S-100 Immunohistochemical Positivity in Rhabdomyoma: An Underestimated Potential Diagnostic Pitfall in Routine Practice.

A 66-year-old man presented with a 2.8 cm lesion of the left vocal cord. On contrast-enhanced computed tomography scans, the tumor extended to the supraglottis, subglottis, paraglottic space and anterior commissure, causing partial obstruction of the laryngeal lumen. At another hospital, a fragmented incisional biopsy was diagnosed as a granular cell tumor, as to the S-100 immunohistochemical positivity. After excision, the tumor revealed to be an adult-type laryngeal rhabdomyoma. The typical cytoplasmic rod-like inclusions and cross striations were more evident in the second specimen. We confirmed the unusual S-100 immunohistochemical positivity (variable intensity, >90% of tumor cells). Muscle markers were not performed on the previous biopsy, resulting positive in our specimen (Desmin: strong, diffuse expression; Smooth Muscle Actin: strong staining in 10% of tumor cells). Melan-A, CD68, GFAP, pan-cytokeratins, CEA, calretinin and neurofilaments resulted negative. To our brief, systematic literature review, S-100 positivity (usually variable, often weak or patchy/focal) was globally found in 19/34 (56%) adult-type rhabdomyomas of the head and neck region. Especially on fragmented biopsy material, the differential diagnoses of laryngeal rhabdomyomas may include granular cell tumors, oncocytic tumors of the salivary glands or of different origin, and paragangliomas.

Double expressor and double/triple hit status among primary cutaneous diffuse large B-cell lymphoma: a comparison between leg type and not otherwise specified subtypes.

Primary cutaneous diffuse large B-cell lymphomas (pcDLBCLs) are rare hematological neoplasms. The pcDLBCL category includes primary cutaneous large B-cell lymphoma leg type (pcDLBCL-LT), characterized by a particularly unfavorable outcome, and primary cutaneous large B-cell lymphoma not otherwise specified (pcDLBCL-NOS), a widely debated subentity with a more indolent course. The negative prognostic impact of double expressor status (DE status, given by coexpression of MYC and BCL2) and double hit/triple hit status (DH/TH status, given by translocations of MYC and BCL2 and/or BCL6) in nodal DLBCL is well known; however, no unanimous conclusions regarding relevance of DE and DH/TH status have been reached in pcDLBCL. Therefore, our purpose has been to investigate the presence and prognostic relevance of DE and DH/TH status among a retrospective multicentric cohort of 16 cases of pcDLBCL-LT and 17 cases of pcDLBCL-NOS. All cases were thoroughly reevaluated, both on a morphological and immunohistochemical level, and tested by means of fluorescence in situ hybridization for MYC, BCL2 and BCL6 rearrangements. DE status was observed in 69% of pcDLBCL-LT cases and in 24% of pcDLBCL-NOS cases; however, it did not impact prognosis in any of the groups examined. Combining molecular results, we highlighted a relevant fraction of DH pcDLBCL cases (three pcDLBCL-LT cases and one pcDLBCL-NOS case) and the very first case of TH pcDLBCL-LT reported to date. All DH cases were characterized by MYC and BCL6 rearrangements. Overall, DH/TH cases represented 15% (5/33) of all pcDLBCLs and were mostly pcDLBCL-LT. DH/TH status and DH status alone were associated with poorer overall survival and disease-specific survival (both p < 0.05) among all pcDLBCLs, without reaching statistical significance in the pcDLBCL-LT and pcDLBCL-NOS groups. In conclusion, MYC, BCL2, and BCL6 cytogenetical testing could be useful in identifying a putative subset of more aggressive pcDLBCLs, although this observation has to be confirmed by further studies.

Mitotically Active Cellular Fibroma of the Ovary Recurring After the Longest Interval of Time (16 yr): A Challenging Case With Systematic Literature Review.

Cellular fibromas represent ~10% of ovarian fibromas. Mitotically active cellular fibromas show mild nuclear atypia but ≥4 mitoses/10 high-power fields: the clinical course is usually uneventful but literature review is lacking. A 34-yr-old woman underwent left oophorectomy for a 9-cm ovarian mitotically active cellular fibroma at another hospital. The tumor was cellular (spindle cells in fascicular and storiform patterns) revealing mild atypia and 4 nonatypical mitoses/10 high-power fields without necrotic areas. After 16 yr, the tumor recurred as a 5-cm peritoneal nodule on the anterior sigmoid wall near the sigmoid-rectal junction. Frozen section revealed a spindle cell tumor invading the intestinal tunica muscularis propria: a gastrointestinal stromal tumor was favored as previous history was unavailable at that time. Intestinal resection was performed: no residual tumor was found. The patient was followed-up for 8 yr without further recurrences. The peritoneal nodule showed 2 mitoses/10 high-power fields and pericellular reticulin staining. The tumor was variably positive for vimentin/bcl-2/melan-A/CD56/ER/PR/α-inhibin/CD10/calretinin, focally positive for desmin, negative for pan-cytokeratin/actin/EMA/CD34/HMB45/CD117/CD99/S100/synaptophysin. The Ki67-index was ~9%. To our systematic literature review, 7 additional recurrent cases were reported. We describe a mitotically active cellular fibroma recurring after the longest interval of time. Extensive sampling of difficult cases should exclude malignant areas. Moderate nuclear atypia, tumor rupture, adhesions to pelvic/abdominal organs, infarction with extraovarian involvement, and incomplete excision may lead to relapse but there are conflicting data: prolonged follow-up can be suggested in these cases.

Paratesticular seminoma: echographic features and histological diagnosis with review of the literature.

Primary extratesticular seminomas exceptionally occur in the epididymis or in the paratesticular region/spermatic cord. Some old papers included poor histological description or insufficient photographic documentation, reducing the number of faithful cases: an up-to-date systematic review is lacking. We report the 4th primary seminoma of the paratesticular region/spermatic cord in a 35-year-old man, including the first echographic description. We provide review of the literature and etiopathogenetic discussion. Ultrasound examination showed a right paratesticular, solid, heterogeneous mass (iso-hypoechoic with hyperechoic striae; peri- and intra-lesional vascular signals) with no testicular involvement: the paratesticular origin was confirmed by pathological examination. Despite careful gross examination and extensive sampling, the 6.5-cm extratesticular tumor revealed only one microscopic focus with minimal invasion (<2 mm) of the atrophic testicular parenchyma. Intratubular germ cell neoplasia or morphologic features of a regressed testicular tumor (fibrosis/scar, necrosis, hyalinization, calcification, inflammation) were not found. Primary seminomas of the paratesticular region/spermatic cord occurred at an older mean age and presented as bigger lesions if compared to the 9 primary epididymal seminomas reported in literature. Clinical-pathological correlation and accurate sampling are mandatory for a correct diagnosis.

Diffuse large B-cell lymphoma genotyping on the liquid biopsy.

Accessible and real-time genotyping for diagnostic, prognostic, or treatment purposes is increasingly impelling in diffuse large B-cell lymphoma (DLBCL). Cell-free DNA (cfDNA) is shed into the blood by tumor cells undergoing apoptosis and can be used as source of tumor DNA for the identification of DLBCL mutations, clonal evolution, and genetic mechanisms of resistance. In this study, we aimed at tracking the basal DLBCL genetic profile and its modification upon treatment using plasma cfDNA. Ultra-deep targeted next generation sequencing of pretreatment plasma cfDNA from DLBCL patients correctly discovered DLBCL-associated mutations that were represented in >20% of the alleles of the tumor biopsy with >90% sensitivity and ∼100% specificity. Plasma cfDNA genotyping also allowed for the recovery of mutations that were undetectable in the tissue biopsy, conceivably because, due to spatial tumor heterogeneity, they were restricted to clones that were anatomically distant from the biopsy site. Longitudinal analysis of plasma samples collected under rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) chemotherapy showed a rapid clearance of DLBCL mutations from cfDNA among responding patients. Conversely, among patients who were resistant to R-CHOP, basal DLBCL mutations did not disappear from cfDNA. In addition, among treatment-resistant patients, new mutations were acquired in cfDNA that marked resistant clones selected during the clonal evolution. These results demonstrate that cfDNA genotyping of DLBCL is as accurate as genotyping of the diagnostic biopsy to detect clonally represented somatic tumor mutations and is a real-time and noninvasive approach to tracking clonal evolution and the emergence of treatment-resistant clones.

Primary cutaneous B-cell lymphoma other than marginal zone: clinicopathologic analysis of 161 cases: Comparison with current classification and definition of prognostic markers.

Categorization of primary cutaneous B-cell lymphomas (PCBCL) other than marginal zone (MZL) represents a diagnostic challenge with relevant prognostic implications. The 2008 WHO lymphoma classification recognizes only primary cutaneous follicular center cell lymphoma (PCFCCL) and primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), whereas the previous 2005 WHO/EORTC classification also included an intermediate form, namely PCDLBCL, other. We conducted a retrospective, multicentric, consensus-based revision of the clinicopathologic characteristics of 161 cases of PCBCL other than MZL. Upon the histologic features that are listed in the WHO classification, 96 cases were classified as PCFCCL and 25 as PCDLBCL-LT; 40 further cases did not fit in the former subgroups in terms of cytology and/or architecture, thus were classified as PCDLBCL, not otherwise specified (PCDLBCL-NOS). We assigned all the cases a histogenetic profile, based on the immunohistochemical detection of CD10, BCL6, and MUM1, and a "double hit score" upon positivity for BCL2 and MYC. PCDLBCL-NOS had a clinical presentation more similar to PCFCCL, whereas the histology was more consistent with the picture of a diffuse large B-cell lymphoma, as predominantly composed of centroblasts but with intermixed a reactive infiltrate of small lymphocytes. Its behavior was intermediate between the other two forms, particularly when considering only cases with a "non-germinal B-cell" profile, whereas "germinal center" cases resembled PCFCCL. Our data confirmed the aggressive behavior of PCDLBC-LT, which often coexpressed MYC and BCL2. The impact of single factors on 5-year survival was documented, particularly histogenetic profile in PCDLBCL and BCL2 translocation in PCFCCL. Our study confirms that a further group-PCDLBCL-NOS-exists, which can be recognized through a careful combination of histopathologic criteria coupled with adequate clinical information.

The genetics of nodal marginal zone lymphoma.

Nodal marginal zone lymphoma (NMZL) is a rare, indolent B-cell tumor that is distinguished from splenic marginal zone lymphoma (SMZL) by the different pattern of dissemination. NMZL still lacks distinct markers and remains orphan of specific cancer gene lesions. By combining whole-exome sequencing, targeted sequencing of tumor-related genes, whole-transcriptome sequencing, and high-resolution single nucleotide polymorphism array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and we compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of nonsilent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ≥3 (9%) cases, including highly prevalent molecular lesions of MLL2 (also known as KMT2D; 34%), PTPRD (20%), NOTCH2 (20%), and KLF2 (17%). Mutations of PTPRD, a receptor-type protein tyrosine phosphatase regulating cell growth, were enriched in NMZL across mature B-cell tumors, functionally caused the loss of the phosphatase activity of PTPRD, and were associated with cell-cycle transcriptional program deregulation and increased proliferation index in NMZL. Although NMZL shared with SMZL a common mutation profile, NMZL harbored PTPRD lesions that were otherwise absent in SMZL. Collectively, these findings provide new insights into the genetics of NMZL, identify PTPRD lesions as a novel marker for this lymphoma across mature B-cell tumors, and support the distinction of NMZL as an independent clinicopathologic entity within the current lymphoma classification.

The NOTCH pathway is recurrently mutated in diffuse large B-cell lymphoma associated with hepatitis C virus infection.

Hepatitis C virus has been found to be associated with B-cell non-Hodgkin lymphomas, mostly marginal zone lymphomas and diffuse large B-cell lymphoma. Deregulation of signaling pathways involved in normal marginal zone development (NOTCH pathway, NF-κB, and BCR signaling) has been demonstrated in splenic marginal zone lymphoma. We studied mutations of NOTCH pathway signaling in 46 patients with hepatitis C virus-positive diffuse large B-cell lymphoma and in 64 patients with diffuse large B-cell lymphoma unrelated to HCV. NOTCH2 mutations were detected in 9 of 46 (20%) hepatitis C virus-positive patients, and NOTCH1 mutations in 2 of 46 (4%). By contrast, only one of 64 HCV-negative patients had a NOTCH1 or NOTCH2 mutation. The frequency of the NOTCH pathway lesions was significantly higher in hepatitis C virus-positive patients (P=0.002). The 5-year overall survival was 27% (95%CI: 5%-56%) for hepatitis C virus-positive diffuse large B-cell lymphoma patients carrying a NOTCH pathway mutation versus 62% (95%CI: 42%-77%) for those without these genetic lesions. By univariate analysis, age over 60 years, NOTCH2 mutation, and any mutation of the NOTCH pathway (NOTCH2, NOTCH1, SPEN) were associated with shorter overall survival. Mutation of the NOTCH pathway retained an independent significance (P=0.029). In conclusion, a subset of patients with hepatitis C virus-positive diffuse large B-cell lymphoma displays a molecular signature of splenic marginal zone and has a worse clinical outcome.

[Primary cardiac Burkitt lymphoma in an African child]. / Linfoma di Burkitt cardiaco primitivo in un giovane ragazzo africano.

Burkitt lymphoma is a non-Hodgkin lymphoma that is endemic in the Equatorial Belt of Africa, usually affecting children and adolescents with primary head-neck or abdominal involvement. Primary cardiac lymphomas are rare entities (1.3% of all primary cardiac tumors) of difficult clinical identification. Delayed discovery contributes to significant mortality. We report a case of a primitive Burkitt lymphoma in a 14-year-old Cameroonian immunocompetent child, presenting with signs and symptoms of severe right inflow impairment. Echocardiography revealed a right atrial mass involving the right atrial ventricular junction. Surgical excision and chemotherapy regimens, administered according to established protocols, were effective in inducing complete remission at 6 months.

Risk factors of central nervous system relapse in mantle cell lymphoma.

Central nervous system (CNS) relapse has not been extensively studied in mantle cell lymphoma (MCL). We retrospectively analyzed the risk factors and pattern of CNS relapse in consecutive patients with MCL. We identified 142 cases of MCL treated from 1980 to 2011. Median age at diagnosis was 68 years; 82% of patients had advanced stage; extranodal disease was reported in 89% of cases and high serum lactate dehydrogenase (LDH) in 40%. Fourteen patients (10%) did not receive treatment at diagnosis. Chemotherapy was administered to 125 patients (88%), in 21 cases (15%) including drugs penetrating into the CNS or given intrathecally; 49 patients (35%) had rituximab. Ten patients had front-line autologous transplant. After a median follow-up of 7.9 years, CNS relapse occurred in 11 cases (7.8%) at a median of 13.8 months. Actuarial risk of CNS relapse was higher in patients with elevated LDH (p = 0.002), higher International Prognostic Index (IPI) score (p = 0.018) and blastoid histology (p < 0.0001). Blastoid histology retained significance at multivariate analysis. Median survival after CNS relapse was 6.3 months. No front-line treatment reduced the risk of CNS relapse. Our analysis confirms the poor outcome of MCL after CNS relapse and may allow the identification of patients needing prophylaxis of CNS relapse.

Thymomaptysis: unusual presentation of invasive thymoma.

Symptomatic thymomas are characterized by non-specific thoracic symptoms or symptoms related to associated para-thymic syndromes. We report the case of a 56-year old Caucasian male who was affected by invasive (Masaoka IVA) WHO mixed AB-B2 thymoma after the elimination through the sputum of a fragment of tumour vegetating in the left upper lobar bronchus. The patient received multimodal treatment consisting of neoadjuvant cisplatinum-based polychemiotherapy, radical surgical resection ('en bloc' thymectomy, thymomectomy and pulmonary left upper lobe exeresis and pleural implants resection) and subsequent mediastinal radiation therapy. At 18-month follow-up, the patient is alive and disease-free.

Single thymic gland metastasis from resected non-small-cell lung cancer.

Primary thymic tumors are rare, but secondary ones are exceptionally uncommon. We report the case of a single metastasis within the thymic gland from a lung adenocarcinoma that had been completely resected 3 years before. There was high diagnostic doubt because the thymic lesion was not associated with the recurrence of the paraneoplastic syndrome or the increased CEA levels described at the moment of the treatment of the primary tumor. The lesion was diagnosed and treated at the same time by transcervical thymectomy. At the one-year follow-up, the patient is alive and disease-free.

Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis.

Richter syndrome (RS) represents the transformation of chronic lymphocytic leukemia to aggressive lymphoma. We explored intraclonal diversification (ID) of immunoglobulin genes in order to (i) follow the evolutionary history of the RS clone (ii) compare the role of ID in clonally related RS vs. clonally unrelated cases. Most (10/11, 90.9%) clonally related RS stem from the predominant clone observed at CLL diagnosis. One single RS had a transformation pattern compatible with sequential evolution from a secondary CLL subclone. Once RS transformation had occurred, all secondary CLL subclones disappeared and were substituted by the dominant RS clone with its own descendants. These observations suggest that genetic lesions associated with RS transformation are acquired by a cell belonging to the original CLL clone, rather than being progressively accumulated by later CLL subclones. Accordingly, most (9/11, 81.1%) clonally related RS harbored a genetic lesion disrupting TP53 that was already present, though at subclonal levels, in 5/11 (45.5%) samples of the paired CLL phase. A fraction of clonally related RS switched off ID (4/11, 36.4%) or reduced the levels of ID (5/11, 45.4%) at transformation. Conversely, all clonally unrelated RS harbored ID and were characterized by a significantly higher mutation frequency compared to clonally related RS (median: 1.18 × 10(-3) vs. 0.13 × 10(-3); p =0.002). These data indicate that (i) clonally related RS stems from a cell that is already present within the initial CLL clone and (ii) clonally unrelated and clonally related RS are biologically distinct disorders also in terms of antigen affinity maturation.

Beta-2-microglobulin is an independent predictor of progression in asymptomatic multiple myeloma.

BACKGROUND: Although serum beta-2 microglobulin (B2M) represents a key variable for symptomatic multiple myeloma (MM) prognostication, its role in predicting the risk of progression of asymptomatic MM to symptomatic disease has not been explored. METHODS: This study was bases on a consecutive series of 148 patients with asymptomatic MM and explored the cumulative probability of progression to symptomatic MM as the primary endpoint. RESULTS: In univariate analysis, a serum B2M level >2.5 mg/L was associated with an increased probability of disease progression (5-year risk, 64.5%; P < .001) along with serum monoclonal component (sMC) (P < .001), urinary monoclonal component (uMC) (P < .001), and bone marrow plasma cells (BMPCs) (P < .001). In multivariate analysis, serum B2M was selected as an independent predictor of progression (hazard ratio, 3.30; P = .002). Serum B2M was combined with sMC, uMC, and BMPC to create a risk-stratification model based on 4 groups with different risk of progression: very low (5-year risk, 0%), low-intermediate (5-year risk, 19.6%), high-intermediate (5-year risk, 60.7%), and high (5-year risk, 80.7%). The model that included serum B2M along with sMC, uMC, and BMPC was able to predict disease progression better than the model that was based on sMC, uMC, and BMPC without serum B2M (C statistics, 0.760 vs 0.726). CONCLUSIONS: The current results indicated that 1) serum B2M is an independent predictor of asymptomatic MM progression, and 2) serum B2M adds prognostic information when combined with the most widely used prognosticators of asymptomatic MM progression.

Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome.

PURPOSE: Few biological prognosticators are useful for prediction of Richter syndrome (RS), representing the transformation of chronic lymphocytic leukemia (CLL) to aggressive lymphoma. Stereotyped B-cell receptors (BCR) may have prognostic effect in CLL progression. We tested the prognostic effect of stereotyped BCR for predicting RS transformation. EXPERIMENTAL DESIGN: The prevalence of stereotyped BCR was compared in RS (n = 69) versus nontransformed CLL (n = 714) by a case-control analysis. Subsequently, the effect of stereotyped BCR at CLL diagnosis on risk of RS transformation was actuarially assessed in a consecutive CLL series (n = 753). RESULTS: RS (n = 69) displayed a higher prevalence of stereotyped BCR (P < 0.001) compared with nontransformed CLL. The actuarial risk of RS transformation was significantly higher in CLL carrying stereotyped BCR (P < 0.001). Among BCR subsets most represented in CLL, subset 8 using IGHV4-39/IGHD6-13/IGHJ5 carried the highest risk of RS transformation [hazard ratio (HR), 24.50; P < 0.001]. Multivariate analysis selected stereotyped BCR (HR, 3.33; P = 0.001) and IGHV4-39 usage (HR, 4.03; P = 0.004) as independent predictors of RS transformation. The combination of IGHV4-39 usage and stereotyped BCR in the same patient identified CLL with a very high risk of RS transformation (5-year risk, 68.7%). The risk carried by stereotyped BCR and IGHV4-39 usage was specific for RS transformation and had no effect on CLL progression without transformation. CONCLUSIONS: Analysis of BCR features may help identify CLL patients at risk of RS. A close monitoring and a careful biopsy policy may help early recognition of RS in CLL patients using stereotyped BCR, particularly if combined with IGHV4-39.