Fibrous Extracellular Spheroids in an Endoscopic Ultrasound-Guided Pancreatic Fine Needle Aspiration Correlating to a Gyriform Pancreatic Endocrine Tumor with a Unique Cobblestone Pavement Growth Pattern.

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.

Case Report: Primary Orbital Squamous Cell Carcinoma.

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.

Deoxycholic Acid and the Marginal Mandibular Nerve: A Cadaver Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. NO LEVEL ASSIGNED: 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 .

Isolated Conjunctival Inflammation as a Manifestation of IgG4-Related Disease.

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.

Microanatomical Location of Hyaluronic Acid Gel Following Injection of the Upper Lip Vermillion Border: Comparison of Needle and Microcannula Injection Technique.

PURPOSE: To compare needle and microcannula injection techniques in regards to the microanatomical location of hyaluronic acid (HA) gel injected in the upper lip vermillion border of cadaver specimens. METHODS: The upper lip vermillion border was injected transcutaneously with HA 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 2-cm region of each lip was excised lateral to a point 1-cm lateral to the philtrum. Specimens were fixed in 95% alcohol, embedded in paraffin, and stained with hematoxylin-eosin for histologic examination. RESULTS: Most HA injected with either a needle or a microcannula was located within the orbicularis oris muscle, and the remaining HA resided within the subcutaneous fat. In 3/4 right (microcannula) hemifaces, 100% of the HA was located within the muscle. Only 2/4 left (needle) hemifaces had at least 95% of the HA 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: Most HA 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 with needle injection.

Colorectal carcinomas with submucosal invasion (pT1): analysis of histopathological and molecular factors predicting lymph node metastasis.

Submucosally invasive colorectal carcinoma (pT1) has the potential to be cured by local excision. In US surgical intervention is reserved for tumors with high-grade morphology, lymphvascular invasion, and close/positive margin. In other countries, particularly Japan, surgical therapy is also recommended for mucinous tumors, tumors with >1000 µm of submucosal invasion, and those with high tumor budding. These histological features have not been well evaluated in a western cohort of pT1 carcinomas. In a cohort of 116 surgically resected pT1 colorectal carcinomas, high tumor budding (P<0.001), lymphatic invasion (P=0.003), depth of submucosal invasion >1000 µm (P=0.04), and high-grade morphology (P=0.04) were significantly associated with lymph node metastasis on univariate analysis. Mucinous differentiation, tumor location, tumor growth pattern, and size of invasive component were not significant. On multivariate analysis, only high tumor budding was associated with lymph node metastasis with an odds ratio of 4.3 (P=0.004). A subset of 48 tumors (22 node-positive and 26 node-negative) was analyzed for mutations in 50 oncogenes and tumor suppressors. No statistically significant molecular alterations in these 50 genes were associated with lymph node status. However, lymphatic invasion was associated with BRAF mutations (P=0.01). Furthermore, high tumor budding was associated with mutations in TP53 (P=0.03) and inversely associated with mutations in the mTOR pathway (PIK3CA and AKT, P=0.02). In conclusion, this study demonstrates the importance of identifying high tumor budding in pT1 carcinomas when considering additional surgical resection. Molecular alterations associated with adverse histological features are identified.

Amyloid Pseudo-Dacryolith and Nasolacrimal Obstruction in a 67-Year-Old Male.

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.

Cat Scratch Disease: Expanded Spectrum.

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.

Amelanotic Irido-Ciliary Ring Melanoma: A Clinicopathological Correlation.

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.

Serrated Polyps and Serrated Polyposis Syndrome.

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.

Microanatomical Location of Hyaluronic Acid Gel Following Injection of the Temporal Hollows.

PURPOSE: To examine the microanatomical location of hyaluronic acid gel injected within the temporal hollows of cadaver specimens. METHODS: The temporal hollows were injected subcutaneously with hyaluronic acid gel in 6 fresh frozen human cadaver hemifaces. Temporal soft tissues were dissected to a preperiosteal plane and fixated in 95% alcohol. A soft tissue section extending from skin to temporal bone was obtained for each specimen. Histologic examination was performed using hematoxylin and eosin stain. RESULTS: In 5 of 6 specimens, at least 95% of the hyaluronic acid was located within the subcutaneous fat. In 1 of 6 specimens, approximately 35% of the material was located within the subcutaneous fat and 60% was located within the superficial temporal fascia. Two specimens had 5% located within the temporalis muscle. In 1 specimen, hyaluronic acid was found to encompass a superficial muscular artery within the superficial temporal fascia. CONCLUSIONS: This study elucidates the location of hyaluronic acid gel after subcutaneous injection within the temporal hollow. Histology confirmed consistent placement of the gel within the subcutaneous tissues, but it also showed that injection in this region may produce unintended deeper location of filler, and a significant perivascular collection of the material. The proximity of dense temporal fascial and muscle arterial networks in this region may pose risk for perivascular injection and associated complications.

Abrupt loss of MLH1 and PMS2 expression in endometrial carcinoma: molecular and morphologic analysis of 6 cases.

Given that endometrial cancer (EC) is often the sentinel cancer for female Lynch syndrome patients, we have successfully implemented universal screening of ECs and have previously shown that this is the preferred method to identify these patients. However, during the course of universal screening of EC, we encountered 6 cases with an unusual pattern of mismatch-repair protein immunohistochemistry that has not been previously described in this setting. In these 6 cases, there was an abrupt loss of MLH1 and PMS2 expression in a portion of the tumor. In 3 cases, marked histologic differences were identified between the areas of the tumor with retained expression and areas with loss of expression. In 2 cases, the areas with loss of expression were of higher grade (1 demonstrated solid growth and the other demonstrated increased nuclear atypia with diffuse p53 expression). In 4 tumors, histologic features associated with microsatellite instability (MSI) were present, including increased intraepithelial lymphocytes. The areas with loss of and retained MLH1/PMS2 expression were separately microdissected and assessed for MSI and MLH1 promoter methylation. The areas with loss of MLH1 and PMS2 more commonly demonstrated MSI compared with the areas with intact expression (83% vs. 33%). MLH1 promoter methylation analysis demonstrated heterogenous hypermethylation, as all areas with loss of MLH1/PMS2 expression had more extensive methylation of MLH1 compared with those areas with retained expression. In summary, we describe the histologic and molecular features of 6 cases of EC with abrupt loss of MLH1 and PMS2 expression and demonstrate that heterogenous methylation of the MLH1 promoter results in this distinct and unusual pattern of immunohistochemical expression.

Regional Variations in Orbicularis Oculi Histology.

PURPOSE: To investigate and compare the histologic compositions of the pretarsal, preseptal, and orbital orbicularis oculi muscle (OOM) using nonpreserved, fresh-frozen, human cadavers. METHODS: The OOM was exposed using sharp and blunt dissection. A metric ruler was used to measure and mark 0.5 cm × 1 cm samples from each portion of the right, superior OOM. Samples were excised, fixed in formalin, and completely embedded in paraffin. Five-micrometer-thick, hematoxylin- and eosin-stained sections were generated for each sample and analyzed by an anatomical pathologist. The relative percentages of the 4 main tissue types (skeletal muscle, fibrous tissue, adipose tissue, and neurovascular tissue) were quantified. RESULTS: Forty-two samples were obtained from 14 Caucasian cadavers. On average, the pretarsal samples were composed of 83.5% skeletal muscle, 0.0% adipose, 5.0% neurovascular, and 11.5% fibrous tissue. Average preseptal OOM was 46.5% skeletal muscle, 12.7% adipose, 9.2% neurovascular, and 31.5% fibrous tissue. The orbital OOM was, on average, 42.7% skeletal muscle, 32.7% adipose tissue, 6.9% neurovascular, and 17.7% fibrous tissue. CONCLUSIONS: The OOM represents a histologically heterogeneous structure.

Isolated Conjunctival Inflammation Suggestive of IgG4-Related Disease.

PURPOSE: In this interventional case report, we present the correlation between an isolated conjunctival inflammatory lesion and IgG4-related disease. RESULTS: A 29-year-old female presented with a solitary conjunctival mass of the right eye. The rest of the ocular examination including orbital assessment was negative. Excisional biopsy was suggestive of IgG4-related disease. The patient was treated with oral steroids and remained disease free at 18 months of follow-up. CONCLUSIONS: Isolated conjunctival inflammation without orbital involvement can be considered within the spectrum of IgG4-related disease.

Risk for esophageal neoplasia in Barrett's esophagus patients with mucosal changes indefinite for dysplasia.

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.

Anatomy and histology of the frontalis muscle.

PURPOSE: To determine the gross and histologic configurations of the medial and lateral frontalis muscle. METHODS: After making a midcoronal incision and bluntly dissecting to the orbital rim, the frontalis muscle was marked and measured. A protractor was used to measure the frontalis-orbicularis angle (FOA) and, when present, the angle of central bifurcation (AOB). Three strips of full-thickness forehead soft tissue measuring 0.5 cm × 8 cm were excised 3, 4.5, and 6 cm above the supraorbital notch and analyzed histologically for the presence of skeletal muscle fibers. Data were analyzed using 2-sample t tests, paired t tests, Pearson correlations, and mixed effect models. A p value of ≤ 0.05 was considered statistically significant. RESULTS: Sixty-four hemifaces of 32 cadavers (16 males) were dissected. All specimens were Caucasian. The average age was 78.2 years (range, 56-102 years). The average FOA was 88.7° (13.0°), and the average AOB was 90.0° (26.4°). A visible midline bifurcation occurred in 28 of 32 subjects (88%) at an average height of 4.7 cm (range, 2.4-7.2 cm) superior to the supraorbital notch. Continuous skeletal muscle fibers were present within the midline bifurcation histologically in 89%, 75%, and 11% of specimens 3.5, 5.0, and 6.5 cm above the supraorbital notch, respectively. In 46% of individuals, skeletal muscle fibers were continuously present microscopically within the gross bifurcation. CONCLUSION: While a medial frontalis muscle bifurcation occurs grossly in most senescent Caucasians, muscle fibers exist microscopically within this zone in nearly half of individuals.

Desmoplastic melanoma of the eyelid and conjunctival melanoma in neurofibromatosis type 1: a clinical pathological correlation.

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.