Significant Atypia Research Articles

Differentiating Intralymphatic Histiocytosis, Intravascular Histiocytosis, and Subtypes of Reactive Angioendotheliomatosis: Review of Clinical and Histologic Features of All Cases Reported to Date.

Reactive angioendotheliomatosis (REA) is a rare benign angioproliferative condition of the skin, which has been noted to occur in patients with a variety of underlying systemic diseases. Histopathologically, this condition is characterized by vascular proliferation, and endothelial cell hyperplasia within the lumina and around dermal vessels, without significant cellular atypia. Since the first case of RAE was reported in 1958, multiple histologic patterns of benign cutaneous vascular proliferations with similar clinical presentations to RAE have been described in the literature and have been proposed as subtypes of the originally described condition. Among these entities are diffuse dermal angiomatosis (DDA), acroangiodermatitis, glomeruloid angioendotheliomatosis, and angiomatosis associated with cryoproteins. It has also been proposed that another entity, characterized by the benign proliferation of histiocytes within the lumina of cutaneous vessels, is a subtype of RAE. Histiocytosis within dermal vessels, in conjunction with skin pathology, was first reported in 1994. Based on the appearance of involved vessels, it was initially believed that the histiocytic proliferations were within the lumina of capillaries. Hence, the term intravascular histiocytosis was introduced to describe this histologic finding. However, subsequent introduction of an immunohistochemical (IHC) marker specific for lymphatic vessels demonstrated that most cases of cutaneous histiocyte proliferation are intralymphatic, rather than truly intravascular. However, there have also been reports of IHC-confirmed cases of true intravascular (intracapillary) histiocytosis. In this study, clinical and histologic data from all of the cases of RAE and IHC-confirmed cases of intravascular histiocytosis and intralymphatic histiocytosis reported in the literature to date are examined. Through comparison of the frequency with which key clinical and histologic features present in cases of each group, the authors provide improved clarity of the similarities and differences between these 3 entities.

Low-Grade Cribriform Cystadenocarcinoma of the Parotid Gland

This is the case of a 44-year-old woman with a one-year history of a left pre-auricular mass. The surgical specimen is a 5 centimeter diameter tan-brown irregularly-shaped tissue whose cut surfaces are brown with cystic spaces. Microscopic sections show cystic and dilated ductal spaces lined by cells forming irregular, variably-sized secondary spaces. These spaces are arranged in a cribriform pattern that is reminiscent of breast ductal hyperplasia. (Figure 1) The ductal cells lining the spaces are small, multilayered, and generally bland. The superficial cells show apocrine-type cytoplasmic snouting. There is no significant nuclear atypia or mitotic activity noted. Necrosis is also absent. (Figure 2) Based on these features, we signed the case as a low-grade cribriform cyastadenocarcinoma (LGCCC).
 
 LGCCC is an uncommon tumor presenting primarily as cystic parotid masses in elderly females. The histologic hallmark of this tumor is its morphologic resemblance to the spectrum of breast lesions ranging from ductal hyperplasia to low-grade ductal carcinoma-in-situ.1-4
 
 Microscopic sections show an unencapsulated tumor consisting of single or multiple cysts lined by proliferated small and bland ductal cells with fine chromatin and small nucleoli. Within the cystic spaces, the cells are often arranged in a cribriform pattern with anastomosing intracystic micropapillae lining the cavity. Many superficial cells show apocrine-type secretions. Thus, the over-all appearance is quite comparable to breast lesions that are termed atypical ductal hyperplasia and low-grade ductal carcinoma-in-situ.1-4 Focal invasion into the surrounding tissue can be seen. Perineural or vascular invasion however is typically absent. Cellular pleomorphism and mitoses are also usually absent and necrosis is rare. Occasional tumors however may demonstrate a transition to an intermediate or high-grade cytology with the appearance of scattered mitoses and focal necrosis.1,2
 
 This tumor needs to be distinguished from a conventional cystadenocarcinoma. The latter is a more frankly invasive tumor with smaller duct-like structures that infiltrate into the salivary parenchyma and surrounding connective tissue. A papillary-cystic variant of acinic cell carcinoma will have areas of acinar differentiation and a greater degree of epithelial proliferation.1,5 A high-grade salivary duct carcinoma will have a high-grade cytology with more frequent necrosis, mitoses, and pleomorphism.6 Special stains that help in the differential diagnosis include Periodic Acid-Schiff (PAS) stain with Diastase digestion (diastase-resistant cytoplasmic granules in an acinic cell carcinoma), and S100 (strong diffuse positivity in LGCCC).1
 
 LGCCC is treated by complete surgical excision. Although there are only a few reported cases with follow-up, to our knowledge, none, to date, have recurred.1-4

MYC immunohistochemistry in angiosarcoma and atypical vascular lesions: practical considerations based on a single institutional experience

Angiosarcoma (AS) is an uncommon vascular malignancy with an aggressive clinical course. Radiation-associated angiosarcoma (RAAS) and Stewart-Treves syndrome are associated with MYC gene amplification and protein overexpression, while other radiation-associated vascular lesions including atypical vascular lesions (AVL) are not associated with MYC overexpression. In contrast, de novo AS represent a group of molecularly heterogeneous tumours, for which MYC expression has not been extensively examined. In this study, MYC immunohistochemistry (IHC) was performed on representative whole tissue sections of a large retrospective cohort of de novo AS, RAAS, Stewart-Treves syndrome, and AVL and evaluated using a semi-quantitative scoring method. MYC is strongly expressed in the majority of RAAS and Stewart-Treves syndrome. De novo AS demonstrate variable MYC expression, with high-grade tumours showing significantly higher MYC expression than low-grade tumours. In contrast, MYC expression in AVL is predominantly negative but may occasionally show focal staining. These results indicate that unequivocal strong MYC IHC staining supports the diagnosis of RAAS. In rare cases of RAAS without strong MYC expression, however, particularly relatively low-grade tumours for which the differential diagnosis includes AVL, the distinction between these lesions should be made on morphological grounds using previously established criteria (i.e., significant atypia, deep invasion, infiltrative growth, etc.). Increased MYC expression in high-grade de novo AS suggests that MYC overexpression may play a role in the pathogenesis of these tumours, and MYC IHC may be a prognostic and/or therapeutic biomarker in a subset of these tumours.

Case report of a choroidal ganglioneuroma

PurposeTo describe an extremely rare ganglioneuroma of the choroid.MethodsA 68 year old man was referred for longstanding retinal detachment on his right eye. There was loss of vision to <0.01 without pain or trauma. The left eye was normal. He was in normal good health. A retinal detachment with subretinal mass mid‐peripheral was detected and a metastatic disease was the most probable diagnosis. After general investigations and full body scan, no other suspicious tumors were found. After consultations the patient choose to have his eye enucleated and the eye was sent for histopathology.ResultsPathology examination revealed a broad and flat choroidal tumor consisting of mature nerves and ganglion cells. A retinal detachment with atrophy of photoreceptor layers, and large zones with hemorrhage were present. There were no signs of atypia, pleiomorphisme or malignancy remarked. The abnormal tissue stained positive with S100, neuron specific enolase, neurofilamnet and synoptophysine. Ki67 was negative.ConclusionsAn unexpected diagnosis of benign ganglioneuroma of the choroid was established. This is an extremely rare tumor an a non‐Neurofibromatosis‐1 adult man.

Heterotopic gastric mucosa in the rectum: Report of a case

Abstract Background Ectopic gastric mucosa has been described in different locations of the digestive tract, but that of the rectum is the least frequent. Clinical case The case is described of a 48 year-old woman being investigated by the gastrointestinal department due to rectal bleeding and rectal tenesmus. Colonoscopy showed a diverticular cavity 3 cm, which was reported by histology as fundic-type heterotopic gastric mucosa. Barium enema and abdominopelvic CT showed a diverticular image at level of the right posterolateral wall of the rectal ampulla. Trans-rectal diverticulectomy was performed with primary closure of the resulting mucosal defect. The surgical specimen showed areas of gastric epithelium with no signs of atypia. Conclusions It is not known whether the origin of heterotopic gastric mucosa occurs during foetal development or is the result of abnormal regeneration under inflammatory conditions. It is usually clinically asymptomatic or presents as haematochezia, especially in cases where gastric acid is being produced. In these cases there must be an initial treatment with proton pump inhibitors, although the definitive treatment is always surgical or endoscopic excision of the mucosa.

Genomic copy number analysis of a spectrum of blue nevi identifies recurrent aberrations of entire chromosomal arms in melanoma ex blue nevus

Blue nevi may display significant atypia or undergo malignant transformation. Morphologic diagnosis of this spectrum of lesions is notoriously difficult, and molecular tools are increasingly used to improve diagnostic accuracy. We studied copy number aberrations in a cohort of cellular blue nevi, atypical cellular blue nevi, and melanomas ex blue nevi using Affymetrix's OncoScan platform. Cases with sufficient DNA were analyzed for GNAQ, GNA11, and HRAS mutations. Copy number aberrations were detected in 0 of 5 (0%) cellular blue nevi, 3 of 12 (25%) atypical cellular blue nevi, and 6 of 9 (67%) melanomas ex blue nevi. None of the atypical cellular blue nevi displayed more than one aberration, whereas complex aberrations involving four or more regions were seen exclusively in melanomas ex blue nevi. Gains and losses of entire chromosomal arms were identified in four of five melanomas ex blue nevi with copy number aberrations. In particular, gains of 1q, 4p, 6p, and 8q, and losses of 1p and 4q were each found in at least two melanomas. Whole chromosome aberrations were also common, and represented the sole finding in one atypical cellular blue nevus. When seen in melanomas, however, whole chromosome aberrations were invariably accompanied by partial aberrations of other chromosomes. Three melanomas ex blue nevi harbored aberrations, which were absent or negligible in their precursor components, suggesting progression in tumor biology. Gene mutations involving GNAQ and GNA11 were each detected in two of eight melanomas ex blue nevi. In conclusion, copy number aberrations are more common and often complex in melanomas ex blue nevi compared with cellular and atypical cellular blue nevi. Identification of recurrent gains and losses of entire chromosomal arms in melanomas ex blue nevi suggests that development of new probes targeting these regions may improve detection and risk stratification of these lesions.

Genomic aberrations in spitzoid melanocytic tumours and their implications for diagnosis, prognosis and therapy

Histopathological evaluation of melanocytic tumours usually allows reliable distinction of benign melanocytic naevi from melanoma. More difficult is the histopathological classification of Spitz tumours, a heterogeneous group of tumours composed of large epithelioid or spindle-shaped melanocytes. Spitz tumours are biologically distinct from conventional melanocytic naevi and melanoma, as exemplified by their distinct patterns of genetic aberrations. Whereas common acquired naevi and melanoma often harbour BRAF mutations, NRAS mutations, or inactivation of NF1, Spitz tumours show HRAS mutations, inactivation of BAP1 (often combined with BRAF mutations), or genomic rearrangements involving the kinases ALK, ROS1, NTRK1, BRAF, RET, and MET. In Spitz naevi, which lack significant histological atypia, all of these mitogenic driver aberrations trigger rapid cell proliferation, but after an initial growth phase, various tumour suppressive mechanisms stably block further growth. In some tumours, additional genomic aberrations may abrogate various tumour suppressive mechanisms, such as cell-cycle arrest, telomere shortening, or DNA damage response. The melanocytes then start to grow in a less organised fashion and may spread to regional lymph nodes, and are termed atypical Spitz tumours. Upon acquisition of even more aberrations, which often activate additional oncogenic pathways or alter cell differentiation, the neoplastic cells become entirely malignant and may colonise and take over distant organs (spitzoid melanoma). The sequential acquisition of genomic aberrations suggests that Spitz tumours represent a continuous biological spectrum, rather than a dichotomy of benign versus malignant, and that tumours with ambiguous histological features (atypical Spitz tumours) might be best classified as low-grade melanocytic tumours. The number of genetic aberrations usually correlates with the degree of histological atypia and explains why existing ancillary genetic techniques, such as array comparative genomic hybridisation (CGH) or fluorescence in situ hybridisation (FISH), are usually capable of accurately classifying histologically benign and malignant Spitz tumours, but are not very helpful in the diagnosis of ambiguous melanocytic lesions. Nevertheless, we expect that progress in our understanding of tumour progression will refine the classification of spitzoid melanocytic tumours in the near future. By integrating clinical, pathological, and genetic criteria, distinct tumour subsets will be defined within the heterogeneous group of Spitz tumours, which will eventually lead to improvements in diagnosis, prognosis and therapy.

Metastasizing Ameloblastoma

A 27-year-old man presented with an 8 cm diameter left maxillary mass and an enlarged cervical lymph node at levels II to III. There was a reported history of a previous unspecified operation on the maxillary mass which had yielded a diagnosis of ameloblastoma. Total maxillectomy with modified radical neck dissection was subsequently performed.
 Microscopic examination of the maxillary mass shows epithelial islands and cords in a fibro-collagenous stroma. (Figure 1) The islands and cords are lined in the periphery by palisaded columnar cells with regular ovoid nuclei exhibiting reverse polarization. The nuclei are uniform with dispersed chromatin and no significant atypia. Towards the center of these islands are loosely arranged spindly to stellate cells (“stellate reticulum”). (Figure 2) Microscopic examination of the largest submitted lymph node shows an epithelial neoplasm with identical histologic features as the maxillary mass and a residual rim of lymphoid tissue at the periphery enclosed by the nodal capsule. (Figure 3) Similarly, there is neither atypia nor pleomorphism and only a few typical mitotic figures are seen in the nodal tumor. (Figure 4) These features support the diagnosis of a metastasizing ameloblastoma (MA).
 
 Metastasizing ameloblastoma is rare with only about 70 reported cases.1-5 Both the gnathic primary tumor and the metastatic foci have typical morphologies of a benign ameloblastoma with bland nuclei and absent to rare mitosis.6,7 There are no morphologic criteria that can predict this metastatic behavior. Thus, this diagnosis can only be made in retrospect upon the appearance of metastasis in a gnathic tumor that would otherwise have been diagnosed as a usual benign ameloblastoma.1-7 Suggested risk factors include rapid tumor growth, large primary tumor, delay in treatment, mandibular site, prior radiotherapy and chemotherapy.4,5 However, what is most consistent in the literature is the history of multiple recurrences and multiple surgical interventions.1,4,5
 
 The differential diagnosis is an ameloblastic carcinoma (AC). Both MA and AC are considered as the malignant counterparts of ameloblastoma.7 However AC is characterized by the presence of the usual cytologic features of a malignant neoplasm, such as nuclear pleomorphism, hyperchromasia and brisk mitotic activilty – features that are lacking in MA.6,7
 
 The literature on metastasizing ameloblastoma lists the lungs (70 to 88% of cases) and the cervical lymph nodes (15-37.8% of cases) as the most common sites of metastasis.1-5 Increased Ki-67 labeling and CD10 immunoreactivity have been reported to have significant correlation with recurrence.8,9 Whether these observations also apply to the risk of metastasis is not known due to the rarity of cases and hence the small subject populations of these studies. 
 
 As the risk of metastasis cannot be predicted by morphology, long-term follow-up appears prudent in all cases of ameloblastoma, especially if characterized by recurrences and prior surgical interventions.

Converting fluid-based cytologic specimens to histologic specimens for immunohistochemistry.

Cavitary effusions are often evaluated cytologically to determine if there is an underlying neoplastic cause. Differentiation of neoplastic epithelial from mesothelial populations within effusions can be difficult using routine cytology. In addition, cytology alone cannot provide information on the immunophenotype of round cell populations. Gel foam techniques can be used to convert effusions into cell blocks for immunohistochemical (IHC) staining which can then be used to differentiate mesothelial from epithelial cell populations, and also allow immunophenotyping of round cell populations within effusions. The aim of this study was to evaluate a gel foam cell block technique for converting potential neoplastic cells in cavitary effusions into cell blocks to characterize these further by IHC. Thirteen canine and 7 feline samples with cohesive cell populations were evaluated using gel foam cell blocks and IHC. Samples evaluated by routine cytology were categorized as (1) epithelial cells, (2) cohesive cell population without cytologic distinction between mesothelial and epithelial cells, and (3) mesothelial cells with signs of atypia. Antibody-mediated staining of vimentin and cytokeratin of the effusion cell blocks yielded further classification of cohesive cell populations. In addition, a total of 4 effusions with malignant round cells were evaluated; they were immunophenotyped as either B- or T-cell lymphoma. The use of cytokeratin and vimentin IHC on gel foam cell blocks from cavitary effusions provided robust staining and allowed characterization of cohesive cells as mesothelial or epithelial and immunophenotyping of lymphoid cell populations. In addition, this method is cost and time effective.

TdT+ T-Lymphoblastic Proliferation in Castleman Disease.

TdT+ T-Lymphoblastic Proliferation in Castleman Disease.

Fluorescence In Situ Hybridization for MDM2 Amplification as a Routine Ancillary Diagnostic Tool for Suspected Well-Differentiated and Dedifferentiated Liposarcomas: Experience at a Tertiary Center.

Background. The assessment of MDM2 gene amplification by fluorescence in situ hybridization (FISH) has become a routine ancillary tool for diagnosing atypical lipomatous tumor (ALT)/well-differentiated liposarcoma and dedifferentiated liposarcoma (WDL/DDL) in specialist sarcoma units. We describe our experience of its utility at our tertiary institute. Methods. All routine histology samples in which MDM2 amplification was assessed with FISH over a 2-year period were included, and FISH results were correlated with clinical and histologic findings. Results. 365 samples from 347 patients had FISH for MDM2 gene amplification. 170 were positive (i.e., showed MDM2 gene amplification), 192 were negative, and 3 were technically unsatisfactory. There were 122 histologically benign cases showing a histology:FISH concordance rate of 92.6%, 142 WDL/DDL (concordance 96.5%), and 34 cases histologically equivocal for WDL (concordance 50%). Of 64 spindle cell/pleomorphic neoplasms (in which DDL was a differential diagnosis), 21.9% showed MDM2 amplification. Of the cases with discrepant histology and FISH, all but 3 had diagnoses amended following FISH results. For discrepancies of benign histology but positive FISH, lesions were on average larger, more frequently in “classical” (intra-abdominal or inguinal) sites for WDL/DDL and more frequently core biopsies. Discrepancies of malignant histology but negative FISH were smaller, less frequently in “classical” sites but again more frequently core biopsies. Conclusions. FISH has a high correlation rate with histology for cases with firm histologic diagnoses of lipoma or WDL/DDL. It is a useful ancillary diagnostic tool in histologically equivocal cases, particularly in WDL lacking significant histologic atypia or DDL without corresponding WDL component, especially in larger tumors, those from intra-abdominal or inguinal sites or core biopsies. There is a significant group of well-differentiated adipocytic neoplasms which are difficult to diagnose on morphology alone, in which FISH for MDM2 amplification is diagnostically contributory.

Atypical umbilical naevi: histopathological analysis of 20 cases.

Melanocytic naevi on the umbilicus have been described as a form of flexural naevi, with the most common feature being a 'nested and dyshesive pattern'. We have encountered a distinct group of umbilical naevi with more significant atypia and prominent fibrosis, not reported previously. This study aimed to characterize these naevi more clearly. Eighty-one umbilical naevi from 2000 to 2013 were reviewed retrospectively, 20 cases of which showed lamellar fibrosis and atypia and were designated as atypical umbilical naevi (AUN). Lamellar fibrosis in AUN was extensive and frequently entrapped dermal melanocytes, resulting in low-grade cytological atypia (74% of cases) and impaired maturation (47%) of the dermal component. Other common features included bridging (95%), shoulder architecture (94%), lentiginous growth (85%) and high-grade junctional cytological atypia (85%). 'Nested and dyshesive pattern' was observed in only 20% of AUN. Ki-67 immunostaining performed on 12 AUN revealed a consistently low proliferation index of <1%. All AUN in this series lacked junctional confluence, florid pagetoid spread and dermal mitoses. A subset of special site naevi in the umbilical region demonstrate characteristic lamellar fibrosis, architectural disorder and cytological atypia. Familiarity with these site-related atypical features would avoid overdiagnosis of melanoma.

Cholesterol-conjugated let-7a mimics: antitumor efficacy on hepatocellular carcinoma in vitro and in a preclinical orthotopic xenograft model of systemic therapy.

BackgroundA major challenge to the clinical utility of let-7 for hepatocellular carcinoma (HCC) therapy is the lack of an effective carrier to target tumours. We confirmed the high transfection efficiency of cholesterol-conjugated let-7a miRNA mimics (Chol-let-7a) in human HCC cells, as well as their high affinity for liver tissue in nude mice. However, their antitumor efficacy via systemic delivery remains unknown.MethodsWe explored the effects of Chol-let-7a on HCC in vitro and in vivo. Cell viability and mobility, let-7a abundance and the target ras genes was measured. Live-cell image and cell ultrastructure was observed. Antitumor efficacy in vivo was analyzed by ultrasonography, hispatholgogy and transmission electronic microscopy in a preclinical model of HCC orthotopic xenografts with systemic therapy.ResultsChol-let-7a inhibited the viability and mobility of HCC cells. Chol-let-7a was primarily observed in the cytoplasm and induced organelle changes, including autophagy. Mild changes were observed in the cells treated with negative control miRNA. Chol-let-7a reached HCC orthotopic tumours, significantly inhibited tumour growth, and prevented local invasion and metastasis. Compared to control tumours, Chol-let-7a-treated tumours showed more necrosis. Tumour cells showed no significant atypia, and mitoses were very rare after systemic Chol-let-7a therapy. Furthermore, let-7a abundance in orthotopic xenografts was coincident with a reduction in the expression of 3 human ras mRNAs and RAS proteins.ConclusionsChol-let-7a exerted significant antitumor effects by down-regulating all human ras genes at the transcriptional and translational levels. Chol-let-7a inhibited cell proliferation, growth, and metastasis, and mainly functioned in the cytoplasm. Chol-let-7a represents a potential useful modified molecule for systemic HCC therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-889) contains supplementary material, which is available to authorized users.

Mixed tumor of the soft tissue (arm)

Mixed tumor of soft tissue is extremely rare; only 15 cases have been reported in English literature. A 56-year-old man presented with a tumor in right arm. Physical examination showed a tumor measuring 3×3×3cm of deep portion of right arm. MRI showed a well-defined deep tumor measuring 3×3×4cm of arm next to fascia. The tumor was resected, and it was found that the tumor is located in deep subcutaneous tissue outside the fascia. Histologically, the tumor was well-defined and contained a fibrous capsule. The tumor cells showed no significant nuclear atypia. The tumor was composed of epithelial, myoepithelial, and stromal elements. The epithelial element formed tubules, and myoepithelial element showed solid nests and periepithelial linings. The epithelial element showed frequent apocrine features including apocrine snouts. The stromal element was composed of cartilage and myxoid tissues. Immunohistochemically, the epithelial element was positive for cytokeratin (CK) AE1/3, CK CAM5.2, CK34BE12, CK7, CK8, CK18, CK19, EMA, CEA, CD56, p53, and Ki-67 (labeling=80%), but negative for CK5/6, CK14, CK20, vimentin, p63, S100 protein, CD10, CD34, ASMA, CD68, myoglobin, bcl-2, BMP-2, TGF-β1, CDK-4, and MDM2. The myoepithelial element was positive for CK AE1/3, CK CAM5.2, CK34BE12, CK5/6, CK7, CK8, CK14, CK18, p63, vimentin, CD10, S100 protein, bcl-2, p53, and Ki-67 (labeling=20%), but negative for CK19, CK20, EMA, CEA, CD34, ASMA, CD68, CD56, myoglobin, BMP-2, TGF-β1, CDK-4 and MDM2. The stromal element was positive for vimentin, S100 protein (cartilage), and Ki-67 (labeling=6%), but negative for other antigens examined including bcl-2, BMP-2, TGF-β1, CDK-4 and MDM2. No findings of metastasis, invasion, and recurrence were recognized clinically. The author speculates that the current mixed tumor was derived from misplaced apocrine glands in the deep soft tissue.

Real Time Histologic Assessment of Dysplasia in IBD Patients Using Probe-Based Confocal Endomicroscopy

Introduction: The endoscopic exam is an important tool in the management of patients with Crohn’s disease and ulcerative colitis. Assessment of mucosal healing and surveillance of precancerous lesions are measures of quality care in patients with IBD. Assessment of precancerous lesions is rather tedious and relies on a random process with low yield. pCLE (probe based confocal endomicroscopy) is a new imaging technology providing real time assessment of histological features that can help focus the random process of tissue biopsy and increase the surface of microscopic examination. Methods: We performed a retrospective analysis of 74 patients with IBD that underwent colonoscopy with pCLE for cancer surveillance and/or disease activity monitoring. Prior to the pCLE exam a 5 ml bolus of 10% fluorescein was administered. All visibly abnormal areas, as well as other newly identified areas in the terminal ileum and each colonic segment were imaged and biopsied by pCLE. Biopsy from pCLE were compared to matching histology from H/E slides. The following criteria were considered: gland symmetry, density, and shape, density of goblet cells, amount of lamina propria cellular infiltrate, overall inflammatory process, and dysplasia vs. inflammation related atypia. In addition, the mucosal blood flow was characterized in terms of vessel density, tortuosity, and flow abnormalities. Extravasations of fluorescein (fluorescein leak) was assessed by pCLE only and used to define the intensity of the inflammatory process. Results: We noted an excellent correlation between standard histologic assessment and real time microscopic assessment of mucosal inflammation and dysplasia. The k agreement for individual descriptors of gland architecture, acute and chronic inflammation and dysplasia was greater than 0.77. pCLE correctly identified all dysplastic lesions and accurately differentiated benign from dysplastic polyps. In the presence of significant inflammation and reactive atypia, pCLE upstaged some of the lesions. A new histologic entity with malignant potential - diffuse segmental serrated transformation of endoscopically normal colonic mucosa was identified by pCLE. NPV of pCLE for dysplastic lesions was 100% and accuracy was 96%. Conclusion: pCLE had excellent performance as a screening tool for dysplasia in conjunction with standard biopsies. False positive results are inherent to the fixed depth of laser and limitations in characterizing nuclear atypia. Given the high NPV and the advantage of probing significantly more areas than standard biopsy protocols, pCLE is expected to increase the diagnostic yield. Incorporating pCLE in routine colorectal cancer screen of IBD patients will likely increase detection rate of dysplastic lesions and improve quality of care. Disclosure - Dr Arsenescu - Abbvie - speaker bureau. Dr Arsenescu - UCB- speaker bureau. Dr Arsenescu - Mauna Kea - speaker bureau.

Clinicopathological and immunohistochemical study of 30 cases of post-radiation atypical vascular lesion of the breast

Atypical vascular lesions (AVL) that occur in the field of prior radiation therapy for breast carcinoma are placed within the differential diagnosis with low grade angiosarcoma and other benign vascular lesions. Although considered a benign entity, the exact biological behavior of AVLs is not fully established because of the small number of cases reported in the literature. We aim to further characterize these lesions clinically and histopathologically, and to study their behavior. We report a series of 30 patients with AVL of the breast occurring after radiation exposure, diagnosed and treated at the European Institute of Oncology, Italy. Immunohistochemical study was performed in all cases, using CD31, D2-40, CD105, and Ki-67 antibodies. Twenty-seven patients were treated with standard doses of conventional adjuvant radiation therapy for the prior breast carcinoma. Three patients were treated with intraoperative radiotherapy with electrons. The post-radiation latency interval from breast carcinoma to AVL was 48.5 months (ranged from 1 to 146 months). Most of the lesions were classified as lymphatic type (78.6 %) based on D2-40 positivity. No extension into subcutaneous tissue or significant atypia was noted in all cases. Despite the fact that the AVL of our series have shown benign behavior in 93.3 %, one patient developed local recurrence of AVL, and two cases progressed to angiosarcoma at the previous AVL site. Further studies should be conducted to better understand the clinical behavior and to propose additional histopathologic diagnostic criteria to distinguish AVL from low grade angiosarcoma and those AVL with increased risk for malignant progression. Concerning current treatments of AVL, we recommend complete excision with free surgical margins and close follow up.

Adult pancreatic hemangioma: A case report.

Vascular neoplasms of the pancreas are extremely rare and usually manifest as symptomatic, cystic lesions. This study presents a case that includes the clinicopathologic information used to discriminate pancreatic hemangioma from other types of cystic lesion of the pancreas. A 40-year-old female visited hospital with a chief complaint of abdominal pain. The serum CEA and CA19-9 levels of the patient were within the normal limits. An abdominal computed tomography scan and magnetic resonance imaging showed a 100-mm mass lesion in the body and tail of the pancreas, and the tumor extended toward the retroperitoneum and surrounded the splenic vein. The lesion was subsequently resected. Macroscopically, it was a multiloculated cyst with intracystic hemorrhage. Microscopically, the lesion was composed of numerous, heterogeneous cysts lined by a flattened single layer of cells without significant atypia. Notably, numerous neoplastic vessels extended into the interlobular septa of the pancreas and surrounded the main pancreatic duct. Immunohistochemical analysis showed that the lining cells expressed CD31 and CD34. The lesion was diagnosed as adult pancreatic hemangioma. Surgical treatment may be required when a direct contact between the lesion and the pancreatic tissue is demonstrated using imaging.

Sclerosing Sertoli Cell Tumor of the Testis

Sclerosing Sertoli cell tumor (SSCT) of the testis is rare, with only 22 previously reported cases. Most have been small, circumscribed masses, and none has had a malignant clinical course; however, follow-up is limited. We have examined 20 new SSCTs to better characterize their features and report long-term follow-up. At least focal tubule formation by sex cord cells in a dense, hypocellular fibrous stroma occupying at least 50% of the lesion was required. The patient age ranged from 23 to 52 years (mean, 37; median, 39). All SSCTs were unilateral with 11 left sided and 9 right sided. The average size was 1.7 cm (range, 0.5 to 6 cm). In most cases, the stroma represented 50% to 70% of the mass but was at least 80% in 2. The Sertoli cells formed cords, trabeculae, small nests, focal tubules (sometimes with a vague pseudovascular or retiform appearance), and rarely single cells. Most tumor cells had small, round, oval to polygonal nuclei with finely granular chromatin, small nucleoli, and modest amounts of pale, eosinophilic cytoplasm. No mitotic figures, significant atypia, or necrosis was seen. All tumors but 1 were circumscribed and lacked lymphovascular invasion. Follow-up in 15 patients (3 mo to 16 y; mean, 6.1 y) showed 9 alive and free of disease, 5 alive with unknown disease status, and 1 patient, who presented with bone metastases, dead of disease at 27 months. The only features in the malignant case that differed from all others in our study were lymphovascular invasion and lack of circumscription. Combining our cases with previously reported ones shows that SSCTs are unilateral, usually small (80% <2 cm) tumors that occur in a wide age range (18 to 80 y old; mean, 35 y) and lack necrosis. Only 1 of 31 with follow-up (mean, 4.4 y) metastasized; this tumor was 3.8 cm and had lymphovascular invasion and invasive growth. We conclude that SSCTs<2 cm with the typical features and lacking those associated with malignancy in Sertoli cell tumors, not otherwise specified, have a negligible risk of metastasis and are adequately managed by orchiectomy alone.

Renal tubular epithelial clusters in voided urine: a potential diagnostic pitfall in renal transplant patients

Urine cytology is often used to screen for polyomavirus in renal transplant patients. There are qualitative cytologic differences between urine from transplant and nontransplant patients, particularly the presence of epithelial cell clusters, that can pose diagnostic difficulty. Voided urine cytology specimens from 100 renal transplant patients and 100 nontransplant patients were reviewed for cell clusters. Immunocytochemistry for renal cell carcinoma marker (RCC) and cytokeratin 7 was performed on 10 recent specimens. Clinical data was reviewed with a focus on evidence of graft dysfunction or malignancy. Eighteen patients (18%) in the renal transplant group and no nontransplanted patients (0%) exhibited cell clusters with characteristic morphology: 3-dimensional cohesive groups; high nucleus-to-cytoplasm ratio; round, eccentrically placed nuclei with a prominent central nucleolus; and granular or vacuolated cytoplasm. Some had significant nuclear atypia. The groups were RCC-positive in 8 of 10 cases, and cytokeratin 7-positive in 6 of 10 cases, which is consistent with renal tubular epithelial clusters (RTECs). Clinical follow-up revealed that 88% (15 of 17) of those with RTECs developed graft dysfunction in a median of 65 days, compared with 6% (4 of 64) without RTECs (sensitivity 79%, specificity 97%, positive predictive value 88%, negative predictive value 94%). No patient developed a urinary tract malignancy. RTECs are relatively common in urine cytology from transplant patients, but are rare in other urine specimens. Recognition is important as they can be mistaken for urothelial carcinoma or adenocarcinoma. There appears to be a strong association with later development of graft dysfunction. These cells are most likely evidence of renal tubular injury secondary to a variety of factors, including rejection.

Diagnostic Findings and Treatment in a 51-Year-Old Woman With Oncogenic Osteomalacia

A 51-year-old woman presented with recurrent insufficiency fractures of the right midfoot, the left femoral condyle, and the ribs. Furthermore, she complained of unspecific muscle and joint tenderness as well as lower back pain that had evolved over the past few years. Initial laboratory testingrevealedhypophosphatemiaand elevated alkaline phosphatase levels; vitamin D and PTH were within normal limits. Subsequent analyses showed elevated levels for fibroblast growth factor 23 (FGF-23) and urinary phosphorus loss at the upper normal limit. Differential diagnoses included congenital forms of hypophosphatemicricketsandrenalphosphatewasting,aswellas (especially in a previously asymptomatic patient) oncogenic osteomalacia due to a phosphaturic mesenchymal tumor. Although bone scintigraphy performed to localize an osseous tumor was negative, whole-body positron emission tomography (PET)/computed tomography (CT) using the radiolabeled somatostatin analog [Ga]DOTATATE revealed a suspicious lesion measuring approximately 20 mm in diameter within the right gluteal region (Figure 1, A–C). Magnetic resonance imaging (MRI) for further surgical planning confirmed the PET finding (Figure 1D) and illustrated markedly increased tumor blood supply (Figure 1E). The patient underwent surgery. Macroscopy showed a sharply demarcated gray tumor without necrosis. Upon histologicalexamination, thetumorwasofmediumcelldensitywith a rich capillary supply and a characteristic deposition of a homogenous eosinophilic substance between the evenly spaced tumor cells (Figure 1, F and G). No signs of atypia, mitosis, or necrosiscouldbeobserved, thus leadingtothefinaldiagnosisof aphosphaturicmesenchymal tumorofmixedconnective tissue type (PMTMCT) (1). Postoperatively, musculoskeletal pain and tenderness relieved and biochemical parameters of disease burden (FGF-23, serum phosphorous) recovered subsequently (Figure 2). Oncogenic osteomalacia (synonym, tumor-induced osteomalacia, or TIO) is a rare cause of hypophosphatemic rickets. Main symptoms include musculoskeletal tenderness, recurrent bone marrow edema, or insufficiency fractures associated with severe hypophosphatemia, hyperphosphaturia, elevated levels of FGF-23, and typically alkaline phosphatase (2, 3). In most cases, hyperphosphaturia is caused by a benign mesenchymal tumor with unregulated secretion of phosphaturic factors/phosphatonins such as FGF-23 and secreted frizzled-related protein 4 (1, 2, 4). However, some reports indicate that this syndrome (as a paraneoplastic condition) is underdiagnosed in malignant tumors, eg, prostate, colon, and small-cell lung cancer (3). Surgical removalof the tumor is thecausative treatment that will stop phosphaturia and normalize bone metabolism (2, 4). Because these tumors may be very small and indolent and occur at unusual anatomic sites, they are generally difficult to localize. Typical manifestations include the long bones (55% of cases) and the soft tissues (45%, including the skin)—with most lesions localized in the lower limbs (ie, femur and tibia) (5). Conventional x-ray, MRI, and CT scans are usually not sufficient for tumor identification and localization. Because these tumors typically express somatostatin receptors, functional imaging with radiolabeled somatosta-