Changes in coffee and caffeine intake during the pandemic in women smokers and non-smokers: a future challenge for cardiovascular prevention.

BACKGROUND: The recent pandemic has led to major lifestyle changes, especially in women, changes that will impact cardiovascular risk. The aim of the present observational study was to evaluate changes occurred during pandemic in coffee and caffeine intake in a group of adult women and compare changes in smoking versus non-smoking women. METHODS: A web questionnaire was sent through a online survey platform to a group of unselected adult women. The consumption of coffee and caffeine were investigated in 2 groups of women by comparing smokers and non-smokers. RESULTS: A total of 435 adult women (256 non-smokers and 179 smokers) answer to all questions. Smokers increase the number of cigarette/days (mean + 3.4 cig/day). Coffee intake was significantly increase in smokers compared to non-smokers (3.1+1.0 versus 1.5+0.6 cups/day p<0.01). In smokers, self-perception of increase stress was related to increased coffee intake (r = 0.84; p <0.001), increased sugar- rich foods (r=0.81; p<0.001), increased chocolate rich snacks (r=0.72; p<0.01), increased sitting time (r=0.79; p<0.01). CONCLUSIONS: These preliminary data must suggest to undertake social campaigns aimed at encouraging a return to a healthy lifestyle that certainly includes a healthy diet but also the suspension of smoking. These observational results need further evaluation with prospective studies in order to quantify the effects of pandemic-induced changes in lifestyle on cardiovascular risk in women.

Cutaneous Melanoma Systematic Diagnostic Workflows and Integrated Reflectance Confocal Microscopy Assessed with a Retrospective, Comparative Longitudinal (2009-2018) Study.

BACKGROUND: The increasing global burden of melanoma demands efficient health services. Accurate early melanoma diagnosis improves prognosis. OBJECTIVES: To assess melanoma prevention strategies and a systematic diagnostic-therapeutical workflow (improved patient access and high-performance technology integration) and estimate cost savings. METHODS: Retrospective analysis of epidemiological data of an entire province over a 10-year period of all excised lesions suspicious for melanoma (melanoma or benign), registered according to excision location: reference hospital (DP) or other (NDP). A systematic diagnostic-therapeutical workflow, including direct patient access, primary care physician education and high-performance technology (reflectance confocal microscopy (RCM)) integration, was implemented. Impact was assessed with the number of lesions needed to excise (NNE). RESULTS: From 40,832 suspicious lesions excised, 7.5% (n = 3054) were melanoma. There was a 279% increase in the number of melanomas excised (n = 203 (2009) to n = 567 (2018)). Identification precision improved more than 100% (5.1% in 2009 to 12.0% in 2018). After RCM implementation, NNE decreased almost 3-fold at DP and by half at NDP. Overall NNE for DP was significantly lower (NNE = 8) than for NDP (NNE = 20), p < 0.001. Cost savings amounted to EUR 1,476,392.00. CONCLUSIONS: Melanoma prevention strategies combined with systematic diagnostic-therapeutical workflow reduced the ratio of nevi excised to identify each melanoma. Total costs may be reduced by as much as 37%.

Expression of aquaporins 3 in low grade risk of recurrence primary bladder cancer.

INTRODUCTION: Bladder cancer (BC) is one of the most frequent malignancy of the urinary tract. Recent studies demonstrated the role of aquaporins urothelial tumor cells (AQPs) as potential prognostic factor for tumor progression and invasion. In this study we investigated the AQP3 expression levels inside primary superficial (pTa) low grade bladder cancer, correlating with pathological parameters and clinical outcomes. MATERIALS AND METHODS: We retrospectively analyzed tumor samples of 66 patients with diagnosis of superficial urothelial (pTa) bladder cancer between 1997 and 2007. All patients underwent transurethral bladder resection (TURB) and immediate single instillation of mitomycin C. All tumors samples were blindly reviewed by two expert anatomopathologists and only pTa low grade urothelial bladder cancer were included. Cancer recurrence was defined as the detection of bladder lesions during follow-up cystoscopy. AQP3-immunoreactive areas detected at immunohistochemical analysis were classified as AQP3 positive. RESULTS: Of these 60.6% of patients was detected as negative for AQP3 expression. Forty-two patients develop cancer recurrence during follow-up with a mean progression free survival of 16.44 months. The absence of reaction for AQP3 was observed 56% (9/16) tumor grading G1 and 62% (31/50) tumor grading G2. No correlation was observed with sexual gender, grading of tumor differentiation, and recurrence of cancer disease. Kaplan-Meier curves of disease-free survival (DFS) showed a significant separation (p = 0.028) between patients AQP3-positive and AQP3-negative. It was observed a mean DFS of 23.83 and 14.43 months respectively in absence and presence of AQP3 expression. CONCLUSION: AQP3 expression is related to disease-free interval (DFI) and the absence of AQP3 expression correlates with a late relapse. The expression of AQP3 does not provide a reproducible quantitative aspect. AQP3 are not suitable to forecast tumor cell behavior but they perform a role as regulator for tumor cell homeostasis and for additional therapeutic developments.

Atypical fibroxanthoma and pleomorphic dermal sarcoma: A reappraisal.

BACKGROUND: Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) share clinical, pathological, immunohistochemical and molecular features, though PDS is associated with a more aggressive behavior. METHODS: We reviewed 71 tumors fulfilling criteria for AFX and PDS to further stratify their biological potential. RESULTS: Lesions were mainly located on the scalps of elderly men, and were often ulcerated. One case was necrotic, one showed vascular invasion, and one showed perineural invasion. Fifty-one tumors were limited to reticular dermis (71.8%), 20 invaded subcutaneous tissue, focally in 13 cases (18.3%), and diffusely in seven (9.9%). Subcutaneous invasion was present significantly more often in tumors showing predominantly spindle compared to pleomorphic/mixed cell morphology (P = 0.02). At a follow-up of 17-125 months, 4 cases recurred locally, 4, 6, 10 and 13 months after surgery; no metastases were observed. Three tumors were composed of spindle cells, and one of clear cells. Three cases had margins focally involved, while the fourth case had clear margins. CONCLUSION: Depth of invasion and state of margins are criteria predicting prognosis in AFX/PDS; in addition, spindle cell morphology seems to be related to a more infiltrative pattern of growth and to aggressiveness. Grouping these tumors on a morphologic base could help to clarify their different biological behavior.

Expression of calretinin in odontogenic keratocysts and basal cell carcinomas: A study of sporadic and Gorlin-Goltz syndrome-related cases.

Gorlin-Goltz syndrome (GGS), is an autosomal dominant inherited disorder related to germline mutation of PTCH1 gene, characterised by the presence of multiple developmental anomalies and tumours, mainly basal cell carcinomas (BCC) and odontogenic keratocysts (OKC). We analysed and compared the expression of calretinin in 16 sporadic OKCs, from 15 patients, and 12 syndromic OKCs from 11 patients; in 19 BCC's and 2 cutaneous keratocysts (CKC) belonging to 4 GGS patients, 15 sporadic BCCs and 3 steatocystomas (SC). Calretinin was negative in 10 of 12 syndromic OKCs, focally positive (<5% of cells) in 2; six sporadic OKCs were negative, 6 focally and 4 diffusely positive (p = .02, cases focally and diffusely positive vs. cases negative). All BCCs of 3 GGS patients were negative, the fourth patient presented two BCCs negative and 5 focally or diffusely positive; 7 sporadic BCCs were negative and 8 focally positive (p = NS). Two CKCs resulted negative in one GGS patient; 2 sporadic SCs were positive, and a third was negative. PTCH1 mutations produce an altered PTCH protein and an aberrant activation of Sonic hedgehog (SHH) pathway, leading to tumoral proliferation. It has been demonstrated that treatment of human foetal radial glia cells with SHH reduces, whereas the blockage of SHH increases calretinin expression. We found a lower expression of calretinin in syndromic OKCs compared to sporadic cases. Although calretinin's value in differential diagnosis between sporadic and syndromic tumours appears not crucial, our results shed light on the possible link between SHH dysfunction and calretinin expression in GGS-related tumours.

The diagnostic delay of oral carcinoma.

This paper describes the results of a retrospective study that analyzed the extent and role of diagnostic delays on the development and prognosis of oral cancer. We consulted the digital archives of the Anatomy and Pathology Department of the University Hospital of Modena and Reggio Emilia for the period from 2000 to 2016, to identify all patients with oral cavity lesions according to the SNOMED coding system. In total, 645 reports of squamous cell carcinoma of the oral cavity were retrieved. Data collected from the reports was supplemented with clinical information, with particular reference to the time of onset of the first signs and/or symptoms and the time elapsed between biopsy and definitive histological diagnosis following surgery. The average delay of patients from onset of signs and/or symptoms and seeking medical care was 112 days, or about 4 months. A longer delay was found for male with respect to female patients (151 days versus 82 days respectively; p < 0.015). An average delay of 40 days was observed between the first biopsy and the postoperative histological diagnosis. Results indicate that diagnostic delays occur frequently in oral tumours and can due to both the patient's wait-and-see conduct upon appearance of the first signs and/or symptoms, and to the organizational and communicative deficiencies among the different medical specialties. In light of these results, we make the recommendation to organize information campaigns through the Public Health Departments and specific screening programs, and to introduce an operational protocol for the prevention and early diagnosis of oral cancer, involving general medicine practitioners and dentists as the main promoters.

Impact of Dermoscopy and Reflectance Confocal Microscopy on the Histopathologic Diagnosis of Lentigo Maligna/Lentigo Maligna Melanoma.

BACKGROUND: Equivocal pigmented lesions of the head are usually biopsied to avoid inappropriate treatment. Clinical approach has evolved from simple visual examination to sophisticated techniques for selecting the biopsy sites. OBJECTIVE: This study aimed to retrospectively evaluate the efficiency of dermoscopy (DE) and reflectance confocal microscopy (RCM) in sampling a histopathologically representative focus of lentigo maligna/lentigo maligna melanoma. METHODS: Punch biopsies and surgical excisions of 72 patients, 37 men and 35 women (median age 70.6 years, range 39-90 years), affected by lentigo maligna/lentigo maligna melanoma of the head, sent from a single dermatology clinic, were reviewed for the presence of 5 histopathologic criteria: atypical junctional melanocytes, increased junctional melanocytes, follicular colonization, pagetoid spread and melanocytic junctional nests, plus other minor features. Forty-two patients were biopsied under DE and 30 under RCM guidance. RESULTS: Accuracy of the 2 techniques in sampling a representative tissue overlapped in most cases, although RCM selected sites to biopsy with more histopathologic criteria, in particular pagetoid spread and melanocytic nests. Interestingly, with RCM, inflammation and melanophages were observed more in biopsy than in excision. False positive cases were not registered. CONCLUSION: Compared with the sampling at naked eye, our results show that DE and RCM help selecting the most appropriate areas for biopsies, thus allowing not only more robust histopathologic diagnoses, but also a more accurate microstaging of tumor.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) Syndrome and Carcinoid Tumors With/Without NECH: A Clinicopathologic, Radiologic, and Immunomolecular Comparison Study.

The diagnostic criteria of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) are not well defined, and DIPNECH can be mistaken for carcinoids associated with neuroendocrine cell hyperplasia (NECH). In this study, we compared clinical, radiologic, histologic, immunohistochemical, and molecular features of DIPNECH and isolated carcinoids with/without NECH. The study population included 151 cases (77 female patients and 74 male patients), 19 with DIPNECH and 132 with carcinoids with/without NECH. None of the cases displayed molecular alterations or anaplastic lymphoma kinase expression. Compared with individuals with carcinoids with/without NECH, patients with DIPNECH were more likely to be female individuals (P<0.0001), nonsmokers (P=0.021), and symptomatic, and to have an obstructive/mixed respiratory defect, peripheral location of the lesions, and air trapping (P<0.0001) on chest computed tomography, and constrictive bronchiolitis on histology (P<0.0001). Among immunohistochemical markers, DIPNECH was associated with higher expression of thyroid transcription factor-1, CD10, and gastrin-releasing peptide/bombesin-like peptide (P<0.0001). Yet, when a purely histopathologic definition of DIPNECH was applied, 40% of isolated carcinoids also met the diagnostic criteria for DIPNECH, even in the absence of symptoms and/or radiologic abnormalities. Therefore, as DIPNECH represents a distinct clinical syndrome, we suggest the term DIPNECH be limited to cases presenting with respiratory symptoms, functional and/or radiologic abnormalities, and constrictive bronchiolitis on histology.

Analysis of a panel of druggable gene mutations and of ALK and PD-L1 expression in a series of thymic epithelial tumors (TETs).

INTRODUCTION: Thymic epithelial tumors (TETs) are rare neoplasms with different prognosis lacking consistent molecular alterations possibly leading to targeted therapy. We collected a consecutive series of TETs aimed at investigating the mutational status of druggable genes (EGFR, c-KIT, KRAS, BRAF, PDGFR-alpha and -beta, HER2 and c-MET) and the expression of ALK and PD-L1. PATIENTS AND METHODS: One hundred twelve consecutive cases of TETs and relative clinico-pathologic features were collected. Immunohistochemical expression of ALK (clone D5F3) and PD-L1 (clone E1L3N), molecular analysis of EGFR (exons 18-21), c-KIT (exons 9,11,13,14,17), KRAS (exon 2), BRAF (exon 15), PDGFR-alpha (exon 12) and -beta (exons 12, 14, 18), HER-2 (exons 19 and 20) and c-MET (exons 14, 17, 18, 19) mutations were performed. Immuno-molecular results were then statistically matched with clinico-pathologic characteristics. RESULTS: Patients were male in 54% of cases, with a median age of 61 years (range 19-83) and affected mainly by thymoma (78%) in stage II (45%). At molecular analysis, there were 4 c-KIT mutations (occurring in exon 11 V559A, L576P, Y553N and exon 17 D820E) in thymic carcinomas (typeC), but not in other tumor types (p=0.003). No mutations were detected in other genes and none case was ALK positive. Twenty-nine (26%) cases were PD-L1 positive (65% of thymic carcinomas and 18% of thymomas). High PD-L1 expression was statistically associated with WHO classification stage type C (p<0.001) and Masaoka stage III-IV disease (p=0.007). In univariate analysis, WHO classification type C, advanced Masaoka stage and absence of myasthenia, but not PD-L1 expressions were correlated with worse survival; at multivariate analysis, only WHO type C confirmed its negative prognostic role. CONCLUSION: A subset of TETs as thymic carcinomas can harbor c-KIT mutations and elevated PD-L1 expression that could represent targets of potential therapeutic use.

Does stem cell therapy induce myocardial neoangiogenesis? Histological evaluation in an ischemia/reperfusion animal model.

BACKGROUND: In an experimental model in the rabbit, a myocardial ischemia-reperfusion injury was obtained. Subsequently, the effects of homologous bone marrow stem cell (BMSC) administration were studied. METHODS: In 21 New Zealand adult rabbits, ischemia/reperfusion damage was induced by temporary occlusion of the anterior descending coronary artery. Homologous BMSCs were isolated, cultured and re-suspended for injection at the level of the ischemic zone. We evaluated the proangiogenetic effect of intramyocardial injections of BMSC at the peri-infarcted area. Histological evaluations were made after 20 days from the surgical procedure. RESULTS: In rabbits treated with intramyocardial BMSC administration, we demonstrated histologically capillary neoangiogenesis, without signs of tissue immunological reaction or of generation of new myocardial cells. On the contrary, only minimal neovascular supply was detected in rabbits treated with intravenous administration of BMSC. Only typical signs of ischemic myocardium injury were observed in the control group. CONCLUSION: These observations suggest that the effect of direct BMSC administration in ischemic myocardium could promote a capillary neoangiogenesis, which helps to prevent ischemic myocardial damage.

Clinical significance of pelvic lymph node status in prostate cancer: review of 1690 cases.

To assess whether any relationship exists between the number of histologically examined lymph nodes and the detection of metastases in pelvic lymph node dissection (PLND) specimens taken from patients with radical prostatectomy (RP) for prostatic adenocarcinoma. 1690 cases of RP with PNLD were included in the study; 54 % of the patients were submitted to extended PLND (ePLND). Kaplan-Meier curves confirm the negative prognostic significance of nodal metastases on the overall patients' survival (P < 0.0001). Nodal metastases are significantly associated with older age of patients (P = 0.0466), higher pT status (P < 0.0001), higher Gleason score (P < 0.0001) and positive surgical margin (P < 0.0001). The frequency of nodal metastases is significantly increased in cases submitted to ePLND (P < 0.0001), presumably due to the significantly higher number of lymphnodes retrieved using this procedure (P < 0.0001). In addition, regardless of the extent of PLND procedure, entire histological examination of PLND specimens is significantly associated with a higher frequency of nodal metastases (P < 0.0001). When we considered only pN0 cases, 21 display adverse prognosis and died of disease during the follow-up. The number of pelvic lymphnodes examined is significantly lower in the group of patients who die of the disease compared to that of survivors (P = 0.0448). In addition, Kaplan-Meier analysis shows that patients with 10 or fewer examined lymphnodes have significantly shorter disease-specific survival (P = 0.0151). Our findings confirm the negative prognostic significance of N status in prostate cancer. We suggest the examination of a minimum number of 10 lymphnodes, together with entire PLND processing, for accurate assessment of N status.

Laparoscopic surgery for colorectal cancer is not associated with an increase in the circulating levels of several inflammation-related factors.

It has been hypothesized that inflammatory response triggered by surgery might induce the release of molecules that could promote proliferation, invasion and metastasis of surviving cancer cells. To test this hypothesis, the levels of multiple inflammation-related circulating factors were analyzed in patients undergoing surgery for colorectal cancer. A Luminex xMAP system was used to simultaneously assess levels of IL-1ß, IL-1ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, FGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1ß, PDGF-BB, RANTES, TNF-α and VEGF in 20 colorectal cancer patients and 10 age-matched non-neoplastic patients. In cancer patients analyses were performed at baseline (before surgery) and at different time points (up to 30 days) following laparoscopic surgery. Significantly higher levels of IL-1ß, IL-7, IL-8, G-CSF, IFN-γ and TNF-α were detected in colorectal cancer patients compared to controls at baseline. In colorectal cancer patients, circulating levels decreased progressively following surgery and after day 30 post-surgery were no longer different from controls. These findings suggest that expression levels of several cytokines are higher in colorectal cancer patients compared to control subjects and no significant increase in several inflammation-related circulating factors is observed following laparoscopic surgery for cancer. Confirmation and validation in a different and larger cohort of patients are warranted.

A comparative analysis between laparoscopy and open colectomy: assessment of perioperative and oncological outcomes.

AIM: Aim of the study was to compare two groups of patients affected by colorectal adenocarcinoma that underwent to open colectomy and laparoscopic colectomy respectively, highlighting the advantage and problems. MATERIAL OF STUDY: This is a retrospective analysis. Between January 2003 and December 2006, 54 patients who underwent colectomy were recruited. Of these, 26 patients underwent open colectomy, and 28 laparoscopy. RESULTS: For open colectomy the average duration of surgery was 177.9 minutes (surgical time) and 280.4 minutes (time of operating room) with a minimum of 110 and a maximum of 360 minutes, with significant differences according to type of surgery performed and the patient's clinical history. For laparoscopy the average duration was 293 minutes, (range 135 - 520), with significant differences depending on the portion of the intestinal tract removed. DISCUSSION: The comparison of two different surgical techniques, laparoscopic and open colectomy revealed some differences. The duration of the resection was greater for laparoscopy when compared to the traditional technique. CONCLUSIONS: Both approaches are technically feasible, safe and oncologically correct. Laparoscopic technique shows a much more favorable outcome in terms of pain, absence of extensive scarring, the incidence of incisional hernias and hospital stay -surgery compared with surgery laparotomy.

Radiotherapy-induced mesorectum alterations: histological evaluation of 90 consecutive cases.

OBJECTIVE: In order to identify the radiotherapy-induced histological modifications in the mesorectum, we reviewed the surgical specimens of 90 rectal resections comprehensive of the total mesorectal excision (23 cases radiologically classified as cT2N0M0 and 67 as cT3N0M0). All patients were preoperative treated with radiotherapy: 20 with 50 Gy, 20 with 20 Gy and 50 Gy irradiation associated to FOLFOX scheme chemotherapy. MATERIAL AND METHODS: Routine hematoxylin and eosin stained serial slides at 5 mm of intervals were obtained from surgical specimens and included the tumor site and the adjacent irradiated mucosa, the submucosa and the muscular layers of the rectal wall and the mesorectal adipose tissue, completely removed until to the mesorectal fascia. Ten subjects (eight cT2N0M0 and two cT3N0M0), who did not received preoperative oncological treatments were adopted as controls. RESULTS: Histologically, examination revealed fibrosis of the adipose tissue in 86 cases (95%), vascular damage including vasculities and fibrotic thickening wall of arteries and veins in 46 cases (51%), sclero-hyalinosis of lymph nodes with pericapsular fibrosis in 22 cases (23%) and perineural deposition of fibrosis in 12 (13%). These findings were ubiquitously observed in the whole mesorectum. Fibrosis of the adipose tissue and vasculitis were mainly associated to the combination of 50 Gy radiations plus chemotherapy (p < 0.05). CONCLUSION: The detection of histopathological alterations in the mesorectum can give reason of the well-known postoperative complications and long-term sequels.

Endobronchial metastasis: an epidemiologic and clinicopathologic study of 174 consecutive cases.

PURPOSE: Endobronchial metastases from extrapulmonary solid tumors are a rare event and currently available epidemiological and clinico-pathological data mainly derive from anecdotal case reports. METHODS: A series of 174 consecutive cases of endobronchial metastases from extrathoracic solid tumors were collected over a period of 18 years. Immunohistochemistry was performed in 115 cases. Complete imaging features were available in 81 patients, and analysis of the latency period between primitive tumor diagnosis and occurrence of endobronchial metastasis was obtained. RESULTS: Among all bronchoscopic examinations performed in the same period for malignancy, a mean of 5.6 cases per year consisted of endobronchial metastases (range 2-17 cases), with a statistically significant increase when comparing the periods 1992-2000 (65 cases, 37%) and 2001-2009 (109 cases, 63%) (p = 0.05). Overall, 4% of endobronchial biopsies for suspected malignancy disclosed an endobronchial metastasis from extrapulmonary tumor. Breast (52 cases, 30%), colorectal (42 cases, 24%), renal (14%), gastric (6%) and prostate (4.5%) cancers and melanoma (4.5%) were the most common metastatic neoplasms presenting as endobronchial mass. One-hundred fifty-four cases were identified after the primitive tumor diagnosis (metachronous cases, 89%), 11 cases were simultaneously evidenced in extrapulmonary and endobronchial sites (synchronous cases, 6%), while 9 occult metastatic cases (5%) first presented as endobronchial mass (anachronous cases). Overall, mean latency from extrapulmonary tumor diagnosis and endobronchial metastasis was 136 months (range, 1-300 months). The most frequent symptoms were dyspnea (23%), cough (15%) and haemoptysis (12%), while 26% of patients were totally asymptomatic. At radiology, 53% presented as multiple pulmonary nodules, while other cases presented as hilar and mediastinal mass, single peripheral nodule, atelectasis or pleural effusion. CONCLUSIONS: Endobronchial metastases from extrapulmonary tumors account for about 4% of all bronchoscopic biopsies performed for suspected malignancy and in 5% of the cases the metastasis is the first manifestation of the neoplasm.

Lung cancer histologic and immunohistochemical heterogeneity in the era of molecular therapies: analysis of 172 consecutive surgically resected, entirely sampled pulmonary carcinomas.

On the basis of seminal studies in the 1980s, appreciable histologic heterogeneity, ranging from 45% to 70% of cases, may be encountered in lung cancer. However, the epidemiologic and histologic landscape of lung cancer in the last 3 decades has radically changed. In this study, 172 consecutive surgically resected primary lung carcinomas evaluated from 2010 to 2012 were entirely sampled and examined according to current histologic classifications. In 129 cases, a positive preoperative biopsy was also available. Major histologic heterogeneity (a single tumor showing at least 2 different histologic types) and minor histologic heterogeneity (a single tumor showing just 1 histologic type but at least 2 different growth patterns) were evaluated in all cases. Immunohistochemical heterogeneity (ie, "aberrant" staining) was also assessed using a panel of markers of adenocarcinoma (TTF-1, napsin, and CK7), squamous cell carcinoma (p63, CK5/6), and neuroendocrine differentiation (chromogranin and synaptophysin), both on positive biopsies and surgical specimens. Overall, major and minor histologic heterogeneity on resections were disclosed in 4% (7 cases) and 50.6% (87 cases), respectively, whereas just 1 case of minor heterogeneity (pleomorphic carcinoma) was observed on biopsies. Minor heterogeneity was limited to adenocarcinomas (82.6%, 81/98 cases) and sarcomatoid carcinomas (6 pleomorphic types among 8 sarcomatoid carcinomas). Immunohistochemical heterogeneity was recorded in 22.6% of the cases, with expression of p63 and CK5/6 in a subset of adenocarcinomas (25 cases, 25.5%), CK7 in 17.4% of squamous cell carcinomas, and synaptophysin in 6 cases of non-neuroendocrine tumors (4%, 6/155). The high rate of adenocarcinomas, accounting for 57% (98 cases) of 172 consecutively resected lung cancers, reflects the new scenario of thoracic oncology and may explain the significant lower rate of major histologic heterogeneity (4%) and the higher frequency of different architectural patterns (minor heterogeneity) that we found in lung cancer compared with previous studies.

The role of molecular analyses in the diagnosis and treatment of non-small-cell lung carcinomas.

Non-small-cell lung cancer (NSCLC) subtyping has recently been a key factor in determining patient management with novel drugs. In addition, the identification of distinct oncogenic driver mutations frequently associated with NSCLC histotype and coupled to the clinical responses to targeted therapies have revolutionized the impact of histologic type and molecular biomarkers in lung cancer. Several molecular alterations involving different genes (EGFR, KRAS, ALK, BRAF, and HER2) seem to have a remarkable predilection for adenocarcinoma and specific inhibitors of EGFR and ALK are now available for patients with adenocarcinoma harboring the relevant gene alterations. The efficacy of histology-based and molecular-targeted therapies had a deep impact in (1) re-defining classification of lung cancer (particularly adenocarcinomas) and (2) routine clinical practice of pathologists involved in optimization of handling of tissue samples in order to guarantee NSCLC subtyping with the help of immunohistochemistry and adequately preserve tumor cells for molecular analysis. In agreement with the modern multidisciplinary approach to lung cancer, we reviewed here the diagnostic and predictive value of molecular biomarkers according to the clinical, pathologic, and molecular biologist viewpoints.