research is needed to better understand the pathogenesis, disease progression, and long-term outcomes of these conditions.

Highlights • This is the first reported case of cystic paraganglioma in the literature. • Paragangliomas in the differential of gallbladder or cystic/hepatic duct lesions. • Importance of thorough investigation, due to association with endocrinopathies., Introduction Biliary system paragangliomas are rare neuroendocrine tumors of embryonic neural crest origin. The majority is asymptomatic and incidentally found due to gallbladder functional disorders. Herein, we present a non-functional, 2.25 mm focus in the cystic duct, which to our knowledge, is the first reported paraganglioma of the cystic duct. Presentation of case The patient presented to the Emergency Department complaining of a sudden-onset, right upper abdominal and epigastric pain. Ultrasound and Computed Tomography were both consistent with signs of early cholecystitis. Laparoscopic cholecystectomy was performed without major complications. In addition to cholelithiasis and chronic cholecystitis, pathological examination reported a neuroendocrine proliferation in the cystic duct measuring 2.25 mm favoring paraganglioma. Incidentally, the patient is unique in that they were also found to have an adrenal nodule and a normocalcemic primary hyperparathyroidism that raised suspicion for an underlying endocrinopathy. Nevertheless, genetic testing was negative. Discussion Extensive literature review demonstrates only nine cases of gallbladder paraganglioma, and three cases of hepatic ducts paraganglioma, but no cases of paraganglioma occurring at the cystic duct. Although a gene mutation and syndrome was not identified in the patient, the fact that an adrenal nodule and normocalcemic primary hyperparathyroidism were present, suggests that a complete hormonal workup should be obtained in these patients. Conclusion It is important to realize that biliary system paragangliomas, although rare, may occur. As they have an association with multiple endocrine neoplasia syndrome, a thorough endocrine investigation should be made.

PURPOSE: To compare needle and microcannula injection techniques in regards to the microanatomical location of hyaluronic acid gel injected in the upper lip vermillion border of cadaver specimens. METHODS: The upper lip vermillion border was injected transcutaneously with hyaluronic acid gel in 8 fresh hemifaces of 4 female human cadavers. Each hemiface was injected by a single experienced injector, the right side using a 27-gauge microcannula and the left side using a 30-gauge needle. A 2cm region of each lip was excised lateral to a point 1cm lateral to the philtrum. Specimens were fixed in 95% alcohol, embedded in paraffin, and stained with hematoxylin and eosin for histologic examination. RESULTS: The majority of hyaluronic acid injected with either a needle or microcannula was located within the orbicularis oris muscle, and the remaining hyaluronic acid resided within the subcutaneous fat. In 3/4 right (microcannula) hemifaces, 100% of the hyaluronic acid was located within the muscle. Only 2/4 left (needle) hemifaces had at least 95% of the hyaluronic acid located within the muscle. Overall, in right (microcannula) hemifaces 93% of the filler was located within the muscle and in left (needle) hemifaces 79% of the filler was located within the muscle (p =0.14 ). CONCLUSIONS: The majority of hyaluronic acid filler injected into the vermillion border after either microcannula or needle injection resides within the orbicularis oris muscle rather than in a subcutaneous/submucosal location. Injection with a microcannula shows a trend for more uniform intramuscular location compared to needle injection.

The incidence of colorectal cancer in the young (under age 40) is increasing, and this population has worse oncologic outcomes. Mucinous histology is a potential prognostic factor in colorectal cancer, but has not been evaluated specifically in young patients.The objective of the study was to determine factors associated with poor outcome in young patients with colorectal cancer (≤40 years) and to determine relationships between mucinous histology and oncologic outcomes in this population.This is a retrospective study.Patients from a single-institution tertiary care center were studied.A total of 224 patients with colorectal cancer under 40 years of age diagnosed between 1990 and 2010 were included (mean age, 34.7 years; 51.3% female). 34 patients (15.2%) had mucinous histology.There were no interventions.Oncologic outcomes were analyzed according to the presence of mucinous histology.The mucinous and nonmucin colorectal cancer study populations were statistically similar in age, sex, tumor location, pathological stage, differentiation, and adjuvant chemotherapy use. Five-year disease-free survival was 29.1% versus 71.3% (p0.0001) and 5-year overall survival was 54.7% versus 80.3% (p0.0001) for mucinous and nonmucinous patients, respectively. Mucinous colorectal cancers recurred earlier at a median time of 36.4 months versus 94.2 months for nonmucin colorectal cancers (p0.001). On multivariate analysis, pathological stage (stage II HR, 3.61; 95% CI, 1.37-9.50; stage III HR, 5.27; 95% CI, 2.12-12.33), positive margins (HR, 1.95; 95% CI, 1.12-3.23), angiolymphatic invasion (HR, 2.15; 95% CI, 1.26-3.97), and mucinous histology (HR, 2.36; 95% CI, 1.44-3.96) were independently associated with worse disease-free and overall survival.This is a retrospective study without genetic information.Mucinous histology is a negative prognostic factor in young patients with colorectal cancer. This is associated with early and high recurrence rates, despite use of standard neoadjuvant and adjuvant regimens. Physicians need to be aware of this association and potentially explore novel treatment options. See Video Abstract at http://links.lww.com/DCR/A575.

Purpose To evaluate the patterns, the risk factors, and the management of recurrence following brachytherapy in patients with posterior uveal melanoma, given that an understanding of the recurrence patterns can improve early recognition and management of local treatment failure in such patients. Design Retrospective cohort study. Methods Setting: Multispecialty tertiary care center. Participants: A total of 375 eyes treated with episcleral brachytherapy for posterior uveal melanoma from January 2004 to December 2014. Exclusion criteria included inadequate follow-up ( Results Twenty-one patients (5.6%) experienced recurrence (follow-up range 12–156 months; median 47 months). The median time to recurrence was 18 months (range 4–156 months). Five-year estimated local recurrence rate was 6.6%. The majority (90.5%) of the recurrences occurred within the first 5 years. The predominant site of recurrence was at the tumor margin (12 patients, 57.1%). Univariate analysis identified 3 statistically significant recurrence risk factors: advanced age, largest basal diameter, and the use of adjuvant transpupillary thermotherapy (TTT). Recurrent tumors were managed by repeat brachytherapy, TTT, or enucleation. Conclusions Local recurrences following brachytherapy are uncommon 5 years after episcleral brachytherapy. Follow-up intervals can be adjusted to reflect time to recurrence. Most of the eyes with recurrent tumor can be salvaged by conservative methods.

Colorectal serrated polyps are intermediate lesions in the serrated neoplastic pathway, which account for up to 30% of colorectal cancers. This pathway is biologically distinct from the adenoma-to-carcinoma sequence, with associated cancers exhibiting mutations in the BRAF oncogene, DNA promoter hypermethylation, and microsatellite instability. An evolving understanding of these unique lesions has led to the development of a more accurate classification, improved endoscopic identification, and tailored clinical management guidelines. This article reviews serrated polyps and serrated polyposis syndrome.

Pancreatic neuroendocrine neoplasms (PanNENs) are uncommon tumors. Fine needle aspiration (FNA) samples from PanNENs are typically of high cellularity and lack necrosis. In cytology slides from these tumors, dyscohesive cells are usually reported with variably round to oval to plasmacytoid forms exhibiting coarsely granular chromatin and showing immunoreactivity for synaptophysin. We present an unusual, and to our knowledge not previously described, example of an FNA of a PanNEN with large extracellular fibrous spheroids containing intrinsic fibroblasts and rimmed by small to intermediate sized neoplastic epithelial cells with high nuclear cytoplasmic ratios. The cytomorphology of the PanNEN in this case was in some ways reminiscent of that expected in adenoid cystic carcinomas of the salivary glands that most often contain large extracellular globules of basement membrane material and a somewhat biphasic population of lesional cells. The cytomorphology in this case was found to correlate well with the resection specimen histomorphology of an exaggerated gyriform pattern of growth resulting in a unique cobblestone-pavement like microscopic appearance. Knowledge of this potential cytomorphology will aid the cytology community through recognition and reporting of this previously undescribed pattern in an uncommon disease.

Background Langerhans cell collections (LCCs) and eosinophils are traditionally considered histologic clues to allergic contact dermatitis (ACD), but rigorous histologic analyses are limited. We correlated the presence of LCCs and eosinophils in skin biopsies with patch test results in patients evaluated for ACD. Methods Charts of all patients patch tested and biopsied at one institution from 2011 to 2013 were reviewed. Biopsies had to have a diagnosis of either spongiotic dermatitis, psoriasiform dermatitis or mixed psoriasiform/spongiotic dermatitis. Various histologic parameters were assessed, including the presence of LCCs and number of eosinophils. Design A total of 68 biopsies met study criteria. Of these, 27 (40%) had ≥1 LCC. Twenty-one out of 27 (78%) with ≥1 LCC were patch test positive; 6 were patch test negative (22%). Of 41 cases with no LCCs, 23 were patch test positive (23/41, 56%) and 18 were patch test negative (18/41, 44%). LCCs were significantly more common in patch test positive patients (p = 0.046). Eosinophil count did not significantly differ in patch test positive and negative cases (p = 0.216). Conclusion LCCs are significantly more common in patch test positive cases. There were no differences with regards to presence of eosinophils between patch test positive and negative groups.

Background: To expand the spectrum of ophthalmic manifestations in cat scratch disease. Methods: Case report. Results: A 7-year-old male was referred for evaluation of his left optic disc after failing vision screening test at school. His visual acuity was 20/20 OD and light perception OS. Fundus examination showed a left optic disc lesion associated with an exudative retinal detachment and vitreous seeding. Ultrasonography revealed a 7 × 7.5 × 3.8 mm lesion with a possible 6.3 mm of retrolaminar extension into the substance of the optic nerve. Brain MRI did not show evidence of optic nerve involvement but revealed a 6-mm nodule of the pineal gland suggestive of a pineoblastoma. Enucleation was performed and histopathology revealed a suppurative granulomatous inflammation suggestive of Bartonella infection. Upon further questioning, the patient had recent exposure to kittens with areas of cat scratches along both of his arms. He was subsequently referred to and treated with a 2-week course of trimethoprim-sulfamethoxazole and rifampin by the pediatric infectious disease specialist. Repeat brain MRI showed interval total resolution of enlarged pineal gland. Conclusion: Optic nerve granulomas are a rare presentation of cat scratch disease and could potentially masquerade as retinoblastoma.

A 67-year-old male with a 35-year history of left-sided epiphora presented with a nonpainful, noninflamed, left medial canthal mass and complete left nasolacrimal obstruction. During routine dacryocystorhinostomy, a lesion was present within the lacrimal sac that mimicked a lacrimal stone in appearance but with a consistency concerning for malignancy. Histologically, the lesion displayed apple-green birefringence on polarized light microscopy and Congo red staining. The patient was referred to the hematology service for evaluation, which failed to reveal systemic disease. There is 1 previous report of localized amyloidosis to the nasolacrimal excretory system in which the lesion was invasive and caused bony erosion. The authors present a second case of localized, nasolacrimal amyloidosis mimicking both neoplasm and dacryolith without bony erosion.

Purpose To describe a case of diffuse conjunctival papilloma in an immunocompromised individual on tacrolimus that was refractory to treatment with interferon α-2b, but responded to topical mitomycin-c. Observations A 79-year-old Caucasian female with a history of a liver transplant twenty years ago, who was immunosuppressed with tacrolimus (2 mg daily) presented with a diffuse conjunctival and corneal squamous papilloma. Following treatment with four weekly subconjunctival interferon-α2b injections (3 million units/0.5 mL) and 3 months of topical interferon-α2b therapy (1 million units/mL), four times daily, slow progression was documented. The patient was switched to topical mitomycin-c drops (0.04%) administered four times daily (one week on and one week off) with dramatic regression of the tumor. Conclusions and importance In cases of conjunctival squamous papilloma that do not respond readily to topical interferon, topical mitomycin-c is an alternate therapeutic option. We hypothesize that use of tacrolimus may have contributed to the lack of response to topical interferon-α2b.

Squamous cell carcinoma (SCC) of the orbit is almost uniformly the result of local invasion from a cutaneous primary, extension by perineural invasion, or the result of metastasis. This is owed to the lack of native squamous epithelium in the orbit. After review of the literature, to date, only 6 reports of 8 patients with primary orbital SCC exist. Of those cases, only 2 reported non-apical orbital SCC. There are 2 reports of orbital SCC after retina surgery with proposed transplanted conjunctival epithelium and subsequent malignant transformation of a conjunctival cyst. The initial signs and symptoms can be vague and lead to delay in diagnosis. We present a case of primary orbital SCC and discuss the workup, imaging, and multidisciplinary management of this rare condition.

Purpose To report a unique case of isolated conjunctival inflammation from IgG4-related disease (IgG4-RD) confirmed by pathology. Methods A single interventional case of conjunctival IgG4-RD. Results A 63-year-old woman presented with a chronic, solitary, vascularized, tan-colored, and raised conjunctival lesion measuring 7.5 × 8.0 × 1.2 mm located at the temporal bulbar conjunctiva. An excisional biopsy was diagnostic of IgG4-RD based on the classic fibrosis pattern, 120 IgG4-positive plasma cells per high-power field, and an overwhelming majority of IgG4-positive cells among IgG plasma cells. No orbital or systemic involvement was found on clinical examination, imaging, and laboratory workup. The serum IgG4 level was normal (87.1 mg/dL). The patient was free of recurrence at 6-month follow-up. Conclusions Isolated conjunctival inflammation without orbital involvement can be a presentation of IgG4-RD.

We report two patients who developed a second distinct choroidal melanoma in the same eye following successful regression of their first choroidal melanoma after iodine-125 plaque brachytherapy. Neither patient demonstrated ocular melanocytosis, local tumor recurrence, or vitreous seeding. One patient had the second tumor arising from a previously documented choroidal nevus, and after undergoing enucleation, there was no detectable connection between the tumors on histopathologic examination. Germline BAP1 mutation was absent in both cases. Multifocal primary uveal melanoma is a rare entity in which the second tumor may occur either de novo or from a malignant transformation of a choroidal nevus. Known risk factors include ocular melanocytosis or germline BAP1 mutation. Additional underlying mechanisms have yet to be elucidated.

We present a rare case of adenocarcinoma of lung metastatic to the colon. A 67-year-old woman was referred for colonoscopy for new onset iron deficiency anemia and occult blood in the stool.

One of the rare but serious complications observed with deoxycholic acid administration is damage to the marginal mandibular nerve. In this study, we evaluated if deoxycholic acid directly induces histologic damage to fresh cadaveric marginal mandibular nerve. A segment of marginal mandibular nerve was harvested from 12 hemifaces of 6 fresh cadavers. The nerve specimen was exposed to either 0.9% sterile saline for 24 h, deoxycholic acid (10 mg/ml) for 20 min, or deoxycholic acid (10 mg/ml) for 24 h. The nerve specimens were then fixed in glutaraldehyde for a minimum of 24 h. Toluidine blue stained sections were evaluated for stain intensity using light microscopy and color deconvolution image analysis. Supraplatysmal fat was harvested as a positive control and exposed to the same treatments as the marginal mandibular nerve specimens, then evaluated using transmission electron microscopy. Toluidine blue staining was less in the marginal mandibular nerve exposed to deoxycholic acid when compared to saline. The specimen exposed to deoxycholic acid for 24 h showed less toluidine blue staining than that of the nerve exposed to deoxycholic acid for 20 min. Transmission electron microscopy of submental fat exposed to deoxycholic acid revealed disruption of adipocyte cell membrane integrity and loss of cellular organelles when compared to specimens only exposed to saline. Deoxycholic acid (10 mg/ml) damages the marginal mandibular nerve myelin sheath in fresh human cadaver specimens. Direct deoxycholic acid neurotoxicity may cause marginal mandibular nerve injury clinically. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Background Presentation of rectal cancer cases at a colorectal cancer multidisciplinary conference (CRC-MDC) is a required standard for the newly formed National Accreditation Program for Rectal Cancer administered by the Commission on Cancer. The aim of this study was to determine the frequency and manner in which CRC-MDC changed the management of rectal cancer patients at a tertiary academic center. Study Design All rectal cancer cases presented at a weekly CRC-MDC between July 2015 and June 2016 were prospectively included. Patient demographics and clinical information were recorded. The presenting physician completed a uniform written questionnaire outlining any changes in management as a result of the discussion. Results There were 408 rectal cancer cases included, and survey responses were obtained for 371 (91%). Thirty-nine patients (11%) had stage IV disease and 20 (5%) had locally recurrent cancer. There was a documented change in plan as a result of the CRC-MDC discussion in 97 of 371 (26%) cases surveyed. Changes in management included a change in therapy or change in therapy sequence in 76 cases, and recommendation of additional evaluation in 36 cases. Rates of management change were similar regardless of surgeon experience. Changes occurred in 23%, 28%, and 26% of cases presented by surgeons with 20 years of experience, respectively (chi-square p = 0.63). Conclusions The CRC-MDC changes clinical management for a significant portion of rectal cancer patients at a tertiary center, independent of the presenting surgeon's years of clinical experience. Our results support the CRC-MDC standard for the National Accreditation Program for Rectal Cancer.

Background and Aim Patients with Barrett's esophagus (BE) are at increased risk for esophageal adenocarcinoma (EAC) and therefore require surveillance. Biopsies are classified as indefinite for dysplasia (IND) when the significance of epithelial abnormalities is uncertain due to inflammation or sampling. Our aim was to characterize the neoplastic risk of IND in BE patients and to identify predictors of neoplastic risk. Methods Our pathology database from 1992 to 2007 was searched for BE and IND. Progression rates were calculated and univariate analysis was performed to identify predictors for neoplasia progression in BE-IND patients. Results Among 85 patients who had a follow-up (FU) biopsy within 1 year, 11 (12.9%) patients had prevalent neoplasia (seven low-grade dysplasia [LGD], two high-grade dysplasia [HGD], and two EAC). Among 82 patients who did not have prevalent neoplasia but had ≥ 1 year FU, 17 progressed to dysplasia (14 LGD, 3 HGD) and 2 developed EAC during a mean FU period of 59 months. The incidence of neoplasia (LGD, HGD, or EAC) and advanced neoplasia (HGD + EAC) was 4.5 and 1.2 cases per 100 patient-years, respectively. Longer length of BE and multi-focal IND on index biopsy were associated with progression to neoplasia. Conclusion Patients with BE-IND carry a significant risk of harboring prevalent dysplasia, but the risk of incident dysplasia is similar to the general BE population. The length of BE and the multifocal IND might tentatively help to identify a patient subpopulation at higher risk of neoplastic progression before more definitive data becomes available.

A 56-year-old woman with neurofibromatosis type 1 (NF1) presented with a left upper eyelid amelanotic nodule with adjacent eyelid margin hyperpigmentation. Physical examination additionally revealed primary acquired melanosis (PAM) on the palpebral conjunctiva of the same eyelid. Full thickness eyelid excision and conjunctival map biopsy identified desmoplastic melanoma of the eyelid in addition to invasive conjunctival melanoma and conjunctival melanoma in situ. Sentinel lymph node biopsy was negative for metastasis. She was treated with surgical excision for the eyelid melanoma and topical mitomycin C for the conjunctival melanoma. We discuss the rare entity of desmoplastic melanoma of the eyelid and its possible association with NF1.

The liver is one of the most commonly involved extrapulmonary sites in sarcoidosis. Hepatic sarcoidosis has a broad range of presentations from scattered, asymptomatic noncaseating granulomas with normal liver enzymes, which are very common in patients with known pulmonary sarcoidosis, to portal hypertension and cirrhosis, which are relatively uncommon. Diagnosis is based on a combination of clinical, laboratory and histological manifestations. The authors' protocol for management of patients with suspected sarcoidosis of the liver without focal lesions includes a transjugular liver biopsy with portal pressure measurements to confirm the diagnosis, rule out coexisting liver diseases and to identify select patients with fibrosis or portal hypertension for consideration of immunosuppression. Steroids and azathioprine are the preferred agents and methotrexate is not recommended.

The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.

Optical coherence tomography (OCT) has become pivotal in the practice of ophthalmology. Similar to other ophthalmic subspecialties, ophthalmic oncology has also incorporated OCT into practice. Anterior segment OCT (AS-OCT), ultra-high resolution OCT (UHR-OCT), spectral domain OCT (SD-OCT) and enhanced depth imaging OCT (EDI-OCT), have all been described to be helpful in the diagnosis, treatment planning and monitoring response of ocular and periocular tumours. Herein we discuss the role of OCT including the advantages and limitations of its use in the setting of common intraocular and adnexal tumours.

Appendiceal serrated polyps often morphologically resemble their colorectal counterparts and most pathologists employ colorectal diagnostic terminology when evaluating appendiceal serrated lesions. We analyzed 132 appendiceal lesions for mutations in the RAS/RAF/MAPK pathway in an attempt to (1) determine the frequency of these mutations in appendiceal serrated lesions and (2) correlate the histopathologic features with molecular alterations. The study group of appendiceal serrated lesions (n = 46) was divided into a non-dysplastic group (28/46, subclassified as 7 hyperplastic polyps and 21 sessile serrated adenoma/polyps (SSA/P) using colorectal diagnostic terminology) and dysplastic group (18/46, subclassified as 9 SSA/Ps with cytological dysplasia, 7 traditional serrated adenomas, and 2 adenomas with prominent serrations). Appendiceal non-serrated dysplastic lesions (n = 86) comprised the control group. Of the 123 lesions analyzed, KRAS mutations were identified in 64 (52%) appendiceal lesions. No significant difference in the presence of KRAS mutations were identified between serrated non-dysplastic lesions (13/25, 52%), serrated dysplastic lesions (7/14, 50%) and the control group of non-serrated dysplastic lesions (44/84, 52%) (P = 1.0). Importantly, KRAS mutations were identified in lesions that were histologically identical to colorectal hyperplastic polyps (2/6, 33%), SSA/Ps (11/19, 58%), and SSA/Ps with cytological dysplasia (4/7, 57%). Of the 126 lesions tested, BRAF V600E mutations were identified in only 5 (4%) appendiceal lesions. Our results indicate that serrated lesions of the appendix often harbor KRAS mutations rather than BRAF mutations and suggest that the serrated pathway in the appendix is likely different than in the colon and rectum.

A 66-year-old woman presented with a blind, painful, hypertensive, and proptotic left eye. Computed tomographic imaging revealed a well-circumscribed mass involving the left orbit and globe. Metastatic work-up failed to reveal extraorbital lesions and the tumor was removed in toto via an evisceration approach orbitotomy. Histopathology and immunohistochemistry were most consistent with mammary-type myofibroblastoma with fascicles of bland, uniform spindle cells that stained positive for desmin and CD34. We are not aware of previous reports of orbital or ocular myofibroblastoma. This neoplasm has not been shown to recur, undergo malignant transformation, or metastasize. Familiarity with its clinical, histopathologic, and immunohistochemical features may improve diagnostic accuracy and treatment decisions for patients presenting with similar findings.

Serous microcystic adenoma of the pancreas is an uncommon tumor in adults, and reported in pediatric patients only a handful of times. The authors present a case of a 6 month patient with incidental finding of a large cystic mass on the tail of the pancreas during an operation for Hirschsprung's disease. Final pathology was consistent with serous microcystic adenoma. This is the second case report describing this lesion in an infant, and the first time it has been associated with Hirschsprung's disease.

Moniliform blepharosis is an ocular diagnostic feature of lipoid proteinosis, a rare autosomal recessive multisystem disorder with dermatological, otorhinolaryngological, ocular and neurological manifestations. Loss of function mutations in the extracellular matrix protein 1 (ECM1) gene have been identified as the causative factor, and their identification confirms the diagnosis. Until now, 41 different mutations have been described, the majority being nonsense and small insertions. Exon 6 and 7 are the most commonly involved.Case report of an 8-year-old girl who presented with bilateral waxy papular lesions on the margins of the upper and lower lids since the age of 2 years.Biopsy of the eyelid lesions showed replacement of the sub-epidermal space by pink, PAS-positive and diastase resistant hyalinized material. Genetic testing of theECM1 gene showed a homozygous nonsense mutation c.1441C T (p.Arg481X) in exon 10, confirming the diagnosis of lipoid proteinosis.Ophthalmologists may be the first physicians to encounter patients with lipoid proteinosis. The disease presents with protean symptoms, hence a careful examination with histopathology and genetic mutation analysis confirms the diagnosis, assisting in the counseling and management of patients.

A persistent omphalomesenteric duct remnant is a rare finding, which typically presents in the pediatric population. Most commonly, it is encountered in the form of a Meckel's diverticulum. In rare instances, omphalomesenteric cysts have been reported in the pediatric population. We present a case of a symptomatic omphalomesenteric cyst in an adult male and our management of this entity.

Background & Aims Most patients, even those who have received a liver transplant, achieve a sustained virologic response (SVR) to therapy for hepatitis C virus (HCV) infection. Little is known about the histologic features of liver biopsy specimens collected after SVR, particularly in patients who have received a liver transplant. We aimed to better characterize the histologic features of allograft liver biopsy specimens from patients who achieved SVR to anti-HCV therapy after liver transplantation. Methods We performed a retrospective analysis of 170 allograft liver biopsy specimens from 36 patients who received a liver transplant for chronic HCV infection, had recurrent HCV infection after transplantation, and subsequently achieved SVR (collected from 1999 through 2015 at 4 medical centers). SVR was defined as an undetectable serum HCV RNA level 24 weeks after completion of HCV treatment. A total of 65 biopsy specimens were post-SVR (at least 1 post-SVR from each patient; some biopsy specimens were collected at later time points from a subset of patients). We performed polymerase chain reaction analysis for HCV RNA on a subset of the biopsy specimens (28 collected before SVR and 32 after SVR). Results Of the 65 post-SVR biopsy specimens, 45 (69%) had histologic features of active HCV infection. Of the initial post-SVR biopsy specimens collected from each of the 36 patients, 32 (89%) showed these changes. For patients with more than 1 post-SVR biopsy specimen, 6 (46%) had no change in fibrosis between biopsies, and fibrosis worsened for 3 patients (23%) based on their most recent biopsy. The HCV RNA level was undetectable in 31 of the 32 biopsy specimens analyzed by polymerase chain reaction. Conclusions In a retrospective analysis of allograft liver biopsy specimens from patients who achieved SVR after a liver transplant for chronic HCV infection, histologic changes associated with active HCV were present in 69% and fibrosis continued to progress in 23%, despite the lack of detection of HCV RNA. Pathologists should be aware of patients' SVR status when analyzing liver biopsy specimens to avoid diagnoses of chronic HCV-associated hepatitis. Because of the persistent inflammatory activity and fibrosis after SVR, clinicians should continue to monitor patients carefully after SVR to anti-HCV therapy.

Since first characterized in 1997, patients with hereditary mixed polyposis syndrome (HMPS) have been difficult to identify because of lack of well-established diagnostic criteria. Recently, HMPS was found to be caused by a duplication on chromosome 15 spanning the 3' end of the SCG5 gene and a region upstream of the GREM1 locus. Clinical testing for the duplication is available; however, the clinical characteristics of hereditary mixed polyposis to support testing are ill defined. The clinicopathological findings of 10 HMPS patients with confirmed germline SCG5-GREM1 duplication were reviewed. Mean age at presentation was 33.3 years. Fifty-one colonoscopies yielded 207 polyp specimens, all of which were reexamined. Adenomas (n = 80) and a fairly unique polyp composed of a mixture of hyperplastic polyp and inflammatory polyp-type changes (n = 74) were the most common findings; however, other polyps, including hyperplastic (n = 28), mixed inflammatory polyp/adenoma (n = 8), inflammatory polyp (n = 7), prolapse-type polyp (n = 6), and lymphoid aggregates (n = 4), were encountered. None of the patients developed colorectal malignancy during surveillance, demonstrated extracolonic manifestations, or underwent colectomy on follow-up (mean, 26.2 years). SCG5-GREM1 duplication-associated polyposis is characterized by a few polyps per endoscopy with a mixture of phenotypes, most commonly adenoma and nondysplastic mixed hyperplastic/inflammatory polyps. Nine of 10 patients had at least 1 mixed hyperplastic-inflammatory polyp, which is the characteristic lesion of SCG5-GREM1 duplication-associated HMPS.

Increased risk for upper tract urothelial carcinoma is described in patients with Lynch syndrome, caused by germline mutations in mismatch repair genes. We aimed to identify the frequency of mismatch repair protein loss in upper tract urothelial carcinoma and its potential for identifying an association with Lynch syndrome. We queried our database to identify upper tract urothelial carcinomas. Patients were cross-referenced for history of colorectal carcinoma or other common Lynch syndrome-associated neoplasms to enrich for potential Lynch syndrome cases. Tumor histopathologic characteristics were reviewed and each case was analyzed for loss of mismatch repair proteins, MLH1, MSH2, MSH6, and PMS2, by immunohistochemistry. Of 444 patients with upper tract urothelial carcinoma, a subset of 215 (encompassing 30 with upper tract urothelial carcinoma and another common Lynch syndrome-associated neoplasm) was analyzed for loss of mismatch repair protein expression. Of 30 patients with Lynch syndrome-associated neoplasms, six had documented Lynch syndrome, including two with Muir-Torre syndrome. Mismatch repair protein loss was identified in 7% of total upper tract urothelial carcinomas and 30% of patients with Lynch syndrome-associated neoplasms (including all patients with Lynch syndrome/Muir-Torre syndrome). Of patients without history of Lynch syndrome-associated neoplasms, 5 of 184 (2.7%) had loss of mismatch repair protein expression. Twelve cases with mismatch repair protein loss demonstrated loss of MSH2 and MSH6, and 2 had isolated loss of MSH6. MLH1 and PMS2 expression were consistently retained. Although increased intratumoral lymphocytes, inverted growth, pushing tumor-stromal interface, and lack of nuclear pleomorphism were more commonly seen in cases with mismatch repair protein loss, only intratumoral lymphocytes and presence of pushing borders were statistically significant. MLH1 and PMS2 testing appear to have little utility in upper tract urothelial carcinoma; however, mismatch repair protein loss of MSH2 and/or MSH6 by immunohistochemistry seems relatively sensitive and specific for identifying patients with potential Lynch syndrome.

SUMMARY Human epidermal growth factor receptor 2 (HER2) is overexpressed in 21% of gastric and 33% of gastroesophageal junction (GEJ) adenocarcinomas. Trastuzumab has been approved for metastatic HER2-positive gastric/GEJ cancer in combination with chemotherapy. This retrospective analysis was undertaken to better define the clinicopathologic features, treatment outcomes, and prognosis in patients with HER2-positive adenocarcinoma of the esophagus/GEJ. Pathologic specimens from 156 patients with adenocarcinoma of the esophagus/GEJ treated on clinical trials with chemoradiation and surgery were tested for HER2. Seventy-six patients also received 2 years of gefitinib. Baseline characteristics and treatment outcomes of the HER2-positive and negative patients were compared both in aggregate and separately for each of the two trials. Of 156 patients, 135 had sufficient pathologic material available for HER2 assessment. HER2 positivity was found in 23%; 28% with GEJ primaries and 15% with esophageal primaries (P= 0.10). There was no statistical difference in clinicopathologic features between HER2-positive and negative patients except HER2-negative tumors were more likely to be poorly differentiated (P < 0.001). Locoregional recurrence, distant metastatic recurrence, any recurrence, and overall survival were also statistically similar between the HER2-positive and the HER2-negative groups, in both the entire cohort and in the gefitinib-treated subset. Except for tumor differentiation, HER2-positive and negative patients with adenocarcinoma of the esophagus and GEJ do not differ in clinicopathologic characteristics and treatment outcomes. Given the demonstrated benefit of trastuzumab in HER2-positive gastric cancer and the similar incidence of HER2 overexpression in esophageal/GEJ adenocarcinoma, further evaluation of HER2-directed therapy in this disease seems indicated.

Distinguishing Barrett esophagus with high-grade dysplasia (BE-HGD) from intramucosal and submucosal adenocarcinomas on biopsies is challenging, yet important, in the choice of therapy. The current study evaluates preresection biopsies from patients who underwent esophagectomy for at least BE-HGD, to compare the recently published histologic categories by the University of Michigan (UM) and Cleveland Clinic (CC), correlate preresection and final resection diagnosis, and identify histologic features in biopsies that might be predictive of adenocarcinoma on esophagectomy. A total of 112 cases with a consensus biopsy diagnosis (agreement by ≥4 of 7 gastrointestinal pathologists) were statistically analyzed to identify histologic features that predicted adenocarcinoma on resection. Applying the UM criteria to the biopsy series showed excellent agreement with the CC system (κ=0.86) and significant correlation between preoperative and esophagectomy diagnoses (P0.001). The likelihood of finding carcinoma on resection was significantly higher with the category of HGD with marked glandular distortion cannot exclude intramucosal adenocarcinoma [CC; odd ratio (OR), 2.8; P=0.046] or HGD suspicious for adenocarcinoma (UM; OR, 4.3; P=0.008), compared to HGD alone. The presence of "never-ending" glands (OR, 3.7; P=0.008), sheet-like growth (P0.001), angulated glands (OR, 8.5; P0.001), ≥3 dilated glands with intraluminal debris (OR, 2.6; P=0.05), and1 focus of single-cell infiltration into the lamina propria (OR, 8.9; P0.001) increased the odds of finding carcinoma on resection. The latter 2 variables remained independent predictors of adenocarcinoma in multivariable analysis. In conclusion, the CC and UM systems show excellent agreement and define histologic categories that can improve prediction of adenocarcinoma on resection.

Purpose: To report a case of an amelanotic irido-ciliary ring melanoma. Design: Interventional case report. Results: A 44-year-old male was followed for asymptomatic amelanotic iris nevus of the right eye that was noted to have a localized ciliary body mass with ring extension along the trabecular meshwork. Fine needle aspiration biopsy was consistent with malignant melanoma. The patient underwent enucleation and remains disease free at 9 years of follow-up. Histopathology revealed malignant melanoma involving the iris and ciliary body with a 360-degree extension along the trabecular meshwork. The tumor was composed of a mixture of spindled and epithelioid cells with scant pigmentation. Conclusions: Amelanotic irido-ciliary ring melanoma with growth along the trabecular meshwork is a rare form of uveal melanoma that could present as an inconspicuous amelanotic iris mass.

Cetuximab and panitumumab are monoclonal antibodies used in the treatment of metastatic colorectal cancer (mCRC) by selectively targeting the epidermal growth factor receptor (EGFR) axis. Studies have shown that mutations in codons 12/13 of exon 2 of the KRAS gene render these therapies ineffective. As a result, the National Comprehensive Cancer Network and American Society of Clinical Oncology recommend KRAS mutation testing in mCRC. Appropriate testing depends on the coordinated efforts of the entire treatment team, including the pathologist, who selects the tumor sample and testing platform as well as interprets and reports results. In addition to describing rationale and methodologies for KRAS mutation testing, the authors also summarize their algorithmic approach and elaborate the potential role of newer molecular biomarkers to predict anti-EGFR resistance in wild-type KRAS tumors.