Filippo Marino

Survival and Disease Progression in Essential Thrombocythemia Are Significantly Influenced by Accurate Morphologic Diagnosis: An International Study

PURPOSE The WHO diagnostic criteria underscore the role of bone marrow (BM) morphology in distinguishing essential thrombocythemia (ET) from early/prefibrotic primary myelofibrosis (PMF). This study examined the clinical relevance of such a distinction. METHODS Representatives from seven international centers of excellence for myeloproliferative neoplasms convened to create a clinicopathologic database of patients previously diagnosed as having ET (N = 1,104). Study eligibility criteria included availability of treatment-naive BM specimens obtained within 1 year of diagnosis. All bone marrows subsequently underwent a central re-review. RESULTS Diagnosis was confirmed as ET in 891 patients (81%) and was revised to early/prefibrotic PMF in 180 (16%); 33 patients were not evaluable. In early/prefibrotic PMF compared with ET, the 10-year survival rates (76% and 89%, respectively) and 15-year survival rates (59% and 80%, respectively), leukemic transformation rates at 10 years (5.8% and 0.7%, respectively) and 15 years (11.7% and 2.1%, respectively), and rates of progression to overt myelofibrosis at 10 years (12.3% and 0.8%, respectively) and 15 years (16.9% and 9.3%) were significantly worse. The respective death, leukemia, and overt myelofibrosis incidence rates per 100 patient-years for early/prefibrotic PMF compared with ET were 2.7% and 1.3% (relative risk [RR], 2.1; P < .001), 0.6% and 0.1% (RR, 5.2; P = .001), and 1% and 0.5% (RR, 2.0; P = .04). Multivariable analysis confirmed these findings and also identified age older than 60 years (hazard ratio [HR], 6.7), leukocyte count greater than 11 × 10(9)/L (HR, 2.01), anemia (HR, 2.95), and thrombosis history (HR, 2.81) as additional risk factors for survival. Thrombosis and JAK2V617F incidence rates were similar between the two groups. Survival in ET was similar to the sex- and age-standardized European population. CONCLUSION This study validates the clinical relevance of strict adherence to WHO criteria in the diagnosis of ET and provides important information on survival, disease complication rates, and prognostic factors in strictly WHO-defined ET and early/prefibrotic PMF.

A prognostic model to predict survival in 867 World Health Organization–defined essential thrombocythemia at diagnosis: a study by the International Working Group on Myelofibrosis Research and Treatment

Diagnosis of essential thrombocythemia (ET) has been updated in the last World Health Organization (WHO) classification. We developed a prognostic model to predict survival at diagnosis, named IPSET (International Prognostic Score for ET), studying patients with WHO-defined ET. Age 60 years or older, leukocyte count ≥ 11 × 10(9)/L, and prior thrombosis significantly affected survival, by multivariable Cox regression. On the basis of the hazard ratio, we assigned 2 points to age and 1 each to leukocyte count and thrombosis. So, the IPSET model allocated 867 patients into 3 risk categories with significantly different survival: low (sum of points = 0; median survival not reached), intermediate (sum = 1-2; median survival 24.5 years), and high (sum = 3-4, median survival 13.8 years). The IPSET model was further validated in 2 independent cohorts including 132 WHO-defined ET and 234 Polycythemia Vera Study Group-defined ET patients. The IPSET model was able to predict the occurrence of thrombosis, and not to predict post-ET myelofibrosis. In conclusion, IPSET, based on age ≥ 60 years, leukocyte count ≥ 11 × 10(9)/L, and history of thrombosis allows prognostic assessment of WHO-defined ET and the validation process makes IPSET applicable in all patients phenotypically appearing as ET.

Initial bone marrow reticulin fibrosis in polycythemia vera exerts an impact on clinical outcome

We examined the prevalence and prognostic relevance of bone marrow reticulin fibrosis in 526 patients with World Health Organization-defined polycythemia vera evaluated at the time of initial diagnosis. Seventy-four patients (14%) displayed mostly grade 1 reticulin fibrosis, with only 2 cases showing higher-grade fibrosis. Presenting clinical and laboratory characteristics, including JAK2V617F allele burden, between patients with and without fibrosis were similar for the most part, with the exception of a higher prevalence of palpable splenomegaly in patients with fibrosis (P < .01). Patients with fibrosis were less prone to experience thrombosis during their clinical course (1.1 vs 2.7 per 100 patient-years; P = .03) and more prone to develop post-polycythemia vera myelofibrosis (2.2 vs 0.8 per 100 patient-years; P = .01). There was no significant difference between the 2 groups in terms of overall or leukemia-free survival. The present study clarifies the incidence, degree, and prognostic relevance of bone marrow fibrosis obtained at time of initial diagnosis of polycythemia vera.

The miR-17-92 microRNA cluster: a novel diagnostic tool in large B-cell malignancies.

Diffuse large B-cell lymphoma (DLBCL) can present as de novo or can arise through the transformation of many indolent lymphomas, including follicular lymphoma (FL). The morphological differentiation between germinal center-DLBCL (GC-DLBCL) and high-grade (grade 3) FL could be challenging; the accurate sub-classification of large B-cell lymphomas is mandatory in order to select the most appropriate among the new-targeted therapies. Recent expression profiling studies reported microRNAs (miRNAs) (and miR-17-92 cluster, in particular) as useful tools in differentiating DLBCL and FL. However, these preliminary results are based on cell line-derived data or did not consider grade 3 FL cases. To investigate this point, 36 cases of GC-DLBCL and 18 cases of grade 3 non-transforming FL were considered. All diagnoses were based on the World Health Organization criteria and were confirmed by clinical, histological, and immunohistochemical data. Six members of the miR-17-92 cluster (ie, miR-18b, miR-19b, miR-20a, miR-92, miR-93, and miR-106a) and two control miRNAs (ie, miR-150 and miR-210) were quantified by quantitative reverse transcription-polymerase chain reaction. All the considered miR-17-92 cluster miRNAs were significantly overexpressed in GC-DLBCL, being miR-20a and miR-106a the most dysregulated (P<0.001). Receiver operating characteristics (ROCs) analysis was used to find the optimal cut-off in distinguishing the two histotypes. The ROC estimated thresholds for miR-18b, miR-19b, miR-20a, miR-92, and miR-106a displayed a sensitivity level higher than 0.80 in achieving the GC-DLBCL diagnosis. The classification tree built on the six thresholds allowed the correct identification of 35/36 GC-DLBCL (97.2%). Profiling the miR-17-92 cluster is a promising investigative method for differentiating GC-DLBCL from high-grade FL. Subject to the validation of these findings in further larger studies; miR-17-92 cluster could represent a reliable, standardizable diagnostic tool for the sub-classification of large B-cell lymphoid neoplasm.

Primary inverted papilloma of the middle ear and mastoid.

Objective Inverted papilloma (Schneiderian-type papilloma), involving the middle ear and mastoid as a primary lesion or as an extension of a sinonasal papilloma, is an extremely rare occurrence. Study Design The study design was a case report format with a review of the literature. Epidemiologic, diagnostic, therapeutic and follow-up problems are discussed. Setting Academic, tertiary referral hospital. Patient and Methods The patient underwent Wullstein type I tympanoplasty and complete mastoidectomy, revealing obliteration of the pneumatic cells by polypoid tissue. The middle ear was completely filled by polypoid tissue. Histopathologic examination revealed an inverted papilloma of the middle ear and mastoid. Conclusion Literature reports indicate that inverted papillomas of the middle ear and mastoid differ pathogenically and epidemiologically from sinonasal inverted papillomas. Recurrence rates and association with squamous cell carcinoma are higher in Schneiderian-type papillomas of the middle ear than in inverted papillomas of the nose and paranasal sinuses. Long-term follow-up after removal of inverted papilloma of the middle ear and mastoid is mandatory. Magnetic resonance imaging is the first follow-up examination to perform.

Benign metastasizing pleomorphic adenoma of the parotid gland: A clinicopathologic puzzle

Pleomorphic adenoma constitutes the most common benign parotid gland tumor. Local recurrence after surgical treatment (lateral or total parotidectomy) has been described in 1% to 5% of cases. Malignant degeneration has been reported in 2% to 9% of cases of pleomorphic adenoma of salivary gland origin. Metastasizing pleomorphic adenomas without histologic evidence of malignancy have rarely been reported. Metastatic lesions have been discovered in bone, lymph nodes, the lung, oral cavity, pharynx, skin, liver, retroperitoneum, kidney, calvarium, and central nervous system. To the best of our knowledge, we hereby report the first case of pleomorphic adenoma of the parotid gland metastasizing to the ipsilateral maxilla.

Protein Kinase CK2 Inhibition Down Modulates the NF-κB and STAT3 Survival Pathways, Enhances the Cellular Proteotoxic Stress and Synergistically Boosts the Cytotoxic Effect of Bortezomib on Multiple Myeloma and Mantle Cell Lymphoma Cells

CK2 is a pivotal pro-survival protein kinase in multiple myeloma that may likely impinge on bortezomib-regulated cellular pathways. In the present study, we investigated CK2 expression in multiple myeloma and mantle cell lymphoma, two bortezomib-responsive B cell tumors, as well as its involvement in bortezomib-induced cytotoxicity and signaling cascades potentially mediating bortezomib resistance. In both tumors, CK2 expression correlated with that of its activated targets NF-κB and STAT3 transcription factors. Bortezomib-induced proliferation arrest and apoptosis were significantly amplified by the simultaneous inhibition of CK2 with two inhibitors (CX-4945 and K27) in multiple myeloma and mantle cell lymphoma cell lines, in a model of multiple myeloma bone marrow microenvironment and in cells isolated from patients. CK2 inhibition empowered bortezomib-triggered mitochondrial-dependent cell death. Phosphorylation of NF-κB p65 on Ser529 (a CK2 target site) and rise of the levels of the endoplasmic reticulum stress kinase/endoribonuclease Ire1α were markedly reduced upon CK2 inhibition, as were STAT3 phospho Ser727 levels. On the contrary, CK2 inhibition increased phospho Ser51 eIF2α levels and enhanced the bortezomib-dependent accumulation of poly-ubiquitylated proteins and of the proteotoxic stress-associated chaperone Hsp70. Our data suggest that CK2 over expression in multiple myeloma and mantle cell lymphoma cells might sustain survival signaling cascades and can antagonize bortezomib-induced apoptosis at different levels. CK2 inhibitors could be useful in bortezomib-based combination therapies.

Extranodal Rosai-Dorfman disease: involvement of eye, nose and trachea

Rosai-Dorfman disease (RDD) is a rare non-neoplastic histiocytic proliferative disorder characterized by painless lymphadenopathy. Extranodal lesions frequently occur in the head and neck regions. We report the clinical and histological features of extranodal RDD in a 43-year-old man with a previously unreported combination of multiple gross anterior epibulbar nodules in the right eye, submucosal masses of nasal septum and trachea, and no lymphadenopathy during the 12-year follow-up. The patient underwent ophthalmological, otolaryngological and systemic evaluation; gallium 67 scintigraphy; bronchoscopy; ophthalmic ultrasound; head and neck CT scan; biopsies of epibulbar, nasal and tracheal tissues; and septoplasty. Histological specimens showed lymphocytophagocytosis and positive immunoperoxidase staining for S100 protein in foamy histiocytes; both features were typical for RDD. No response to topical or systemic steroids or to radiation therapy was recorded. Removal of nasal septum masses resolved nasal obstruction. The diagnosis of RDD requires histological and, in challenging cases, immunohistological specimens and is difficult – especially with pure extranodal localizations as in our case. RDD should be suspected in cases of subconjunctival mass and/or submucosal nasal and tracheal swellings not responding to systemic steroids.

Endoglin (CD105) expression in head and neck basaloid squamous cell carcinoma.

Conclusions. This comparison of neo-angiogenesis performed by analysing CD105 expression seems to suggest that the biological behaviour of head and neck BSCCs is similar to that of site- and stage-matched conventional SCCs. Objective. Basaloid squamous cell carcinoma (BSCC) is an uncommon, high-grade biomorphic variant of SCC with a predilection for the head and neck region. It is a matter of controversy whether the biological and clinical behaviour of BSCC is more aggressive than that of SCC. Angiogenesis is essential for tumour growth. It has been established that endothelial cells of tumour-associated neovasculature proliferate more rapidly than endothelial cells of normal tissue. Endoglin (CD105) has been shown to be a useful marker for identifying proliferating endothelium involved in tumour angiogenesis. The aim of this study was to investigate the expression of CD105 in head and neck BSCCs and to compare it with that in SCCs. Material and methods. Nine head and neck BSCCs (five cases in the larynx, three in the tongue and one in the tonsil) were considered. A group of nine site- and stage-matched SCCs was examined simultaneously. For each sample, CD105 reactivity was evaluated immunohistochemically. The mean area fraction (percentage of fields occupied by vessels), the percentage of vessel-presenting fields and the vessel density were considered. Results. The median values of the mean area fraction were 1.01% and 0.9% in BSCCs and SCCs, respectively. The median values of the percentage of vessel-presenting fields were 57.5% and 46.67% in BSCCs and SCCs, respectively. The median values of vessel density were 2.07% and 1.58% in BSCCs and SCCs, respectively. Statistical analysis did not disclose any significant differences between BSCCs and SCCs for any of the above-mentioned parameters.

High risk of malignancy in patients with incidentally discovered adrenal masses: accuracy of adrenal imaging and image-guided fine-needle aspiration cytology.

AIMS AND BACKGROUND The incidental finding of nonfunctioning adrenal masses (incidentalomas) is common, but no reliable criteria in differentiating between benign and malignant adrenal masses have been defined. The aim of this preliminary study was to assess the usefulness of adrenal imaging and image-guided fine-needle aspiration cytology in patients with nonfunctioning adrenal incidentalomas with the aim of excluding or confirming malignancy before surgery. METHODS Forty-two consecutive patients (18 men and 24 women; median age, 54 years; range, 25-75 years) with incidentally discovered adrenal masses of 3 cm or more in the greatest diameter were prospectively enrolled in the study. All patients underwent helical computerized tomography scan and image-guided fine-needle aspiration cytology, 33 (78.6%) underwent magnetic resonance imaging, and 26 (61.9%) underwent norcholesterol scintigraphy before adrenalectomy. RESULTS The revised final pathology showed 30 (71.4%) benign (26 adrenocortical adenomas, of which 3 were atypical, 2 ganglioneuromas, and 2 nonfunctioning benign pheochromocytomas) and 12 (28.6%, 95% CI = 15-42) adrenal malignancies (8 adrenocortical carcinomas and 4 unsuspected adrenal metastases). The definitive diagnosis of adrenocortical carcinoma was made according to Weiss criteria and confirmed on the basis of local invasion at surgery or metastases. The sensitivity, specificity and accuracy were 75%, 67% and 83% for computerized tomography scan, 92%, 95% and 94% for magnetic resonance imaging, 89%, 94% and 92% for norcholesterol scintigraphy, and 92%, 100% and 98% for fine-needle aspiration cytology. The sensitivity and accuracy of image-guided fine-needle aspiration cytology and magnetic resonance imaging together reached 100%. Immediate periprocedural complications of fine-needle aspiration cytology occurred in 2 (4.7%) patients: self-limited pneumothorax (n = 1), and severe pain (n = 1) requiring analgesic therapy. No postprocedural or late complications were observed. CONCLUSIONS With the aim of selecting for surgery patients with a non-functioning adrenal incidentaloma of 3 cm or more in diameter, the combination of magnetic resonance imaging and fine-needle aspiration cytology should be considered the strategy of choice.