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.

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.

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.

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.

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.

Knuckle pads, in an epidermal palmoplantar keratoderma patient with Keratin 9 R163W transgrediens expression.

Epidermolytic PalmoPlantar keratoderma (EPPK) Vörner-type is an autosomal dominantly inherited skin disease, characterized by severe thickening of the palms and soles, caused by mutations in the keratin K9 (KRT9) gene. To date, a number of KRT9 mutations have been detected, most of which affect the highly conserved 1A region of the central alpha-helical domain, important for keratin heterodimerization. The most common mutation is the substitution of the arginine in position 163 with a tryptophan (R163W), which has been reported in North American, European, and Japanese populations. In a small number of cases, EPPK is associated with knuckle pad keratosis, but no correlation between this additional phenotype and a specific mutation has been found. Moreover, K9 is not normally expressed in knuckle skin, raising the question of the pathogenic mechanism leading to this additional phenotype. Here we show that in a family affected by EPPK and knuckle pad keratosis, carrying the R163W substitution, wild type (wt) and mutated K9 are strongly expressed in knuckle pads. These results suggest that the knuckle pad phenotype is due to ectopical expression of K9.

Biological and clinical risk factors of chronic lymphocytic leukaemia transformation to Richter syndrome.

Predictors of chronic lymphocytic leukaemia (CLL) transformation to Richter syndrome (RS) are not established and were investigated in 185 consecutive CLL cases. Actuarial incidence of RS (n = 17; all diffuse large B-cell lymphomas) at 10 years was 16.2% (95% confidence interval: 8.0-24.4%). At CLL diagnosis, prognosticators of RS by univariate analysis were IGHV homology >/=98% (P = 0.006), IGHV4-39 usage (P < 0.001), del13q14 absence (P = 0.004), expression of CD38 (P < 0.001) and ZAP70 (P = 0.004), size (P < 0.001) and number (P < 0.001) of lymph nodes, advanced Binet stage (P = 0.002), and lactate dehydrogenase (P < 0.001). Multivariate analysis, performed separately for biological and clinical variables, identified CD38 expression [Hazard ratio (HR) = 4.26; P = 0.018], IGHV4-39 usage (HR = 4.29; P = 0.018), and lymph node size >/=3 cm (HR = 9.07; P < 0.001) as independent RS prognosticators. A multivariate model simultaneously analysing biological and clinical variables identified lymph node size >/=3 cm (HR = 6.51; P = 0.001) and del13q14 absence (HR = 4.08; P = 0.031) as independent RS prognosticators. Risk factors of CLL transformation differed from risk factors of CLL progression. These results suggest that CD38 and del13q14 may identify biological subsets of CLL with different RS predisposition. Predominant nodal disease, CD38 expression, IGHV4-39 usage, and absence of del13q14 may help in predicting RS at CLL diagnosis. Close monitoring and a careful biopsy policy are needed in patients carrying transformation risk factors.

Bone marrow necrosis complicating post-transplant lymphoproliferative disorder: resolution with rituximab.

Bone marrow necrosis is a rare cause of bone marrow failure. Malignancy is the most frequent cause of bone marrow necrosis. Among malignancies, non-Hodgkin lymphoma (NHL) accounts for 10% of cases of bone marrow necrosis. Virtually all reported cases of NHL-associated bone marrow necrosis have developed in immunocompetent hosts. We report on a case of bone marrow necrosis complicating post-transplant lymphoproliferative disorder (PTLD) and resolving after rituximab monotherapy. This case report provides the first evidence of (i) bone marrow necrosis as a complication of PTLD; (ii) rapid resolution of NHL-associated bone marrow necrosis after rituximab treatment.

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.

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.

Fine needle aspiration cytology in the diagnosis of non-Hodgkin's lymphomas of the muscle: a report of 2 cases.

BACKGROUND: Primary skeletal muscle lymphoma has been reported in very few cases. Although such imaging techniques as computed tomography and magnetic resonance imaging can supply diagnostic indications, the most reliable data are obtained by means of muscle biopsy investigations. Fine needle aspiration cytology (FNAC) has not been considered before for the diagnosis of muscle lymphoma. CASES: In case 1, 60-year-old man presented with 2 masses in the pectoral muscle and neck. FNAC of the neck mass was performed. The diagnosis was non-Hodgkin's diffuse B-cell lymphoma of the muscle; the diagnosis was confirmed by surgical biopsy of the pectoral muscle. In case 2, a 70-year-old man presented with a mass in the quadriceps muscle. The results of FNAC aroused suspicion of lymphoma, and a muscle biopsy confirmed the presence of a non-Hodgkin's B-cell lymphoma. Immunohistochemistry identified it as non-Hodgkin's marginal zone B-cell lymphoma of MALT type. CONCLUSION: FNAC can be a valuable starting point in muscle involvement by lymphoma because of the possibility of obtaining material by means of multiple aspirations without causing patients any discomfort.

[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.