Bone marrow stroma CD40 expression correlates with inflammatory mast cell infiltration and disease progression in splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is a mature B-cell neoplasm characterized by rather indolent clinical course. However, nearly one third of patients experience a rapidly progressive disease with a dismal outcome. Despite the characterization of clone genetics and the recognition of deregulated immunologic stimulation in the pathogenesis of SMZL, little is known about microenvironment dynamics and their potential biological influence on disease outcome. Here we investigate the effect of stroma-intrinsic features on SMZL disease progression by focusing on the microenvironment of the bone marrow (BM), which represents an elective disease localization endorsing diagnostic and prognostic relevance. We show that the quality of the BM stromal meshwork of SMZL infiltrates correlates with time to progression. In particular, we describe the unfavorable prognostic influence of dense CD40 expression by BM stromal cells, which involves the contribution of CD40 ligand (CD40L)-expressing bystander mast cells infiltrating SMZL BM aggregates. The CD40/CD40L-assisted crosstalk between mesenchymal stromal cells and mast cells populating the SMZL microenvironment finds correlation in p53(-/-) mice developing SMZL and contributes to the engendering of detrimental proinflammatory conditions. Our study highlights a dynamic interaction, playing between nonneoplastic elements within the SMZL niche, toward disease progression.

Reproducibility of the WHO histological criteria for the diagnosis of Philadelphia chromosome-negative myeloproliferative neoplasms.

This study, performed on behalf of the Italian Registry of Thrombocythaemias (Registro Italiano Trombocitemie), aimed to test the inter-observer reproducibility of the histological parameters proposed by the WHO classification for the diagnosis of the Philadelphia chromosome-negative myeloproliferative neoplasms. A series of 103 bone marrow biopsy samples of Philadelphia chromosome-negative myeloproliferative neoplasms consecutively collected in 2004 were classified according to the WHO criteria as follows: essential thrombocythaemia (n=34), primary myelofibrosis (n=44) and polycythaemia vera (n=25). Two independent groups of pathologists reviewed the bone marrow biopsies. The first group was asked to reach a collegial 'consensus' diagnosis. The second group reviewed individually all the cases to recognize the main morphological parameters indicated by the WHO classification and report their results in a database. They were subsequently instructed to individually build a 'personal' diagnosis of myeloproliferative neoplasms subtype just assembling the parameters collected in the database. Our results indicate that high levels of agreement (≥70%) have been reached for about all of the morphological features. Moreover, among the 18 evaluated histological features, 11 resulted statistically more useful for the differential diagnosis among the different Philadelphia chromosome-negative myeloproliferative neoplasms. Finally, we found a high percentage of agreement (76%) between the 'personal' and 'consensus' diagnosis (Cohen's kappa statistic >0.40). In conclusion, our results support the use of the histological criteria proposed by the WHO classification for the Philadelphia chromosome-negative myeloproliferative neoplasms to ensure a more precise and early diagnosis for these patients.

The sea urchin sns5 insulator protects retroviral vectors from chromosomal position effects by maintaining active chromatin structure.

Silencing and position-effect (PE) variegation (PEV), which is due to integration of viral vectors in heterochromatin regions, are considered significant obstacles to obtaining a consistent level of transgene expression in gene therapy. The inclusion of chromatin insulators into vectors has been proposed to counteract this position-dependent variegation of transgene expression. Here, we show that the sea urchin chromatin insulator, sns5, protects a recombinant gamma-retroviral vector from the negative influence of chromatin in erythroid milieu. This element increases the probability of vector expression at different chromosomal integration sites, which reduces both silencing and PEV. By chromatin immunoprecipitation (ChIP) analysis, we demonstrated the specific binding of GATA1 and OCT1 transcription factors and the enrichment of hyperacetylated nucleosomes to sns5 sequences. The results suggest that this new insulator is able to maintain a euchromatin state inside the provirus locus with mechanisms that are common to other characterized insulators. On the basis of its ability to function as barrier element in erythroid milieu and to bind the erythroid specific factor GATA1, the inclusion of sns5 insulator in viral vectors may be of practical benefit in gene transfer applications and, in particular, for gene therapy of erythroid disorders.

Pathophysiology of age-related diseases.

A Symposium regarding the Pathophysiology of Successful and Unsuccessful Ageing was held in Palermo, Italy on 7-8 April 2009. Three lectures from that Symposium by G. Campisi, L. Ginaldi and F. Licastro are here summarized. Ageing is a complex process which negatively impacts on the development of various bodily systems and its ability to function. A long life in a healthy, vigorous, youthful body has always been one of humanity's greatest dreams. Thus, a better understanding of the pathophysiology of age-related diseases is urgently required to improve our understanding of maintaining good health in the elderly and to program possible therapeutic intervention.

Associations between Notch-2, Akt-1 and HER2/neu expression in invasive human breast cancer: a tissue microarray immunophenotypic analysis on 98 patients.

OBJECTIVE: We aimed to investigate the existence of associations between well-established and newly recognized biological and phenotypic features of breast cancer involved in tumor progression and prognosis. METHODS: Ninety-eight cases of invasive breast cancer were assessed for the immunohistochemical expression of estrogen and progesterone receptors, Ki-67, HER2, Akt-1, and Notch-2, using the tissue microarray technique. Data regarding tumor histotype, histological grade, tumor size and lymph node status were collected for each patient and included in the analysis. RESULTS: Several significant associations between histological and/or immunophenotypic features came from the analysis of our data. Positive associations were observed between estrogen and progesterone receptors, tumor grade and proliferation index, tumor grade and HER2, Akt-1 and estrogen receptors, and Notch-2 and HER2. Inverse associations were noted between hormone receptors and tumor grade, hormone receptors and HER2, Akt-1 and tumor grade, and Akt-1 and nodal invasion. CONCLUSIONS: Our results, showing the existence of a number of estrogen receptor-positive tumors with Akt-1 expression, better degree of differentiation, and no lymph node involvement, along with the presence of HER2-positive tumors with strong Notch-2 expression, support the role of Notch and Akt in breast cancer progression and suggest that they may also represent new appealing therapeutic targets.

Clinical implications of a rare renal entity: Pleomorphic Hyalinizing Angiectatic Tumor (PHAT).

Pleomorphic Hyalinizing Angiectatic Tumor (PHAT) is a rare benign lesion characterized by slow growth, infiltrative behavior and high rate of local recurrences. Only one case has been described in retroperitoneum, at renal hilum, but not involving pelvis or parenchyma. Here we present the first case of PHAT arising in the renal parenchyma. A nodular lesion in right kidney lower pole was diagnosed to a 61 year old woman. The patient underwent right nephrectomy. Microscopically, the lesion showed solid and pseudo-cystic components with hemorrhagic areas characterized by aggregates of ectatic blood vessels. Pleomorphic cells were characterized by large eosinophilic cytoplasm with irregular and hyperchromatic nuclei. Immunohistochemistry was performed and the lesion was classified as a Pleomorphic Hyalinizing Angiectatic Tumor (PHAT). Due to the clinical behavior of this tumor, in spite of its benign nature, review of the surgical margins and close follow up after partial nephrectomy are mandatory.

Essential thrombocythemia or chronic idiopathic myelofibrosis? A single-center study based on hematopoietic bone marrow histology.

We reviewed a large series of patients with essential thrombocythemia diagnosed on the basis of the Polycythemia Vera Study Group criteria, and reclassified them by evaluating their major morphologic features and clinical course using the World Health Organization classification. The morphologic review of the bone marrow biopsies of 116 patients (44 males and 72 females; aged 19 - 83 years, median 55 years; median follow-up 121 months) led to 22 cases (19%) being classified as essential thrombocythemia (ET), 24 (21%) as chronic idiopathic myelofibrosis (CIMF)-0, 44 (37%) as CIMF-1, 13 (12%) as CIMF-2, 9 (8%) as latent phase polycythemia vera, and four (3%) as chronic myeloproliferative disorder, unclassifiable. There was a significant difference in the median age of the ET and fibrotic CIMF patients (54.7 +/- 13.55 vs. 59.13 +/- 15.05 years; P = 0.03). Histologic analysis showed that the simultaneous presence of loose clusters of large/giant megakaryocytes and nuclear hyperlobulation was significantly different between the ET and the prefibrotic CIMF (P<0.01) and fibrotic CIMF patients (P<0.01), and that the association of dense clusters of megakaryocytes with maturation defects and bulbous nuclei also distinguished the prefibrotic CIMF (P<0.05) and fibrotic CIMF patients (P<0.001) from those with ET. The association of cellularity, granulocytic proliferation and reticulin fibers was helpful in distinguishing prefibrotic from fibrotic CIMF (P<0.001).

European consensus on grading bone marrow fibrosis and assessment of cellularity.

Quantification of characteristic bone marrow biopsy features includes basic parameters such as cellularity and fiber content. These are important to assess the dynamics of disease processes with a significant impact on risk stratification, survival patterns and, especially, therapy-related changes. A panel of experienced European pathologists and a foreign expert evaluated, at a multi-headed microscope, a large number of representative slides of trephine biopsies from patients with myelofibrosis in an attempt to reach a consensus on how to grade cellularity and fibrosis. This included a critical evaluation of previously described scoring systems. During the microscopic analysis and subsequent discussion and voting, the importance of age-dependent decrease in cellularity was recognized. Grading of myelofibrosis was simplified by using four easily reproducible categories including differentiation between reticulin and collagen. A consensus was reached that the density of fibers must be assessed in relation to the hematopoietic tissue. This feature is especially important in order to avoid a false impression of a reduced fiber content in fatty and/or edematous bone marrow samples after treatment. The consensus for measuring myelofibrosis by clear and reproducible guidelines achieved by our group should allow for precise grading during the disease process and after therapy.

Intravesical chemotherapy for intermediate risk non-muscle invasive bladder cancer recurring after a first cycle of intravesical adjuvant therapy.

CONTEXT: The therapeutic strategy in intermediate risk (IR) non-muscle invasive bladder cancer (NMIBC) recurring after intravesical therapy (IT) is not well defined. Most patients are usually retreated by Bacillus Calmette-Guerin (BCG). AIMS: To evaluate the efficacy of intravesical chemotherapy (ICH) given at recurrence after the first cycle of ICH in IR-NMIBC recurring 6 months or later. SETTINGS AND DESIGN: Retrospective analysis of the efficacy of ICH given after previous IT. MATERIALS AND METHODS: The clinical files of IR-NMIBC patients recurring later than 6 months after transurethral resection (TUR) and IT and retreated by IT were reviewed. The patients should be at intermediate risk both initially and at the first recurrence. BCG should have been given at full dose. Cytology and cystoscopy were performed 3 monthly for 2 years and then 6 monthly. STATISTICAL ANALYSIS: The RFS was estimated by the Kaplan-Meier method and the differences between treatment groups were compared by log-rank test. Mann Whitney U-test was used to compare the parameters' distribution for median time to recurrence. Multivariate Cox proportional hazards models were used. RESULTS: The study included 179 patients. The first IT was ICH in 146 (81.6%) and BCG in 33 (18.4%), re-IT was ICH in 112 (62.6%) and BCG in 67 (37.4%) patients. Median time to recurrence was 18 and 16 months after first and second IT (P = 0.32). At 3 years, 24 (35.8%) and 49 (43.8%) patients recurred after BCG and ICH, respectively (P = 0.90). No difference in RFS was found between BCG and ICH given after a first cycle of ICH (P = 0.23). CONCLUSIONS: Re-treatment with ICH could represent a legitimate option to BCG in patients harboring IR-NMIBC recurring after TUR and previous ICH. Prospective trials are needed.

Rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone as first-line treatment for splenic marginal zone lymphoma: a Fondazione Italiana Linfomi phase II study.

Rituximab® provides high response rates and effective disease palliation in patients with splenic marginal zone lymphoma (SMZL). We conducted a phase II trial in patients with SMZL who were either untreated or were splenectomized but had shown disease progression within 1 year after splenectomy. Treatment consisted of six courses of Rituximab with cyclophosphamide, vincristine, non-pegylated liposomal doxorubicin and prednisone (R-COMP). Fifty-one patients were eligible for the analysis. The overall response rate was 84%. The 6-year progression-free survival and overall survival were 54% and 72%, respectively. Toxicity was substantial (grade≥3 neutropenia: 26%; grade≥3 infections: 8%). Of the 15 deaths, two occurred on treatment (one sepsis and one pneumonia). Six deaths were due to lymphoma progression, four to secondary neoplasia, one to sepsis, one to pneumonia and one to splenectomy complications. R-COMP should be restricted to patients with bulky disease associated with symptoms or to patients with possible histological transformation.

Value of bone marrow biopsy in the diagnosis of essential thrombocythemia.

BACKGROUND AND OBJECTIVES: Essential thrombocythemia (ET) is a Philadelphia chromosome-negative chronic myeloproliferative disorder (CMPD) whose diagnosis, according to the Polycythemia Vera Study Group (PVSG) criteria, does not include histopathological data. The new WHO classification of CMPD has supplied new diagnostic guidelines which highlight the value of histopathology and facilitate a more precise differentiation of ET from reactive conditions and other CMPDs. DESIGN AND METHODS: Bone marrow biopsies from 142 adult patients diagnosed with ET according to PVSG criteria were evaluated using the new WHO classification. Megakaryocyte morphology and arrangement, amount of fibrosis and a clustering index were studied along with determination of microvessel density (MVD), amount of CD34+ cells and percentage of MIB-1+ cells and megakaryocytes. The last value, indicated as megakaryocyte proliferation index (MPI), was determined and expressed as a percentage of the counted cells. RESULTS: According to WHO criteria the 142 biopsies were classified as follows: ET (21%); Idiopathic myelofibrosis (IMF) grade 0 (30%); IMF-1 (34%); IMF-2 (10%) ET/IMF-0 (5%). A significant difference (p<0.001) was observed between clustering index values in ET and IMF cases. A peculiar proliferative feature of megakaryocytes, defined coupling, was detected in all ET cases. MVD was more pronounced and the number of CD34+ cells higher in cases of IMF than in cases of ET (p <0.005; p = 0.001, respectively) and MVD significantly correlated with the extent of fibrosis (r=0.861). ET cases showed the lowest values of proliferation; IMF-0 and IMF-1 showed higher values while a decrease of MPI was observed in IMF-2 in accordance with the increase of fibrosis. INTERPRETATION AND CONCLUSIONS: In the diagnosis of thrombocythemic disorders, a multidisciplinary approach must include the evaluation of bone marrow biopsies. Some histopathological criteria, along with the use of markers related to activity and proliferation such as CD34 and MIB-1, underline the biological differences between ET and prefibrotic states of IMF.

Long-lasting remission of primary hepatic lymphoma and hepatitis C virus infection achieved by the alpha-interferon treatment.

Primary hepatic lymphoma is a rare but well-defined lymphoma entity that often pursues an aggressive clinical course. Most cases have been described in hepatitis C virus (HCV)-related chronic liver disease patients. Although anthracycline-based chemotherapy has been reported to be highly effective, the best therapeutic strategy has not been defined yet. The prognosis is dismal especially in patients treated with chemotherapy alone or when an advanced liver disease is present. Herein, we describe a case of primary hepatic large B-cell non-Hodgkin's lymphoma, in a patient with HCV chronic infection. After a minor response with eight cycles of CHOP chemotherapy, a complete and sustained remission was obtained with alpha-interferon at the daily dose of 3 MU. HCV-RNA clearance pace from the blood almost paralleled the response of the lymphoma and both diseases went in remission within 1 year of therapy. The possible place of alpha-Interferon in the treatment of primary hepatic lymphoma is discussed.

Bone marrow biopsy in hemophagocytic syndrome.

AIMS: Hemophagocytic syndrome (HPS) is a severe and acute clinical event occurring with fever, hepatosplenomegaly, and pancytopenia due to uncontrolled phagocytosis of blood cells and precursors. Although HPS represents a secondary phenomenon, it can mask the underlying condition, generally a neoplastic or infective disease, thus making the patient management rather difficult. The aims of this study were to point out the main pathological features useful to highlight the primary disease and show the eventual discrepancies among the different cases. METHODS AND RESULTS: Bone-marrow biopsies (BMBs) of 26 patients with HPS were morphologically and immunophenotypically evaluated; the patients were 12 females and 14 males with mean age of 45.8 years (range 18-80 years). Fifteen patients had a hematological neoplasia either at onset (13 cases) or relapse (2 cases); 5 patients had evidence of active infection immediately prior to HPS development, whereas in 6 patients no definite etiology was established. Cases were therefore divided into neoplasia related, infection related, and "idiopathic". In all cases BMB showed marked histiocyte hyperplasia with hemophagocytosis. In cases of bone-marrow lymphoma or leukemia involvement, immunohistochemistry allowed diagnosis of the underlying disease to be made; infection-related cases showed a reactive marrow with mature interstitial T-lymphoid infiltration, whereas in idiopathic cases T-cells were mainly aggregated in small clusters. In no cases were significant percentages of natural-killer (NK) cells detected. INTERPRETATION AND CONCLUSIONS: Although no strict morphological or immunophenotypical criteria able to allow an immediate diagnosis of underlying disease were pointed out, in most cases BMB proved to be an essential and reliable diagnostic tool. According to our experience, when HPS occurs, the first diagnosis to investigate is a neoplastic disease which sometimes can be latent or hidden.

[BETWEEN HORROR AND SCIENCE: THE BIRTH OF A CABINET OF PATHOLOGICAL ANATHOMY AT THE UNIVERSITY OF PALERMO]. / TRA ORRORE E SCIENZA: LA NASCITA DEL GABINETTO DI ANATOMIA PATOLOGICA DELL'UNIVERSITÁ DI PALERMO.

This paper outlines the history of the Cabinet of Pathological Anathomy at the University of Palermo, describes rapidly its current status and analyzes the composition of its displays in 1859. It aims to highlight the analogies with other collections of a similar kind and to pinpoint potential actions to endorse and develop this important scientific asset.

Discordance rate of HER2 status in primary breast carcinomas versus synchronous axillary lymph node metastases: a multicenter retrospective investigation.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is considered to be a therapeutic and prognostic marker in the management of breast carcinoma (BC), although discordance rates between primary and metastatic or locally recurrent lesions have been reported. METHODS: One hundred and forty-eight paraffin-embedded BC tissues from patients of mean age 59.27 (33-96) years and corresponding synchronous lymph node metastases were collected and retrospectively studied using immunohistochemistry and fluorescence in situ hybridization to evaluate HER2 status. Fleiss-Cohen weighted k statistics were used to assess the concordance rate between HER2 status of the primary BC and the synchronous metastatic lesions. RESULTS: The overall concordance rate for HER2 was 95.28%. Eighty-nine cases were concordantly HER2-negative in primary BC and nodal metastases, and 52 cases were HER2-positive in both primary and metastatic tumors. Changes in HER2 status between primary BC and corresponding synchronous metastases were observed in seven (4.72%) cases. Three of the discordant cases were HER2-negative in the primary tumor and HER2-positive in the metastases, while four cases were HER2-positive in the primary BC and HER2-negative in the metastases. No significant correlations were identified between HER2 status and expression of hormone receptors, growth fraction (Ki-67), or other histopathological parameters (pT, pN, grade). CONCLUSION: Simultaneous determination of HER2 in BC and corresponding metastatic lymph nodes is not mandatory, but may strongly influence the therapeutic management. It was demonstrated that loss of HER2 amplification results in worse post-relapse survival and overall survival in BC patients and, on the other hand, a gain in HER2 expression in metastatic lymph nodes of BC may allow the possibility of a targeted treatment. Thus, our opinion is that significant prognostic information may be obtained by simultaneous assessment of HER2 status in both primary and synchronous metastatic BC.

Challenges and new prospects in hepatosplenic γδ T-cell lymphoma.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoid neoplasms characterized by aggressive clinical behavior and dismal prognosis. Hepatosplenic γδ T-cell lymphoma (γδ-HSTL) is a particular form of PTCL that arises from a small subset of γ/δ T-cell receptor-expressing lymphocytes. γδ-HSTL has a rapidly progressive course and poor outcome due also to its refractoriness to conventional chemotherapy regimens. The very low incidence of γδ-HSTL, along with its propensity to mimic different pathological entities, makes this lymphoma a true diagnostic challenge. In this review, we highlight the biological and clinical features of γδ-HSTL that contribute to making this lymphoma a mostly incurable disease. Moreover, we provide a new insight into the crosstalk between HSTL clones and the bone marrow, liver and spleen vascular microenvironment, in which neoplastic cells reside and proliferate. We further discuss γδ-HSTL associated molecules that might be proposed as potential targets for novel therapeutic approaches.

R-CVP versus R-CHOP versus R-FM for the initial treatment of patients with advanced-stage follicular lymphoma: results of the FOLL05 trial conducted by the Fondazione Italiana Linfomi.

PURPOSE: Although rituximab (R) is commonly used for patients with advanced follicular lymphoma (FL) requiring treatment, the optimal associated chemotherapy regimen has yet to be clarified. PATIENTS AND METHODS: We conducted an open-label, multicenter, randomized trial among adult patients with previously untreated stages II to IV FL to compare efficacy of eight doses of R associated with eight cycles of cyclophosphamide, vincristine, and prednisone (CVP) or six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or six cycles of fludarabine and mitoxantrone (FM). The principal end point of the study was time to treatment failure (TTF). RESULTS: There were 534 patients enrolled onto the study. Overall response rates were 88%, 93%, and 91% for R-CVP, R-CHOP, and R-FM, respectively (P=.247). After a median follow-up of 34 months, 3-year TTFs were 46%, 62%, and 59% for the respective treatment groups (R-CHOP v R-CVP, P=.003; R-FM v R-CVP, P=.006; R-FM v R-CHOP, P=.763). Three-year progression-free survival (PFS) rates were 52%, 68%, and 63% (overall P=.011), respectively, and 3-year overall survival was 95% for the whole series. R-FM resulted in higher rates of grade 3 to 4 neutropenia (64%) compared with R-CVP (28%) and R-CHOP (50%; P< .001). Overall, 23 second malignancies were registered during follow-up: four in R-CVP, five in R-CHOP, and 14 in R-FM. CONCLUSION: In this study, R-CHOP and R-FM were superior to R-CVP in terms of 3-year TTF and PFS. In addition, R-CHOP had a better risk-benefit ratio compared with R-FM.

Treatment of pulmonary neuroendocrine tumours: state of the art and future developments.

The current classification of pulmonary neuroendocrine tumours includes four subtypes: low-grade typical carcinoid tumour (TC), intermediate-grade atypical carcinoid tumour (AC), and two high-grade malignancies: large cell neuroendocrine carcinoma and small cell lung cancer (SCLC). Unfortunately, with the exclusion of SCLC, no large phase II and III trials for pulmonary neuroendocrine tumours have been published. Thus, several treatment approaches are available for their treatment but none of them has been validated in appropriately designed and adequately sized clinical trials. The main problem of the published studies is that they include neuroendocrine tumours from various sites of origin with different clinical behaviour. It is important that future studies consider these tumours separately. In this regard, increased awareness and referral of these patients to tertiary centres, in which a multidisciplinary management is available, may be of value. The aim of this review is to evaluate the state of the art and discuss future developments in the management of pulmonary neuroendocrine tumours excluding SCLC which we consider should be addressed in a different issue.

EGFR mutations detected on cytology samples by a centralized laboratory reliably predict response to gefitinib in non-small cell lung carcinoma patients.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are reliably detected by referral laboratories, even if most lung cancer cytology specimens sent to such laboratories contain very few cells. However, EGFR mutations may be distributed heterogeneously within tumors, thereby raising concerns that mutations detected on cytology are not representative of the entire tumor and, thus, are less reliable in predicting response to tyrosine kinase inhibitor (TKI) treatment than mutations detected on histology. To address this issue, the authors reviewed their clinical practice archives and compared the outcome of TKI treatment among patients who were selected by cytology versus patients who were selected by histology. METHODS: From July 2010 to July 2012, 364 cytology samples and 318 histology samples were received. Exon 19 deletions and the L858R point mutation in exon 21, detected by fragment assay and TaqMan assay, respectively, were confirmed by direct sequencing; discrepancies were resolved by cloning polymerase chain reaction products. The response rate (RR) and progression-free survival (PFS) at 12 months (range, 3-34 months) were evaluable in 13 EGFR-mutated patients who were selected for treatment by cytology and 13 patients who were selected by histology. RESULTS: The mutation rate was similar in histology samples (8.5%) and cytology samples (8.8%). The RR (54%) and PFS (9.2 months) were similar in histologically selected patients and cytologically selected patients (RR, 62%; PFS, 8.6 months; P = .88). The disease control rate (responsive plus stable disease) was 92% in histologically selected patients and 100% in cytologically selected patients. CONCLUSIONS: EGFR mutations detected on cytology specimens by a centralized laboratory can predict TKI treatment response equally well as mutations identified on histology samples.