Prognostic value of chromosomal imbalances, gene mutations, and BAP1 expression in uveal melanoma.

Uveal melanoma (UM) exhibits recurring chromosomal abnormalities and gene driver mutations, which are related to tumor evolution/progression. Almost half of the patients with UM develop distant metastases, predominantly to the liver, and so far there are no effective adjuvant therapies. An accurate UM genetic profile could assess the individual patient's metastatic risk, and provide the basis to determine an individualized targeted therapeutic strategy for each UM patient. To investigate the presence of specific chromosomal and gene alterations, BAP1 protein expression, and their relationship with distant progression free survival (DPFS), we analyzed tumor samples from 63 UM patients (40 men and 23 women, with a median age of 64 years), who underwent eye enucleation by a single cancer ophthalmologist from December 2005 to June 2016. UM samples were screened for the presence of losses/gains in chromosomes 1p, 3, 6p, and 8q, and for mutations in GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. BAP1 protein expression was detected by immunohistochemistry (IHC). Multivariate analysis showed that the presence of monosomy 3, 8q gain, and loss of BAP1 protein were significantly associated to DPFS, while BAP1 gene mutation was not, mainly due to the presence of metastatic UM cases with negative BAP1 IHC and no BAP1 mutation detected by Sanger sequencing. Loss of BAP1 protein expression and monosomy 3 represent the strongest predictors of metastases, and may have important implications for implementation of patient surveillance, properly designed clinical trials enrollment, and adjuvant therapy.

Accuracy in melanoma detection: a 10-year multicenter survey.

BACKGROUND: Early excision is the only strategy to reduce melanoma mortality, but unnecessary excision of benign lesions increases morbidity and healthcare costs. OBJECTIVE: To assess accuracy in melanoma detection based on number-needed-to-excise (NNE) values over a 10-year period. METHODS: Information was retrieved on all histopathologically confirmed cutaneous melanomas or melanocytic nevi that were excised between 1998 and 2007 at participating clinics. NNE values were calculated by dividing the total number of excised lesions by the number of melanomas. Analyses included changes in NNE over time, differences in NNE between specialized clinical settings (SCS) versus non-specialized clinical settings (NSCS), and patient factors influencing NNE. RESULTS: The participating clinics contributed a total of 300,215 cases, including 17,172 melanomas and 283,043 melanocytic nevi. The overall NNE values achieved in SCS and NSCS in the 10-year period were 8.7 and 29.4, respectively. The NNE improved over time in SCS (from 12.8 to 6.8), but appeared unchanged in NSCS. Most of the effect on NNE in SCS was due to a greater number of excised melanomas. Higher NNE values were observed in patients younger than 40 years and for lesions located on the trunk. LIMITATIONS: No data concerning the use of dermatoscopy and digital monitoring procedures were collected from the participating centers. CONCLUSION: Over the 10-year study period, accuracy in melanoma detection improved only in specialized clinics maybe because of a larger use of new diagnostic techniques such as dermatoscopy.

Primary undifferentiated large cell carcinoma of the lacrimal gland.

PURPOSE: To report a unique case of primary undifferentiated large cell carcinoma (LCCA) of the lacrimal gland, a tumor not previously described in the ophthalmic literature. DESIGN: Single interventional case report. PARTICIPANTS: A patient affected by undifferentiated LCCA of the lacrimal gland. METHODS: A 65-year-old white man with a 3-month history of a painful mass in the left lacrimal gland fossa underwent an incisional biopsy that revealed a "high-grade" epithelial malignancy. Systemic workup revealed enlargement of the regional lymph nodes, and subsequently the patient underwent extended exenteration with clear histologic margins and radical neck lymphadenectomy followed by adjunctive radiotherapy. Fifteen months postoperatively, the patient is alive and well without evidence of local recurrence or metastatic disease. MAIN OUTCOME MEASURES: Treatment result, evidence of local recurrences or distant metastasis, and follow-up. RESULTS: Histologic examination revealed a poorly circumscribed tumor composed of large cells invading orbital fat, lateral rectus muscle, and peripheral nerves. The surrounding orbital bone was infiltrated, but the surgical margins were clear. The cell population was composed of large cells (>30 µm) with eosinophilic cytoplasm and ovoid and irregular nuclei containing a prominent nucleoli and coarse chromatin. The cell borders were well defined. Mitosis figures were abundant, and Ki-67 was positive in more than 60% of the cells. The cells were arranged in cords and trabeculae or irregular sheets of discohesive cells. The immunophenotype analysis showed positivity for cytokeratin but negative cytokeratin 20 stains, which is considered a distinctive feature of LCCA. CONCLUSIONS: Undifferentiated LCCAs are rare tumors of the major salivary glands, especially the parotid gland. Primary undifferentiated LCCA of the lacrimal gland has never been reported in the literature. Differential diagnosis must include a primary source in another organ. Given the aggressive nature of the tumor, radical surgery followed by radiotherapy is recommended, but evidence-based indications regarding the preferred line of treatment are lacking and the prognosis remains guarded. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Fluorescent in situ hybridization as a screening test for HER2 amplification in G2 and G3 breast cancers of lobular and ductal histotype and metastases.

The aim of the present study was to evaluate the effectiveness of fluorescence in situ hybridisation (FISH), as a screening test, in moderately- (G2) or poorly- (G3) differentiated breast cancers of the ductal (IDC) and lobular (ILC) histotypes and distant metastases. HER2 FISH was performed on 486 G2 and 477 G3 both of IDC and ILC histotypes and in 241 metastases. A significant difference in the HER2 amplification was observed between G2 (14.8%) and G3 (31.9%), with no difference according to the histotype. However, the rate of amplification increased to 36% in the G2/hormone receptor-negative cases as compared to 10.6% in the G2/receptor-positive cases (p<0.0001). HER2 was amplified in 17% of metastases with some differences depending on the location. These data suggest that the HER2 FISH analysis may be an effective screening test in breast cancer metastases and G3 tumors, irrespective of the hormone receptor status or presence of lymphovascular invasion.

The UroVysion F.I.S.H. test compared to standard cytology for surveillance of non-muscle invasive bladder cancer.

OBJECTIVE: To evaluate the potential contribution of urinary fluorescent in situ hybridization in the prediction of the risk of recurrence and progression of men undergoing followup for NMIBC. MATERIALS AND METHODS: Patients with a history of NMIBC being followed with urinary cytology and cystoscopy were included in the study. Patients with Carcinoma in situ or tumour stage higher than pT1 were excluded from this analysis. F.I.S.H. Test consisted in the UroVysion kit, able to detect four chromosomal abnormalities, specifically, 9p21, Ch 3, 7 and 17. RESULTS: Of a total of 133 evaluable patients that constitute the subject of the present report 87 patients had a positive urinary F.I.S.H. At a median follow up time of 36 mos 58 patients underwent recurrence (43.6%). In this group 42 (72.6%) and 27 (46.6%) patients had a positive F.I.S.H. and UC, respectively (p = 0.005). A total of 17 patients (12.8%) underwent progression of stage or grade; of those with a positive F.I.S.H. Test and positive UC were 14 (82.4%) and 8 (47.1%), respectively (p = 0.049). CONCLUSION: In patients with history of NMIBC, F.I.S.H. showed a statistically significantly greater capability that UC in identifying patients with recurrence and progression of disease.

Prevalence of stratified epithelium-specific antinuclear antibodies in 138 patients with lichen planus.

BACKGROUND: Antibodies to stratified epithelia characterize chronic ulcerative stomatitis, an entity that very closely resembles erosive lichen planus both clinically and histologically. These antibodies are directed against a 70-kd antigen. OBJECTIVE: Our aim was to verify whether antibodies to stratified epithelia are present in patients with common lichen planus. PATIENTS AND METHODS: One hundred thirty-eight patients with various forms of lichen planus were studied. Indirect immunofluorescence was performed on both monkey esophagus and HEp2-2000 cells. Immunoblotting was done with cultured keratinocytes used as the source antigen. RESULTS: Nineteen patients had antibodies to stratified epithelia (in 9 directed against an antigen of 70 kd). Forty-eight patients had circulating antibodies detected by indirect immunofluorescence on both monkey esophagus and HEp2-2000 cells (in 7 directed against an antigen of 70 kd). Indirect immunofluorescence was positive only on HEp2-2000 cells in 21 patients. Indirect immunofluorescence was negative in 50 patients on both HEp2-2000 cells and monkey esophagus. None of the last 71 patients had antibodies directed to an antigen of 70 kd. LIMITATIONS: This is a serological study; results from direct immunofluorescence studies would be interesting. CONCLUSION: Antibodies to stratified epithelia directed to an antigen of 70 kd are not exclusive to chronic ulcerative stomatitis, but are also present in some patients with lichen planus.

Cancer detection with TRUS-guided 10-core biopsy of the prostate. an institutional assessment at the first, repeated and surgical specimen biopsy.

OBJECTIVES: We retrospectively investigated the results of the 10-core scheme that our institute has adopted for three years. The aim of this study is to evaluate the cancer detection rate in different sets of biopsies (first, second, third and surgical specimen biopsy). MATERIAL AND METHODS: Patients with clinical suspicion of prostate cancer based on abnormal digital rectal examination, increase of PSA or hypoechoic lesion at transrectal ultrasound were subjected to a 10-core biopsy. Ten biopsies were taken following the traditional sextant technique and 4 more biopsies were obtained from the lateral peripheral zone. In addition, a group of 19 specimens of retropubic radical prostatectomy were biopsied immediately following surgery. RESULTS: Of 664 patients 247 (37.2%) were positive for prostate cancer at first biopsy. Eighty-one out of 664 patients were subjected to a second biopsy for persistent elevation or increasing of PSA, or in case of tumor associated histological findings such as high PIN and ASAP. The cancer detection rate in this group was 19.8% (16/81). Of the remaining 65 patients who were negative at second biopsy, 12 received a third biopsy for persistent clinical suspect of cancer, and 2 were positive (16.7%). In 19 surgical specimens, 14 biopsies were confirmed positive and 5 were negative (73.7%). CONCLUSIONS: The extended biopsy such as the 10-core scheme showed to be a reliable protocol, taking an adequate cancer detection rate either at first or repeated biopsy with no increase in morbidity.

Prevalence of oral human papillomavirus in men attending an Italian sexual health clinic.

A high-risk population, formed by 79 consecutive male attendees of our sexually transmissible infections clinic, and who did not have any overt signs of human papillomavirus (HPV) infection, were examined. Oral HPV prevalence (37%) was much higher than previously reported. Periurethral HPV-DNA was found in 49% of the patients and anal HPV-DNA was found in 43% of the patients. Considering the high prevalence of oral HPV obtained in the current study, it is important to further investigate the burden of oral HPV, not only in men who have sex with men, but also in heterosexual men and in women.

Deleted in colon cancer protein expression in colorectal cancer metastases: a major predictor of survival in patients with unresectable metastatic disease receiving palliative fluorouracil-based chemotherapy.

PURPOSE: To determine whether deleted in colon cancer (DCC) protein expression in colorectal cancer (CRC) metastases could predict outcome to palliative fluorouracil (FU)-based chemotherapy and to assess whether it is similar to that observed in the corresponding primary tumors. PATIENTS AND METHODS: DCC protein expression was assessed immunohistochemically on archival specimens of CRC metastases from 42 patients homogeneously treated by methotrexate-modulated bolus FU alternated to 6-S-leucovorin-modulated infused FU and was retrospectively correlated with patient characteristics and clinical outcome. In a subset analysis, DCC immunoreactivity was compared between metastatic CRC and the corresponding primary tumors and regional lymph node metastases. RESULTS: Positive immunoreactivity for DCC was found in 45% of patients. Eighteen (78%) of 23 patients for whom multiple samples were available displayed a similar pattern of expression in distant metastases and primary tumors. The median survival time was 14.3 months in patients without DCC expression and 21.4 months in patients with DCC-positive tumors (log-rank test, P =.04); the 2-year survival rates were 8.5% and 42.5%, respectively. Response rates to chemotherapy were not significantly different between the two groups. By multivariate analysis, DCC protein expression maintained its prognostic value and showed to be the single best predictor of survival, with a relative risk of 2.16. CONCLUSION: Our results indicate that expression of the DCC protein in CRC metastases is similar to that observed in the corresponding primary tumors and represents a dominant predictor of survival in patients with unresectable, advanced CRC who are undergoing palliative FU-based chemotherapy.

Still a place for the classical systematic sextant technique? Cancer detection rates and complications in 1025 consecutive prostatic biopsies.

OBJECTIVES: To verify if there might still be an indication to the sextant biopsy technique we reviewed the cancer detection rate obtained and the complications encountered during a five years interval, at our hospital. METHODS: From January 1997 to December 2002 we have submitted to prostatic biopsy a total of 1025 consecutive patients with a clinical suspect of prostate cancer. A total of six cores were obtained in all the patients with an additional core at suspect lesions. RESULTS: Overall, prostate cancer was present in the biopsies of 444 of 1025 patients giving a detection rate of 43.3%. In patients with serum PSA levels between 4.1 and 10 ng/ml., 169 of 466 biopsies were positive, for a detection rate of 36.3%. An increase in percentage of positivity was observed with increasing decades of age. Overall complication rate was 1.4%. CONCLUSIONS: In patients older than 70 years, and with PSA levels higher than 10 ng/ml, the sextant technique may offer cancer detection rates comparable with techniques using an increased number of cores, and with lower complication rates.

Lymph Node Metastasis from Tall-Cell Thyroid Cancer Negative on 18F-FDG PET/CT and Detected by 18F-Choline PET/CT.

A 77-year-old woman underwent thyroidectomy and (131)I remnant ablation for tall-cell differentiated cancer (DTC) of the left lobe. Detectable Tg levels (4.1 µg/L) under TSH suppression, with undetectable serum Tg-antibody levels, prompted neck ultrasonography, which revealed a lymph node in the left laterocervical region and in the right retroclavicular region. (18)F-FDG PET/CT showed uptake by the left lymph node. (18)F-choline PET/CT showed increased uptake by both lymph nodes. Histopathology revealed DTC solid metastasis in the left lymph node and solid and cystic metastasis in the right one. (18)F-choline PET/CT can locate virulent DTC recurrence, thereby increasing (18)F-FDG PET/CT information.

Late-onset metastasis of renal cell carcinoma into a hot thyroid nodule: an uncommon finding not to be overlooked.

We report the case of a 74-year-old man with a four-year history of right nephrectomy for clear cell renal carcinoma (CCRC) who was diagnosed with hyperthyroidism. On ultrasound (US), a 5 cm solid isohypoechoic nodule with intranodular vascularization was found in the left thyroid lobe. The nodule was deemed autonomous on (99m)Tc thyroid scan. Methimazole was started and serum thyroid hormone levels quickly normalized; euthyroidism was maintained with a very low dosage of antithyroid drug. Over time, compressive symptoms and local pain occurred and US revealed growth of the nodule. Total thyroidectomy was performed and the combined histological and immunohistochemical evaluation deemed the nodule compatible with metastasis of CCRC; on 2-year follow-up, no tumor relapse was ascertained. In patients with a history of cancer, a thyroid nodule, even if hyperfunctioning, must be suspected of being a metastasis and investigated. Hot nodules, which are largely benign, may be vulnerable to metastatic colonization owing to their rich vascularization. In these cases, surgery may be curative.

Diagnostic value of MRI proton density fat fraction for assessing liver steatosis in chronic viral C hepatitis.

OBJECTIVE: To assess the diagnostic performance of a T1-independent, T2*-corrected multiecho magnetic resonance imaging (MRI) technique for the quantification of hepatic steatosis in a cohort of patients affected by chronic viral C hepatitis, using liver biopsy as gold standard. METHODS: Eighty-one untreated patients with chronic viral C hepatitis were prospectively enrolled. All included patients underwent MRI, transient elastography, and liver biopsy within a time interval <10 days. RESULTS: Our cohort of 77 patients included 43/77 (55.8%) males and 34/77 (44.2%) females with a mean age of 51.31 ± 11.27 (18-81) years. The median MRI PDFF showed a strong correlation with the histological fat fraction (FF) (r = 0.754, 95% CI 0.637 to 0.836, P < 0.0001), and the correlation was influenced by neither the liver stiffness nor the T2* decay. The median MRI PDFF result was significantly lower in the F4 subgroup (P < 0.05). The diagnostic accuracy of MRI PDFF evaluated by AUC-ROC analysis was 0.926 (95% CI 0.843 to 0.973) for S ≥ 1 and 0.929 (95% CI 0.847 to 0.975) for S = 2. CONCLUSIONS: Our MRI technique of PDFF estimation allowed discriminating with a good diagnostic accuracy between different grades of hepatic steatosis.

Myenteric plexitis: A frequent feature in patients undergoing surgery for colonic diverticular disease.

BACKGROUND: Diverticular disease of the colon is frequent in clinical practice, and a large number of patients each year undergo surgical procedures worldwide for their symptoms. Thus, there is a need for better knowledge of the basic pathophysiologic mechanisms of this disease entity. OBJECTIVES: Because patients with colonic diverticular disease have been shown to display abnormalities of the enteric nervous system, we assessed the frequency of myenteric plexitis (i.e. the infiltration of myenteric ganglions by inflammatory cells) in patients undergoing surgery for this condition. METHODS: We analyzed archival resection samples from the proximal resection margins of 165 patients undergoing left hemicolectomy (60 emergency and 105 elective surgeries) for colonic diverticulitis, by histology and immunochemistry. RESULTS: Overall, plexitis was present in almost 40% of patients. It was subdivided into an eosinophilic (48%) and a lymphocytic (52%) subtype. Plexitis was more frequent in younger patients; and it was more frequent in those undergoing emergency surgery (50%), compared to elective (28%) surgery (p = 0.007). All the severe cases of plexitis displayed the lymphocytic subtype. CONCLUSIONS: In conclusion, myenteric plexitis is frequent in patients with colonic diverticular disease needing surgery, and it might be implicated in the pathogenesis of the disease.

Focus on high-risk DTC patients: high postoperative serum thyroglobulin level is a strong predictor of disease persistence and is associated to progression-free survival and overall survival.

INTRODUCTION: No parameters predicting recurrence are available for high-risk differentiated thyroid cancer (DTC) patients, and 2-year-follow-up is required to modify the initial prognostic classification. High thyroglobulin (Tg) levels before ¹³¹I-remnant-ablation, during L-thyroxine-withdrawal (ablation-Tg) have undetermined predictive/prognostic significance in low-risk DTC patients. Our study aimed to assess the positive predictive value (PPV) of ablation-Tg in high-risk DTC patients and to evaluate whether high ablation-Tg levels were associated with progression-free-survival (PFS) and overall survival (OS). PATIENTS AND METHODS: We selected 243 high-risk DTC patients. All patients underwent total thyroidectomy and ¹³¹I-remnant-ablation (initial therapy). Clinical data obtained during a median 5-year follow-up were used to assess the response and outcome. The association between disease persistence/recurrence after initial therapy, ablation-Tg, and other risk-factors (T, N, G, histology, and MACIS score) was evaluated through univariate and multivariate analyses, as was the association between PFS, OS ablation-Tg, and other risk factors. RESULTS: Ablation-Tg of 50 µg/L or greater displayed the highest PPV(97%) for disease persistence. In the univariate analysis, high levels of ablation-Tg were confirmed in patients with persistent disease after initial therapy: the higher the odds ratios, the higher the ablation-Tg levels. On multivariate analysis, ablation-Tg was the best predictive factor, especially on comparing patients with ablation-Tg levels of 50 µg/L or greater and those with ablation-Tg less than 2 µg/L (adjusted OR, 818). In a multivariate Cox model, ablation-Tg was the factor most closely associated with PFS (HR, 65.9). The prognostic value of ablation-Tg was confirmed by the overall-survival curves and adjusted risk estimates (adjusted HR=26.7). CONCLUSIONS: Ablation-Tg levels of 50 µg/L or greater are a valuable initial predictor of disease persistence/recurrence in high-risk DTC patients. A significant association emerged between high ablation-Tg levels of 50 µg/L or greater and both progression-free survival (PFS) and overall survival (OS).

A randomized, placebo-controlled, preoperative trial of allopurinol in subjects with colorectal adenoma.

Inflammation and oxidative stress play a crucial role in the development of colorectal cancer (CRC) and interference with these mechanisms represents a strategy in CRC chemoprevention. Allopurinol, a safe molecular scavenger largely used as antigout agent, has been shown to increase survival of patients with advanced CRC and to reduce CRC incidence in long-term gout users in epidemiologic studies. We conducted a randomized, double-blind, placebo-controlled preoperative trial in subjects with colorectal adenomatous polyps to assess the activity of allopurinol on biomarkers of colorectal carcinogenesis. After complete colonoscopy and biopsy of the index polyp, 73 subjects with colorectal adenomas were assigned to either placebo or one of two doses of allopurinol (100 mg or 300 mg) and treated for four weeks before polyp removal. Change of Ki-67 labeling index in adenomatous tissue was the primary endpoint. Secondary endpoints were the immunohistochemical (IHC) expression of NF-κB, ß-catenin, topoisomerase-II-α, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) in adenomatous polyps and normal adjacent colonic tissue. Compared with placebo, Ki-67 levels were not significantly modulated by allopurinol, whereas ß-catenin and NF-κB expression levels decreased significantly in adenomatous tissue, with a mean change from baseline of -10.6%, 95% confidence interval (CI), -20.5 to -0.7, and -8.1%, 95% CI, -22.7 to 6.5, respectively. NF-κB also decreased significantly in normal adjacent tissue (-16.4%; 95% CI, -29.0 to -3.8). No dose-response relationship was noted, except for NF-κB expression in normal tissue. Allopurinol can inhibit biomarkers of oxidative activation in colon adenomatous polyps and normal adjacent tissue. Further studies should define its potential chemopreventive activity.

Fast growing penis ulcer: an unusual coincidence.

A 57-year-old man was seen with a 2-week history of progressive enlargement of an asymptomatic genital ulcer associated with bilateral inguinal lymphadenomegaly. Multiple unprotected heterosexual contacts were reported. The family doctor misdiagnosed primary syphilis with the following laboratory results: negative findings on the Venereal Disease Research Laboratory test, positive findings on the Treponema pallidum particle agglutination assay (titer 1:1280), and IgM negative on the Treponema pallidum particle agglutination assay. The patient was treated with penicillin G for the diagnosis of indeterminate latent syphilis and initially denied authorization for a skin biopsy. After 2 weeks, fast enlargement of the lesion was documented. He underwent skin biopsy, and the histopathologic examination revealed squamous cell carcinoma, and polymerase chain reaction for human papillomavirus 16 was positive.

Prognostic significance of fluorescent in situ hybridisation in the follow-up of non-muscle-invasive bladder cancer.

AIM: To evaluate the potential contribution of a fluorescent in situ hybridization (FISH) as prognostic indicator of the risk of recurrence or progression in patients undergoing follow-up for non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A total of 126 consecutive patients with a history of NMIBC being followed-up with urinary cytology and cystoscopy at a referral centre were studied. Patients with carcinoma in situ, or tumour stage higher than pT1 were excluded. A UroVysion FISH kit was used to detect four chromosomal abnormalities, specifically, locus 9p21, Ch 3, 7, and 17. Three FISH patterns were defined: negative; low-risk positive, i.e. positive staining for 9p21 and/or Ch3 abnormalities; and high-risk positive, i.e. positive staining for Ch7 and/or 17. RESULTS: Overall 73 out of 126 patients (57.9%) had a positive urinary FISH test. After a median time of 14 months, 46 FISH-positive patients underwent recurrence (36.5%) and in 15 patients there was progression of disease (11.9%). Among positive patients, the low-risk category was found in 34, and the high-risk in 39. Low-risk FISH-positive patients had a higher rate of recurrence as compared to FISH-negative patients, with a hazard ratio (HR) of 1.6. The recurrence rate was even greater in patients with a high-risk positive test, with an HR of 1.9. The limitation of the study was that the impact of intravesical treatment was not assessed. CONCLUSION: The urinary FISH test can be used as an aid in predicting the risk of recurrence during follow-up of patients with history of NMIBC.