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Objective: Human colorectal cancer (CRC) is characterized by a sequence of biological events that determine its induction and progression. Gut microbiota has an important role in this multistep model of carcinogenesis, as well as constitutive activation of Signal Transducer and Activator Factors 3 (p-STAT3) and Protein Inhibitor of Activated STAT3 (PIAS3), which negatively controls STAT3. It has been reported that a liver growth factor, the Augmenter of Liver Regeneration (ALR), an anti-apoptotic, anti-metastatic factor, exerts protective/cell survival and anti-metastatic activities and has been detected highly expressed in neoplastic cells., Patients and Methods: To evaluate, by immunohistochemistry, p-STAT3, PIAS3 and ALR expression in neoplastic human tissues from CRC patients, grouping the data in accordance with the histological alterations (G1, G2 and G3) and metastasis presence. Western blot (WB) analysis of ALR was also determined in neoplastic and surrounding tissues. Finally, cell proliferation (Ki-67) and apoptosis (Bcl-2) were determined., Results: Colon cancer tissue samples showed: (1) ALR and p-STAT3 strongly over-expression in 100% of G1 tissue samples, reducing in G2 and G3 tissue samples; (2) PIAS3 immunological determination was poorly expressed in G1 tissue samples and highly expressed in the 100% of colorectal tissues from group G2 and G3. Ki-67 progressively increases with the importance of the anatomic-pathological alterations and Bcl-2 resulted higher in G3 tissue samples compared to G1 neoplastic tissues. WB data evidenced, in neoplastic tissues, compared to the tumour-surrounding tissues, ALR over-expressed in G1 neoplastic tissues and down-expressed in G3 neoplastic tissues., Conclusions: Our data demonstrate a different dynamism of the investigated factors in relation to the severity of CRC histological findings. We hypothesize that the positive expression of ALR and p-STAT3 in the neoplastic tissue samples from CRC G1 group, associated to the absence of PIAS3, could be useful marker to identify an early stage of the disease. Based on these data and on our previous studies on gut microbiota in precancerous intestinal lesions, we are confident that, after microbial priming, a cascade of molecular events is started. So, the detectable molecules acting in these initial steps should be considered for the study of CRC progression and therapy.

Rationale: Placental site trophoblastic tumor (PSTT) is a very rare malignant tumor, belonging to a family of pregnancy-related illnesses, called gestational trophoblastic diseases (GTD). Less than 300 cases of PSTT have been reported in literature, with an incidence of ≈ 1/50,000-100,000 pregnancies representing only 0.23% to 3.00% of all GTDs., Patient Concerns: Our report describes 2 additional cases of PSTT outlining their main diagnostic features and the subsequent management. The first case presented contemporary to a persistent hydatidiform mole in a 37-year-old woman, para 2042; whereas the second one originated 5 years after a miscarriage in 43-year-old woman, para 1031 with a previous diagnosis of breast cancer, and shared some features with placental site nodule (PSN), a benign condition., Diagnosis: The first case had a difficult diagnosis because there was an amenorrhea of 11th week with high serum beta-human chorionic gonadotropin (beta-HCG) and an initial ultrasound image of vesicular mole. After the Dilatation and Curettage, histology confirmed the previous hypothesis. However, the final histology of PSTT was obtained after major surgery. On the contrary, the diagnosis of the second case was less challenging but surprising, thanks to a routine trans-vaginal ultrasound showing a suspicious endometrial thickness positive for PSTT at a subsequent hysteroscopic guided biopsy., Interventions: The treatment consisted of hysterectomy and subsequent follow up. Lymphadenectomy or lymph node sampling were not performed due to the initial stage of the disease., Outcomes: In the first case, there were high values of serum beta-HCG that plummeted after the surgery, whereas in the second one they had been always negative. Hereafter, both went through a follow up with periodic serum oncological markers, imaging studies and clinical evaluation, which have showed negative result for 3 years and 15 months, respectively., Lessons: A detailed gynecological ultrasound examination could be extremely helpful to understand the next diagnostic step of echo-guided D&C or hysteroscopic biopsy and for a pre-operative staging assessment. On the contrary, determining the serum beta-HCG's curve is crucial just in case of an initial positive value to pursue clinical evaluation and follow-up. In case of good prognostic factors, the main therapy remains hysterectomy.

Diabetic nephropathy patients (DN) are characterized by increased lysine63 ubiquitination (Lys63-Ub) at the tubular level. Autophagy is deregulated under diabetic conditions, even though the molecular mechanisms and the consequences of this alteration need to be elucidated. The aim of this study was to investigate the link between Lys63-Ub and autophagy in DN and the involvement of these two processes in tubular cell fate. Immunohistochemistry of beclin-1, LC3, and p62 on kidney biopsies highlighted increased protein expression of all these autophagic factors at the tubular level in DN compared to other nephritis. Transmission electron microscopy confirmed the presence of diffuse vacuolization and autophago(lyso)somal structures in proximal tubular cells in DN. Accumulation of Lys63-Ub proteins in DN increased in accordance with the tubular damage and was associated to increased LC3 expression both in vivo and in vitro. Hyperglycemia (HG) induced LC3 and p62 protein expression in HK2 cells together with Lys63-ubiquitinated proteins, and the inhibition of HG-induced Lys63-Ub by NSC697923 inhibitor, significantly reduced both LC3 and p62 expression. Moreover, in DN, those tubules expressing LC3 showed increased caspase-3 expression, supporting the hypothesis that deregulated autophagy induces apoptosis of tubular cells. In vitro, we confirmed a tight association between impaired autophagy, Lys63-Ub, and apoptosis since Lys63-Ub inhibition by NSC697923 abrogated HG-induced cell death and LC3 silencing also blocked hyperglycemia-induced caspase-3 activation. Our data suggested that prolonged hyperglycemia in diabetic patients can impair autophagy as a consequence of Lys63-Ub protein accumulation, thus promoting intracellular autophagic vesicles increase, finally leading to tubular cell death in DN., Key Messages: In vivo autophagy is deregulated in diabetic patients with renal disease (DN). Accumulation of Lys63 ubiquitinated proteins is associated to autophagy deregulation. Accumulation of Lys63 ubiquitinated proteins correlated with apoptosis activation. Lys63 ubiquitination inhibition abrogated hyperglycemia-induced autophagy and apoptosis.

Rationale: PNETs (primitive neuroectodermal tumors) are a family of highly malignant neoplasms characterized by small round cells of neuroepithelial origin. They usually involve bone and soft tissues, and have a higher incidence in childhood., Patient Concerns: In this case report, we describe the obstetric and oncological outcome of a huge mass diagnosed as a leiomyoma in a 39-year-old pregnant woman who complained of low back pain, dysuria, and urinary frequency at 22 weeks of gestation., Diagnoses: During the 25th week of pregnancy, the patient was referred to our hospital at night with severe anemia and suspected hemoperitoneum. She underwent an emergency caesarean section, delivering a female fetus weighing 400 g, with an Apgar score of 7 at 1 minute and 9 at 5 minutes., Intervention: During surgery, we found a huge uterine sarcoma-like metastatic tumor, invading the pelvic peritoneum and parametria bilaterally; the adnexae seemed disease-free. We performed a type B radical hysterectomy, bilateral salpingo-oophorectomy, pelvic peritonectomy, omentectomy, appendectomy, and excision of a bulky lymph node. Seven days after delivery, staging computed tomography (CT) scan demonstrated a large lombo-aortic lymph node compressing the left renal vein and we completed debulking with a second surgery, including diaphragmatic peritonectomy and excision of a huge lymph node by lombo-aortic lymphadenectomy, requiring partial reconstruction of an infiltrated renal vein., Outcome: Ten days after the second surgery, echo-color Doppler showed a regular microcirculation in the left kidney. The patient was discharged after 10 days, and the baby after 1 month, both in good health.Histological examination revealed a uterine body cPNET (central primitive neuroectodermal tumor) orienting the clinical management toward chemotherapy with cisplatin and etoposide., Lessons: PNETs are aggressive neoplasms, usually diagnosed at an advanced stage. Due to their low incidence, universally accepted guidelines are still unavailable. Radical surgery leaving no macroscopic residual disease is mandatory in advanced stages. A good fertility-sparing procedure can be performed only in young women at early stages of disease, when the wish for childbearing is not yet fulfilled., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Aim: To evaluate mucosal baseline mRNA expression of tissue transglutaminase 2 (tTG2), interferon gamma (IFNγ), toll-like receptor 2 (TLR2) and Myeloid Differentiation factor 88 (MyD88) in patients with microscopic enteritis (ME)., Methods: We retrospectively enrolled 89 patients with ME of different etiology, which was defined within a 2-year mean period of follow-up. Baseline histological examination was performed on Hematoxylin-Eosin stained sections and CD3 lymphocyte immunohistochemistry was used for intraepithelial lymphocyte count (IELs). ME was defined according to the criteria of Bucharest Consensus Conference. For each patient, formalin embedded biopsy samples of the duodenum referred to the period of ME diagnosis were retrieved. Real-time polymerase chain reaction (RT-PCR) was used to detect the amount of mRNA coding for tTG2, IFNγ, TLR2 and MyD88, and the quantity was expressed as fold change compared to controls. Control group was represented by duodenal normal specimens from 15 healthy subjects undergoing endoscopy for functional symptoms. Comparisons among continuous variables were performed by One way analysis of variance (ANOVA) and Bonferroni's test. The χ(2) test was used for categorical variables. Pearson's test was used to evaluate correlations. Receiver operating curves were drawn for all four markers to estimate sensitivity and specificity in discriminating the development of CD and GS., Results: After a period of follow up of 21.7 ± 11.7 mo, the following diagnoses were achieved: gluten related disorders in 48 subjects (31 CD; 17 GS) and non-gluten related ones in 41 (29 Irritable Bowel Syndrome - IBS; 12 Others). CD patients had the highest tTG2 levels (8.3 ± 4.5). The ANOVA plus Bonferroni analysis showed that CD > Other ME > GS = IBS > negative controls. A cut off value of 2.258 was able to discriminate between CD and GS with a sensitivity of 52.94% and a specificity of 87.1%. Additionally, CD patients had the highest IFNγ levels (8.5 ± 4.1). ANOVA plus Bonferroni demonstrated CD > Other ME > GS = IBS > negative controls. A cut off of 1.853 was able to differentiate CD and GS with a sensitivity of 47.06% and a specificity of 96.77%. Patients with non gluten-related causes of ME exhibited the highest TLR2 levels (6.1 ± 1.9) as follows: Other ME > CD = GS = IBS > negative controls. TLR2 was unable to discriminate CD from GS. Patients with CD overexpressed MyD88 levels similarly to non gluten-related causes of DL (7.8 ± 4.9 and 6.7 ± 2.9), thus CD = Other ME > GS = IBS > negative controls. A cut off of 3.722 was able to differentiate CD from GS with a sensitivity of 52.94% and a specificity of 74.19%. IELs count (15-25 and more than 25/100 enterocytes) strongly correlated with mRNA levels of all tested molecules (P < 0.0001)., Conclusion: Our results confirm that a single marker is unable to predict a discrimination among ME underlying conditions as well as between CD and GS. Mucosal high levels of tTG and IFNγ mRNA may predict the development of CD more than GS with high specificity, despite an expected low sensitivity. TLR2 does not discriminate the development of CD from GS. MyD88 levels indicate that intestinal permeability is more increased when a severe intestinal damage underlies ME in both gluten related and unrelated conditions. Therefore, the results of the present paper do not seem to show a clear translational value., Competing Interests: Conflict-of-interest statement: No conflict of interest is declared by authors.

Background/aim: In celiac disease (CD), there is increased mRNA coding for tissue transglutaminase (tTG) and interferon gamma (IFNα). In seronegative celiac patients, the mucosal immune complexes anti-tTG IgA/tTG are found. We assayed tTG- and IFNα-mRNA in the mucosa of patients with a clinical suspicion of seronegative CD and correlated the values with intraepithelial CD3 lymphocytes (IELs)., Materials and Methods: Distal duodenum specimens from 67 patients were retrieved and re-evaluated for immunohistochemically proven CD3 IELs. Five 10 μm sections were used for the extraction and assay of tTG and IFNα coding mRNA levels using reverse transcriptase real-time polymerase chain reaction (RT-PCR). Samples from 15 seropositive CD patients and 15 healthy subjects were used as positive and negative controls. Results were expressed as fold-change., Results: Our series was divided into three groups based on IEL count: >25 (14 patients: group A), 15-25 (26 patients: group B), and 0-15 (27 patients: Group C). tTG-mRNA levels were (mean ± SD): CD = 9.8 ± 2.6; group A = 10.04 ± 4.7; group B = 4.99 ± 2.3; group C = 2.26 ± 0.8, controls = 1.04 ± 0.2 (CD = group A > group B > group C = controls). IFNα-mRNA levels were: CD = 13.4 ± 3.6; group A = 7.28 ± 3.6; group B = 4.45 ± 2.9; group C = 2.06 ± 1.21, controls = 1.04 ± 0.4., Conclusions: Our results suggest that tTG- and IFNγmRNA levels are increased in both seropositive and potential seronegative patients with CD, showing a strong correlation with the CD3 IEL count at stage Marsh 1. An increase in both molecules is found even when IELs are in the range 15-25 (Marsh 0), suggesting the possibility of a "gray zone" inhabited by patients which should be closely followed up in gluten-related disorders.

Background: Overall, the comparative data available on the timing of metopic suture closure in present-day and fossil members of human lineage, as well as great apes, seem to indicate that human brain evolution occurred within a complex network of fetopelvic constraints, which required modification of frontal neurocranial ossification patterns, involving delayed fusion of the metopic suture. It is very interesting that the recent sequencing of the Neanderthal genome has revealed signs of positive selection in the modern human variant of the RUNX2 gene, which is known to affect metopic suture fusion in addition to being essential for osteoblast development and proper bone formation. It is possible that an evolutionary change in RUNX2, affecting aspects of the morphology of the upper body and cranium, was of importance in the origin of modern humans. Thus, to contribute to a better understanding of the molecular evolution of this gene probably implicated in human evolution, we performed a comparative bioinformatic analysis of the coding sequences of RUNX2 in Homo sapiens and other non-human Primates., Results: We found amino-acid sequence differences between RUNX2 protein isoforms of Homo sapiens and the other Primates examined, that might have important implications for the timing of metopic suture closure., Conclusions: Further studies are needed to clear the potential distinct developmental roles of different species-specific RUNX2 N-terminal isoforms. Meantime, our bioinformatic analysis, regarding expression of the RUNX2 gene in Homo sapiens and other non-human Primates, has provided a contribution to this important issue of human evolution.

Background: Even if endometriosis is usually an exclusively gynecological issue, atypical locations fall within the interest of general surgery. The aim of our retrospective study focuses on the need for surgeons to face this rare condition, in order to avoid unnecessary or inadequate treatment., Methods: We retrospectively analyzed clinical presentations, previous endometriosis diagnosis and surgical acts on a group of 60 patients, whose mean age was 38.2 years old, with extra-genital endometriosis., Results: Among the 60 cases of extra-genital endometriosis collected, bowel foci, 37 cases - 61,7% - were the most frequent; then we collected 13 (21.7%) skin, 7 (11.7%) urinary tract and 3 (5%) whole pelvis localizations. It's important to underline the finding of 2 aggressive malignant transformations., Conclusions: Extra-genital endometriosis should be considered as a cause of otherwise inexplicable abdominal pain in young women. Since imaging techniques lack in specificity, we propose explorative laparoscopy as a powerful diagnostic means. Moreover laparoscopy can be turned into a therapeutic act, also limiting the adherences issue, which is associated with this illness and would worsen with open surgery. Extra-genital endometriosis should be treated also to avoid rare, but possible, risk of cancerization.

Aim: To investigate tumor necrosis factor-α (TNF-α), syndecan 1 and basic fibroblast growth factor (bFGF) balance in Crohn's disease (CD) strictures., Methods: Our study was performed on 24 surgical specimens of CD fibrotic stenosis. Ten histological normal surgical samples were retrieved for both the large and small bowel from patients with benign conditions and healthy tissue represented control collection. Sex and age in controls did not differ from CD group. Three endoscopic biopsy specimens taken after informed consent in subjects with normal colon were also used as negative controls. TNF-α, syndecan 1 and bFGF were detected by both reverse transcriptase reverse transcriptase polymerase chain reaction after mRNA extraction (results expressed as fold-change) and immunohistochemistry., Results: TNF-α did not show any significant difference between CD and control specimens (1.54 ± 1.19; P > 0.05). Very high levels of bFGF were observed in CD (11.76 ± 4.65; P < 0.001) unlike syndecan 1 which showed a moderate increase (5.53 ± 2.18; P < 0.005). analysis of variance (ANOVA) plus Student-Neumann-Keuls showed: bFGF > syndecan 1 > TNF-α = control. Immunoreactivity for bFGF was observed in epithelial, stromal, endothelial cells and even in the muscular layer, whilst in normal tissue it was almost unexpressed. Syndecan 1 and TNF-α staining was confined to mucosal epithelial and stromal cells, while in controls syndecan 1 was found in its normal site, i.e., basolateral area of the crypts and TNF-α very poorly expressed., Conclusion: Fibrotic stenosis of CD may be the final result of an irreversible transformation of different cells into fibrogenic phenotype no longer inhibited by post-transcriptional regulation.

The role of vitamin D in maintaining health appears greater than originally thought, and the concept of the vitamin D axis underlines the complexity of the biological events controlled by biologically active vitamin D (1,25(OH)(2)D3), its two binding proteins that are the vitamin D receptor (VDR) and the vitamin D-binding protein-derived macrophage activating factor (GcMAF). In this study we demonstrate that GcMAF stimulates macrophages, which in turn attack human breast cancer cells, induce their apoptosis and eventually phagocytize them. These results are consistent with the observation that macrophages infiltrated implanted tumors in mice after GcMAF injections. In addition, we hypothesize that the last 23 hydrophobic amino acids of VDR, located at the inner part of the plasma membrane, interact with the first 23 hydrophobic amino acids of the GcMAF located at the external part of the plasma membrane. This allows 1,25(OH)(2)D3 and oleic acid to become sandwiched between the two vitamin D-binding proteins, thus postulating a novel molecular mode of interaction between GcMAF and VDR. Taken together, these results support and reinforce the hypothesis that GcMAF has multiple biological activities that could be responsible for its anti-cancer effects, possibly through molecular interaction with the VDR that in turn is responsible for a multitude of non-genomic as well as genomic effects.

We developed a modified transcranial sonography technique to study the morphology of the temporal lobe, a brain region involved in language, memory and social functions in humans that can be visualized in correspondence of the acoustic window of the temporal squama. Previous studies raise the possibility that a unique derived feature of Homo sapiens is a relatively larger temporal lobe compared to those of other hominins and apes. Such a brain reorganization might have contributed to the evolution of various "higher" cognitive functions of Homo sapiens, including language. Hence, the importance of further comparative analyses of the temporal region. With the technique that we developed we were able to study the meninges, the subarachnoidal space and the cortex of the human temporal lobe. The spatial resolution and the ability to visualize structures of 200-300 microm size led us to hypothesize that the linear structures parallel to the subarachnoidal space might be referred to the neuronal layers of the cortex. The low cost, simplicity and safety of the procedure suggest that this technique may have a significant potential in the comparative study of the primate temporal lobe. Furthermore, the procedure described here can also be used for the study of vascularization of the meninges, in order to better understand the evolutionary relationships between the neurocranial shape and the middle meningeal vessels in living and fossil human species.

Objective: To verify the ultrafine conformation of term villi in diabetic and normal placentae. Villar dysmaturity and chorangiosis are considered the most frequent findings in diabetic placentae, but their histogenesis is still unclear., Study Design: We performed a morphometric study of 38 term villi in 5 diabetic placentae and of 37 term villi of 5 normal placentae in order to know the different extension of endothelial surface (VL), the maximum (D max) and minimum (D min) distance of the vessels from the basal membrane, as well as the exact thickness of basal membrane (MT BM). The villi were examined with transmission electron microscopy, and parameters were automatically acquired with the iTEM software (Soft Imaging System, Münster, Germany)., Results: VL results were statistically higher in diabetic placentae than in normal ones. Also D max and D min were higher in diabetic disease. MT BM was not different in the two groups., Conclusion: Our findings show that, in the presence of chorangiosis, the vessel surface in diabetic placentae is higher than in normal group, but the vessels are randomly distributed in term villi. The basal membrane is not different in the two groups. Morphometric evaluation seems to be more accurate using ultrafine samples.

According to the World Health Organization, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a neurological disease characterized by widespread inflammation and multi-systemic neuropathology. Aetiology and pathogenesis are unknown, and several agents have been proposed as causative agents or as factors perpetuating the syndrome. Exposure to heavy metals, with particular reference to mercury and gold in dental amalgams, has been considered among the triggers of ME/CFS. Here we hypothesize that cadmium, a widespread occupational and environmental heavy metal pollutant, might be associated with some of the neurological findings described in ME/CFS. In fact, ME/CFS patients show a decrease of the volume of the gray matter in turn associated with objective reduction of physical activity. Cadmium induces neuronal death in cortical neurons through a combined mechanism of apoptosis and necrosis and it could then be hypothesized that cadmium-induced neuronal cell death is responsible for some of the effects of cadmium on the central nervous system, i.e. a decrease in attention level and memory in exposed humans as well as to a diminished ability for training and learning in rats, that are symptoms typical of ME/CFS. This hypothesis can be tested by measuring cadmium exposure in a cohort of ME/CFS patients compared with matched healthy controls, and by measuring gray matter volume in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients. In addition, we hypothesize that cadmium exposure could be associated with reduced cerebral blood flow in ME/CFS patients because of the disruptive effects of cadmium on angiogenesis. In fact, cadmium inhibits angiogenesis and low global cerebral flow is associated with abnormal brain neuroimaging results and brain dysfunction in the form of reduced cognitive testing scores in ME/CFS patients. This hypothesis can be tested by measuring cerebral cortex blood flow in un-exposed healthy controls, exposed non-ME/CFS subjects, un-exposed ME/CFS patients and exposed ME/CFS patients. If our hypothesis is demonstrated correct, the consequences could affect prevention, early diagnosis, and treatment of ME/CFS. Implications in early diagnosis could entail the evaluation of symptoms typical of ME/CFS in cadmium-exposed subjects as well as the search for signs of exposure to cadmium in subjects diagnosed with ME/CFS. Nutritional supplementation of magnesium and zinc could then be considered, since these elements have been proposed in the prophylaxis and therapy of cadmium exposure, and magnesium was demonstrated effective on ME/CFS patients' symptom profiles., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The authors describe the first case of eye amelanotic cellular blue nevus reported in literature and discuss the main differential diagnosis.

Purpose: To describe a rare case of an orbital undifferentiated sarcoma arising in an eviscerated eye socket with a silicone implant., Methods: The clinical and histopathological findings of the case are reviewed and presented., Results: A patient who had undergone post-traumatic evisceration of the right eye and a silicone prosthesis implant 8 years earlier, presented to our observation with a painful eye, on which a brownish, bleeding mass, measuring 1 cm in diameter, was evident. After removal of the silicone prosthesis, the mass was found to arise from the scleral socket. Histopathological analysis demonstrated a malignant tumor composed of markedly pleomorphic cells with a high mitotic rate. An undifferentiated high-grade pleomorphic sarcoma was diagnosed. Complete right orbital exenteration was performed and the patient underwent radiotherapy, Conclusions: This is the first report of an undifferentiated high-grade pleomorphic sarcoma arising from a scleral socket with a silicone implant.

Purpose: To describe a rare case of conjunctival leiomyosarcoma initially diagnosed as a poorly differentiated squamous cell carcinoma., Methods: Clinical, light microscopic, immunohistochemical, and ultrastructural findings are reported., Results: A 56-year-old Caucasian woman was referred with a history of a progressive, rapidly growing mass in her left eye. Biopsy of the mass and histology yielded a first diagnosis of a poorly differentiated conjunctival squamous cell carcinoma. Orbital exenteration was performed 2 weeks later. Macroscopically, the exenteration specimen showed a soft mass completely involving the conjunctiva and extending to the eyelids and orbital structures. Histological examination revealed a malignant tumour composed of atypical, predominantly epithelioid large cells. Immunohistochemical and ultrastructural studies combined with the light microscopic findings contributed to clarify the diagnosis of epithelioid leiomyosarcoma. The patient was started on chemotherapy and radiotherapy, but died a few months later from widespread metastases., Conclusions: primary involvement of the orbit by a leiomyosarcoma is rare, but this eventuality should be considered in the differential diagnosis of rapidly growing orbital and conjunctival masses.

Melanomas of the oral cavity are extremely rare. Their rarity and their independence on exposure to UV radiation make them particularly interesting. The authors analyzed an oral multiphasic melanoma composed by a nodular nonpigmented ulcerated central region, a nodular ulcerated pigmented area, a pigmented nonulcerated region, and an area similar to a dysplastic nevus. They determined the expression of some genes involved in the differentiation and cellular transformation in morphologically different regions of melanoma. All these areas were also analyzed by electron microscopy. The various regions composing the melanoma expressed genes involved in melanogenesis and melanoma progression in a different manner. Electron microscopy observation of ultrathin sections of each region evidenced ultrastructural differences, being the cellular architecture more compromised in the most aggressive parts of the neoplasm. This pilot study identified morphological, molecular, and ultrastructural differences that characterize each region of the multiphasic melanoma.

A 65-year-old woman presented with a long standing, progressive exophthalmos of the right eye. Her medical history was significant for Churg Strauss syndrome, and was treated with immunosuppressive therapy. She had undergone two previous orbital biopsies showing inflammatory reactive lymphoid hyperplasia. A diagnosis of orbital inflammation in Churg-Strauss syndrome was suspected, and the immunosuppressive therapy was increased. Because of the lack of response to therapy, a further biopsy was performed, by lateral orbitotomy approach. Biopsy of the mass revealed a granular cell tumor composed of S-100 positive cells with an acidophilic granular cytoplasm and peripheral lymphocytic infiltration. A granular cell tumor, which is very rare in the orbit, should be considered in the differential diagnosis of orbital tumors, and if suspected, an excisional biopsy must be undertaken. Typical histopathological aspect of the granular cell tumor is characterized by the presence of S-100 positive closely packed polygonal cells with a granular cytoplasm.

We report a case of benign multicystic mesothelioma in a 20-year-old woman referred because of amenorrhea. She underwent pelvic transabdominal ultrasound, which disclosed a micropolycystic appearance of the ovaries and a fluid collection in the pouch of Douglas. Tumor serum markers revealed an increase in CA19.9. Abdominal and pelvic computed tomography scans confirmed the presence of ascites. Laparoscopy disclosed small, thin-walled, translucent cysts in the Douglas cavity. The cysts were free-floating in a yellowish, sticky, gelatinous material. Microscopically, cystic lesions showed mesothelium-lined cystic spaces surrounded by a delicate thin fibrovascular wall. With immunohistochemistry, the tumor cells were strongly positive for cytokeratin and calretinin. These aspects were suggestive of benign multicystic mesothelioma. Electron microscopy confirmed the mesothelial nature of this tumor. Serial evaluation of the CA19.9 concentration showed a progressive decrease in the serum marker in the normal range. The patient is now well and symptom-free with no recurrence 24 months after surgery. The association between benign multicystic mesothelioma and increased CA19.9 serum concentration has been described only once, in a man. To our knowledge, this is the second case of benign multicystic mesothelioma associated with increased CA19.9 serum concentration and the first diagnosed in a woman. In the present case, a minimally invasive laparoscopic approach enabled not only histologic diagnosis of benign multicystic mesothelioma but also its surgical treatment. Although benign multicystic mesothelioma is a rare pathologic entity, it is important that sonologists include it in the differential diagnosis of diseases that manifest with ascites. Furthermore, all surgeons should be aware of the macroscopic and laparoscopic appearance of the lesion, and its generally benign course., (Copyright 2010 AAGL. Published by Elsevier Inc. All rights reserved.)

Cyclosporin-A (CsA) and tacrolimus (FK-506) are immunomodulating agents used to prevent rejection in organ transplantation. They are both associated with several side effects, including nephrotoxicity and severe hypertension due to vascular injury, which often appears as a microvascular occlusive disorder (thrombotic microangiopathy, TMA). We report the first case of a microvascular occlusive disorder with the features of TMA in the small bowel of an orthotopic liver transplant (OLT) patient after immunosuppressive therapy with CsA and FK506. The patient presented with severe recurrent abdominal colics and distal subocclusion, requiring aggressive surgical treatment. Histological and ultrastructural analysis of the resected specimen disclosed intestinal TMA. Although rare, such a complication should be considered in the differential diagnosis of abdominal colics in patients undergoing immunosuppressant therapy after OLT.

We present a case of squamous spindle cell carcinoma of the external auditory meatus in a 38-year-old man. The tumour was extended to the inner ear, the temporal bone, the middle cranial fossa and the meningo-cerebral tissue. The surgical intervention of temporo-occipital craniotomy removed most of the neoplasia. At pathologic examination, the tumour showed an undifferentiated spindle cell pattern. Immunohistochemistry with a large antibody panel found a weak positivity only to EMA. The diagnosis was made when the electron microscopy showed rare junctional structures and tonofilaments.

Aim: Airways humidification during mechanical ventilation (MV) can be performed by means of heat and moisture exchangers (HME). Good performance of selected hygroscopic HME was shown in terms of tracheal temperature and humidity control and low tube obstruction rates. However, few data are available on their effects on tracheobronchial ciliated cells. The purpose of this study was to evaluate the effects of 2 different HME on ciliated cell during MV., Methods: Twenty consecutive patients undergoing elective surgery lasting <4 h were randomly assigned to be treated with Rusch (Group 1) or Mediflux (Group 2) hygroscopic HME. The morphology of tracheobronchial ciliated cells was evaluated from cytologic smears of endotracheal aspirate. Smears were prepared by using the thin-prep processor, stained using the Papanicolau method and examined in triplicate: recognizable respiratory cells were graded on a six-point scale, according to the normal appearance of cilia, cytoplasm and nucleus., Results: In Group 1, 178.3+37 cells were retrieved from aspirates and , 155.6+58 in Group 2 (NS). The score was 739+241 in Group 1 and 617+329 in Group 2 (NS). Cilia and end plate were undamaged in 80+17% and 81+20% cells respectively in Group 1 and in 56+23% and 62+22% cells respectively in Group 2 (P<0.01 and <0.05)., Conclusions: During MV epithelial tracheobronchial cells can be affected by the humidification device used. Our findings suggest that the 2 HME tested in the present study have a different impact on ciliated cells structure.

Lymphangioleiomyomatosis (LAM) is an uncommon progressive disease characterized by a hamartomatous tumor-like proliferation of smooth muscle cells that occurs most often in women. This disease commonly involves the lymph nodes, lungs, and mediastinum, and rarely the abdominal sites. We report a case of mesenteric LAM occurring in a 37-year-old man affected by Klinefelter syndrome with a 17-year history of androgen replacement therapy. Histology revealed a hamartomatous proliferation of spindle cells surrounding multiple ectatic lymphatic spaces intermixed with lymphatic follicles. When subjected to immunohistochemical studies, the tumor cells stained positive for muscular markers and negative for estrogen, progesterone, and androgen receptors. The occurrence of LAM in association with Klinefelter syndrome has never been reported in the literature and could represent a further clue in the still unclear pathogenesis of this disease.

Introduction: Osteosarcoma is a malignant bone neoplasm with an usually high metastatic potential. Besides the common metastatic sites such as lungs, bone, and pleura, metastases to unusual sites such as liver, brain and regional lymph nodes have also been reported with increasing frequency; among them, gastrointestinal metastases represent an extraordinarily rare event in the natural history of this neoplasia., Materials and Methods: We describe a case of a 27 year old man, who was diagnosed with a grade IV osteoblastic osteosarcoma of the left tibia and submitted to 5 courses of pre-surgical chemotherapy; later he underwent tibial resection with implantation of a prosthesis, followed by 2 further courses of adjuvant chemotherapy. Five years after the patient presented with melena and acute anemia; during endoscopic examination, a large bleeding duodenal polyp was found, so a surgical resection of the gastric antrum, duodenum, head of the pancreas, main bile ducts and gallbladder was performed. The surgical specimen was formalin fixed and paraffin embedded, and sections obtained by the blocks were stained with haematoxylin-eosin; immunohistochemical and ultrastructural analysis were performed., Results: Microscopically, the tumor mass showed a mostly fasciculated architecture, composed of spindle and epithelioid cells in a scarce fibromyxoid stroma, featuring large areas of coagulative necrosis and small foci of sclerohyalinosis. Tumor cells featured large vesciculous nuclei, with a few prominent nucleoli; no foci of osteoid matrix were detectable. The ultrastructural analysis revealed small calcified electron-dense depots both in the perinuclear cytoplasm and in the extracellular collagen matrix compatible with an "early osteoid formation". Due to alteration of the natural history of the tumor induced by multiagent chemotherapy, the rate of metastases of osteosarcoma to unusual sites has been increasing. We report the 9th case of a gastrointestinal metastasis of osteosarcoma reported thus far, and only the second one arising in the duodenum. Both the histological features and the immunohistochemical findings were not suggestive for osteosarcoma metastases because the tumor appeared dedifferentiated; in our case the combination of electron microscopy and clinical history played a pivotal role to establish the final diagnosis.

The examination of a large series of cervical lymph nodes in patients with head and neck cancer revealed the presence of incidental metastases of occult thyroid carcinoma in eight patients, of which six cases were squamous cell carcinoma of glottic and supraglottic sites of the larynx and two cases were pyriform sinus and tongue carcinomas. Three patients had two lymph nodes and the remaining patients had one lymph node each involved. The nodal chains affected were the jugular (n=5; level IV), Kuttner (level II), supraomohyoid (level III) and supraclavicular (level VI). In four cases, a subtotal thyroidectomy or unilateral lobectomy was performed during laryngectomy (for surgical reasons) or after histologic nodal examination; a minimal focus of thyroid papillary carcinoma was detected in one patient. Three of eight patients died from recurrence of the squamous cell carcinoma; no case presented clinical evidence of thyroid malignancy. The differential diagnosis from benign thyroid heterotopia was based on the presence of minimal nuclear atypia. The choice of treatment of patients with a coexisting neoplasm characterized by poor prognosis is difficult, and contrasting opinions exist regarding the use of radical thyroidectomy and the subsequent management. As reported in the literature (66 cases), the more aggressive squamous cell carcinoma will determine the prognosis of these patients; in fact, only one of the referred cases died of cerebellar metastases of the thyroid cancer. Our results emphasize the importance of an accurate re-evaluation and follow-up of patients with incidental occult metastases for detection of a primary thyroid tumor. In the general population, this incidental nodal involvement may be related to a minimal occult thyroid carcinoma.

Both gonadotropin-releasing hormone (GnRH agonists) and progestational agents are commonly used in order to reduce the size of uterine leiomyomas before surgery. So far, little is known about the histologic changes underlying such shrinkage mechanism. Probably the conflicting data on this subject are due to the qualitative and subjective methods used by most previous reports. In this study we analyzed 42 leiomyomas from patients treated with GnRH agonists (14 different patient samples), patients treated with progestational agents (14 different patient samples) and age-matched control patients (14 different patient samples), using qualitative (light microscope analysis) and quantitative (morphometric analysis by a specific software) methods. We assessed the following parameters: areas of necrosis, areas of hyalinization, vasal density, vasal thrombi, thickness of vasal walls, size of vasal lumina, cell density, maximum nuclear diameter, maximum cytoplasmic diameter, mitotic index on each sample. The analysis showed that leiomyomas from women treated with GnRH agonist exhibited broader areas of necrosis, greater cell density, and wider vasal lumina, while those from women treated with progestational agents exhibited thicker vasal walls than the other two groups, respectively. In conclusion, our results suggest that vasal wall changes are the basis of leiomyomas shrinkage after GnRH agonist therapy.

Several histological variants of colorectal carcinoma have been reported, some of them bearing prognostic significance, others only incidental findings showing unusual morphological features. The current report was aimed to describe the histological, immunohistochemical and ultrastructural features of an oncocytic adenocarcinoma of the rectum occurring in a 66-year-old woman. Histologically, it was a moderately differentiated adenocarcinoma composed by glandular structures lined by eosinophilic cells. The latter showed abundant granular cytoplasm and large nuclei with prominent nucleoli. Several glandular structures contained intraluminal, basophilic and non-birifrangent microcalcifications. The tumour cells displayed consistent anti-mitochondrial antigen, carcinoembryonic antigen, p53, CDX2 and cytokeratin 20 immunoreactivity. Ultrastructurally, more than 80% of the cytoplasmic area was occupied by abnormal mitochondria, while exocrine or endocrine granules were undetectable. The tumour infiltrated the intestinal wall through the subserosal tissue, but lymph node or distant metastases were absent. The patient is disease free 22 months after surgery. Based on the above features, this case could be appropriately named oncocytic adenocarcinoma with intraluminal microcalcifications. Like gastric neoplasms showing similar morphologic features, this tumour might have a better prognosis, and the presence of microcalcifcations could help its proper recognition at a pre-operative stage.

The aim of this work was to estimate the frequency of abnormal Papanicolau (Pap) smears in a group of HIV-infected women undergoing cervical screening. We re-examined 162 Pap smears from 118 patients infected with HIV. The patients were aged 23-55 years. A total of 108 smears (66.6%) from 80 patients were negative; 14 smears (8.6%) from 14 patients showed inflammation; 3 smears (1.8%) from 3 patients had atypical squamous cells of undetermined significance (ASCUS); 20 smears (13.5%) from 16 patients were abnormal for human papillomavirus (HPV); 13 smears (8.0%) from 9 patients revealed low-grade, squamous intraepithelial lesions; 10 smears (6.2%) from 7 patients were SIL-HG; the diagnosis of carcinoma was made in 3 cases (1.8%) and 2 smears from 2 patients were unsatisfactory. HIV-infected women have an increased rate of abnormal Pap smears for both HPV infections and cervical dysplasia. These results confirm the validity of cervical screening by Pap test.

Gastro-intestinal stromal tumors (GISTs), as currently defined, represent the largest category of primary non epithelial neoplasms of the gastrointestinal tract. They arise from mesenchymal cells located in the wall of the organ and show a remarkable variability in their differentiation pathways. For this reason there is relevant degree of confusion in their interpretation. On the basis of immunohistochemical and ultrastructural studies these neoplasms are divided into several categories: leiomyomas, schwannomas and less differentiated tumors referred as GIST. In the small bowel GIST are uncommon. Usually asymptomatic, they could be the cause of surgical emergencies like massive bleeding, obstruction, intussusception or perforation. Generally benign, an higher percentage of malignant cases are described in the small bowel. The Authors report a case of malignant GIST of the small intestine presented with bowel obstruction by ileal invagination. In this case, as usually it happens in malignant GIST, the final diagnosis was obtained by an abdominal surgical exploration.

A few cases of malignant fibrous histiocytoma (MFH) of the larynx have been reported to date. All ages may be affected, but the tumor is more prevalent in the sixth and seventh decade of life. We describe a case of MFH in a 71-year-old Italian man who 8 years before underwent a right cordectomy and radiotherapy for squamous cell carcinoma. Recurrent tumor was found to be MFH. The clinico-pathological features of this tumor are presented and the possible relationship between radiotherapy and MFH discussed. The neoplasm was characterized by spindle-shaped atypical cells arranged in a diffuse storiform pattern. Mitoses were prominent, numerous, and often atypical. Immunohistochemically, neoplastic cells were strongly positive for vimentin and alpha1-antichymotrypsin but were negative for cytokeratins and S-100 protein. These findings confirmed the diagnosis and excluded possible sarcomatoid carcinoma, inflammatory pseudotumor, and a new carcinosarcoma. The risk of sarcoma after radiotherapy for squamous cell carcinoma in the larynx is very low when considering the frequent use of radiotherapy, but long follow-ups are required.