Ultrasound-guided core needle biopsy compared with open biopsy: a new diagnostic approach to salivary gland enlargement in Sjögren's syndrome?

OBJECTIVE: Persistent (≥2 months) major salivary gland enlargement in primary SS (pSS) patients is a well-known sign of possible involvement by B cell lymphoma. The study aimed to evaluate the diagnostic accuracy and safety of US-guided core needle biopsy (CNB) of major salivary glands compared with open surgical biopsy. METHODS: Prospective pSS patients (cases) with clinically persistent salivary gland enlargement underwent US-guided CNB and were compared with retrospective pSS patients (controls) submitted to open surgical biopsy. The features analysed were pre-biopsy clinical and laboratory findings, adequacy of the material for histology and diagnostic-rendered and biopsy-related complications (reported by the patient with a questionnaire and clinically verified). RESULTS: Thirteen cases underwent US-guided CNB: in nine, biopsy was performed on the parotid gland and in four it was performed on the submandibular gland. Sufficient material was obtained for pathological diagnosis in all samples. The final diagnoses were 5 (38.5%) B cell lymphoma, 1 (7.7%) lymphoepithelial sialadenitis, 4 (30.7%) other sialadenitis (granulomatous consistent with sarcoidosis, IgG4-related disease, chronic sclerosing, diffuse chronic) and 3/13 (23.1%) miscellaneous lesions. Thirteen controls underwent open surgical biopsy of the parotid. In one, inadequate material was obtained, while in 12 (92.3%) the pathologic diagnoses were 4 (33.3%) B cell lymphoma, 2 (16.7%) lymphoepithelial sialadenitis, 4 (33.3%) uncertain lymphoproliferative lesions and 2 (16.7%) miscellaneous lesions. Six cases (46.1%) reported six transient complications and 12/13 (92.3%) controls had 2 persistent and 14 transient complications. CONCLUSION: US-guided CNB represents a novel, clinically relevant and safe approach for the management of pSS patients with parotid or submandibular persistent enlargement.

Comprehensive analysis of 34 MiT family translocation renal cell carcinomas and review of the literature: investigating prognostic markers and therapy targets.

Recently cabozantinib, a tyrosine kinase inhibitor with activity against VEGF, MET, AXL, and downregulating cathepsin K in vitro, has been proposed for the treatment of advanced clear and non-clear renal cell carcinomas. Since it is well known that cathepsin K is expressed in the majority of MiT family translocation renal cell carcinomas, we investigated cathepsin K, MET, AXL, and VEGF in a large series of those tumours, looking for possible predictive markers. We collected the clinicopathological features of 34 genetically confirmed MiT family translocation renal cell carcinomas [26 Xp11 and 8 t(6;11) renal cell carcinomas] and studied them using an immunohistochemical panel including PAX8, cathepsin K, HMB45, Melan-A, CD68 (PG-M1), CK7, CA9, MET, AXL and by FISH for VEGFA and MET. Cathepsin K was expressed in 14 of 26, HMB45 in 8 of 25, and Melan-A in 4 of 23 Xp11 renal cell carcinomas, whereas labelling for CK7 and CA9 was minimal. In t(6;11) renal cell carcinoma, cathepsin K and melanogenesis markers were constantly positive, whereas CK7 and CA9 were negative. None of the 34 carcinomas showed CD68 (PG-M1) and AXL expression. One aggressive Xp11 renal cell carcinoma showed increased VEGFA gene copy number (4-5 copies) with concurrent gains of TFE3 and TFEB. None of the 34 carcinomas showed MET gene amplification, whereas staining for MET was found in 7 of 8 t(6;11) and in 16 of 24 Xp11 renal cell carcinomas, and in the latter cases, when the expression was >50%, correlated with aggressiveness (p=0.0049). In Xp11 renal cell carcinomas, the aggressiveness was also correlated with larger tumour size (p=0.0008) and the presence of necrosis (p=0.027) but not nucleolar grading (p=1). Interestingly, in patients with tumours exhibiting two of three parameters (necrosis, larger tumour size and MET immunolabelling >50%) an aggressive clinical behaviour was observed in 88% of cases. In conclusion, cathepsin K, CD68 (PG-M1), CK7, CA9, and PAX8 is a useful panel for the diagnosis. Larger tumour size, the presence of necrosis and MET immunohistochemical expression correlate with aggressive behaviour in Xp11 renal cell carcinomas, especially in combination. VEGF, MET, cathepsin K but not AXL may be potential predictive markers for targeted therapy in MiT family translocation renal cell carcinomas.

Effects of Delayed Hypothermic Machine Perfusion on Kidney Grafts with a Preliminary Period of Static Cold Storage and a Total Cold Ischemia Time of Over 24 Hours.

BACKGROUND Hypothermic machine perfusion (HMP) appears to exert a reconditioning effect on the ischemic damage of kidney grafts. However, some concerns still remain about its real effectiveness when it is delayed after a preliminary period of static cold storage (SCS) or with prolonged overall cold ischemia time (CIT). MATERIAL AND METHODS The effect of HMP on hemodynamic, metabolic, histological and ultrastructural features of grafts was investigated in 21 single-kidney grafts treated with a delayed HMP after SCS and with a total CIT of over 24 h. RESULTS The mean CIT, SCS, and HMP times were 29 h, 12 h, and 18 h, respectively. Longer SCS was associated with higher vascular resistance and lower arterial flow. In the pre- vs. post-HMP comparison, a significant decrease in arterial resistances and increase of flow were recorded. The hemodynamic improvement was independent of HMP duration. The perfused grafts retained some metabolic activity, with a statistically significant decrease of pH, pO2, and glucose levels, and increase of lactates in the perfusion liquid, by the end of HMP. Longer SCS was associated with higher pH and greater pO2 decrease during HMP. Light microscopy and transmission electronic microscopy revealed no significant variations in nuclear, cytoplasmic, or ultrastructural damage. SCS, HMP, and CIT were not identified as risk factor for delayed graft function or rejection. CONCLUSIONS A delayed and extended HMP can recover the graft hemodynamic function, maintain some metabolic activity, and stabilize the accumulated ischemic damage due to a preliminary SCS.

Application of an Artificial Intelligence Algorithm to Prognostically Stratify Grade II Gliomas.

(1) Background: Recently, it has been shown that the extent of resection (EOR) and molecular classification of low-grade gliomas (LGGs) are endowed with prognostic significance. However, a prognostic stratification of patients able to give specific weight to the single parameters able to predict prognosis is still missing. Here, we adopt classic statistics and an artificial intelligence algorithm to define a multiparametric prognostic stratification of grade II glioma patients. (2) Methods: 241 adults who underwent surgery for a supratentorial LGG were included. Clinical, neuroradiological, surgical, histopathological and molecular data were assessed for their ability to predict overall survival (OS), progression-free survival (PFS), and malignant progression-free survival (MPFS). Finally, a decision-tree algorithm was employed to stratify patients. (3) Results: Classic statistics confirmed EOR, pre-operative- and post-operative tumor volumes, Ki67, and the molecular classification as independent predictors of OS, PFS, and MPFS. The decision tree approach provided an algorithm capable of identifying prognostic factors and defining both the cut-off levels and the hierarchy to be used in order to delineate specific prognostic classes with high positive predictive value. Key results were the superior role of EOR on that of molecular class, the importance of second surgery, and the role of different prognostic factors within the three molecular classes. (4) Conclusions: This study proposes a stratification of LGG patients based on the different combinations of clinical, molecular, and imaging data, adopting a supervised non-parametric learning method. If validated in independent case studies, the clinical utility of this innovative stratification approach might be proved.

Tumour-infiltrating lymphocytes, programmed death ligand 1 and cyclooxygenase-2 expression in skin melanoma of elderly patients: clinicopathological correlations.

Age is an important prognostic factor in melanoma; notably, elderly patients tend to present with advanced stage skin melanoma (SM) and worse outcome. Moreover, SM is an immunogenic cancer, and its interaction with the aging immune system could have an effect on biologic behaviour of this disease. Tumour-infiltrating lymphocytes (TILs) could represent the host response in SM; it has been shown that higher grade of TILs is associated with better survival. Moreover, programmed death ligand 1 (PD-L1) and cyclooxygenase-2 (COX-2) are potential markers of host immune response and inflammation. We retrospectively reviewed 113 consecutive cases of early-stage SM that occurred in patients aged greater than or equal to 65 years at the time of diagnosis, followed between January 2010 and March 2014 at the University and General Hospital of Udine, Italy. The aim of this study was to evaluate TILs grade, PD-L1 expression on TILs and tumour expression of PD-L1 and COX-2 and their prognostic value in elderly patients with early SM. A better disease-free survival as well as melanoma-specific survival (MSS) was significantly associated with TILs [hazard ratios (HR): 0.41, 95% confidence interval (CI): 0.20-0.84, P=0.02 and HR: 0.37, 95% CI: 0.17-0.82, P=0.01, respectively]. PD-L1 positivity on TILs was associated with a better MSS (HR: 0.41, 95% CI: 0.17-0.97, P=0.04). Moreover, among patients with TILs, those showing COX-2 positivity on tumour cells and no PD-L1 expression on TILs had a worse disease-free survival and MSS (HR: 5.18, 95% CI: 1.33-20.23, P=0.018; HR: 6.21, 95% CI: 1.20-32.24, P=0.03; respectively). Immune and inflammatory markers deserve further investigation in aging patients with melanoma.

Sequential therapy with belimumab followed by rituximab in Sjögren's syndrome associated with B-cell lymphoproliferation and overexpression of BAFF: evidence for long-term efficacy.

OBJECTIVES: The overexpression of B-cell activating factor (BAFF) in mucosa-associated lymphoid tissue (MALT) may decrease the efficacy of rituximab treatment in Sjögren's syndrome (SS). Anti-CD20 therapy was effective on marginal zone B cells, in the murine model for human CD20 expression only when preceded by anti-BAFF therapy. The possible efficacy of a sequential anti-BAFF/anti-CD20 therapy in SS was investigated. METHODS: We treated with belimumab, a monoclonal anti-BAFF antibody, and soon after with rituximab a patient with severe, refractory SS, parotid low-grade B-cell MALT lymphoma and cryoglobulinaemic vasculitis. Previous treatments with rituximab and with rituximab plus high dose glucocorticoids, as well as with cyclophosphamide, azathioprine, plasma exchange, hyperbaric therapy, VAC therapy, prostacyclin, mycophenolate mofetil and surgery, had previously failed. Treatment with belimumab was then given, but it also failed. A new course of rituximab (375 mg/m2; four weekly infusions) was started 49 days after the last infusion of belimumab. RESULTS: This sequential belimumab-rituximab treatment was followed by a marked amelioration, with the complete and persistent regression of lymphoma and healing of a refractory skin ulcer. A full cycle of rituximab was then repeated 6 and 12 months later; no further treatment was given in the following 22 months up to now. Serum cryoglobulins and rheumatoid factor became persistently negative and serum BAFF and C4 persistently normal. No relevant side effects were noticed, except for a marked decrease in serum IgM. The follow up after belimumab-rituximab sequential therapy is now three and a half years. CONCLUSIONS: Therapy with belimumab followed by rituximab may be effective for SS-related B-cell lymphoproliferation. The efficacy and safety of the sequential or concomitant targeting of BAFF and CD20 deserves further evaluation in SS.

High prevalence of Chlamydophila psittaci subclinical infection in Italian patients with Sjögren's syndrome and parotid gland marginal zone B-cell lymphoma of MALT-type.

OBJECTIVES: To assess Chlamydophila psittaci (Cp) subclinical infection in patients with Sjögren's syndrome (SS). METHODS: Seventy-four SS patients (55.4 ±13.4 yrs; 94.6% females) were studied. Among them, 18 had salivary gland mucosa-associated lymphoid tissue (MALT) B-cell lymphoma, 20 myoepithelial sialoadenitis (MESA), and 36 no lymphoproliferative disorders (LPD). The presence of Cp DNA was assessed in peripheral blood of all patients by specific PCR protocols. Paired salivary gland samples were also investigated whenever available (34 cases), including lymphomatous and non-lymphomatous samples, as well as major and minor salivary gland tissues. As controls, 225 blood donors were analysed in the peripheral blood. RESULTS: Overall, Cp DNA was detected in 11/74 (14.9%) SS patients vs. 1/225 (0.4%) controls (p<0.0001). Cp was detected at higher frequency in MALT lymphoma patients (6/18, 33.3%), as compared with MESA (3/20, 15%) or patients without LPD (2/36, 5.6%), (MALT lymphomas vs. others: p=0.02). A similar Cp prevalence was observed in blood vs. salivary gland tissues, however with a higher frequency in the major than in the minor salivary glands (5/18, 27.8%, vs. 1/17, 5.9%, p=0.18). Cp-positive patients were all rheumatoid factor positive (11/11, 100% vs. 40/63, 63.5% Cp-negative; p=0.014), while no difference was noticed for anti-SSA/SSB positivity. CONCLUSIONS: In the light of accepted models of MALT B-cell lymphomagenesis and considering previous data implicating Cp infection in ocular adnexa MALT lymphoma, our results suggest that Cp infection could be involved also in a fraction of patients with SS developing lymphoma. The potential therapeutic implications of these findings appear worthwhile.

Expression of thymidine phosphorylase and cyclooxygenase-2 in melanoma.

Several studies have reported an increase in vascular structures in malignant melanoma. Neovascularization can be enhanced by several factors. Among them, thymidine phosphorylase (TP) and cyclooxygenase-2 (COX-2) have been reported to play a role. The expressions of TP and COX-2 were evaluated trough immunohistochemistry in a series of 78 primary cutaneous melanomas diagnosed between 2000 and 2004. The expressions of TP and COX-2 through mRNA and western blot analysis were also evaluated in several melanoma cell lines. TP expression and COX-2 expression were considered positive in 25 cases (32%) and 22 cases (28.2%), respectively. TP-positive melanomas showed a lower mitotic rate (P=0.008), smaller thickness (P=0.01), and absence of lymphovascular invasion (P=0.04). COX-2-positive melanomas showed a higher mitotic rate (P=0.01) and higher thickness (P=0.03). COX-2 expression was associated with reduced disease-free survival (P=0.01). COX-2-positive cases showed a trend toward reduced survival, whereas TP was not correlated with overall survival. COX-2 expression was detected in four of 11 melanoma cell lines both by mRNA and by western blot analysis. Our data show that TP expression is associated with more favorable prognostic factors (such as thin melanoma, low mitotic count, and absence of lymphovascular invasion), whereas COX-2 expression is associated with poor prognostic factors (thicker melanoma and high mitotic count).

Minor salivary gland biopsy and Sjögren's syndrome: comparative analysis of biopsies among different Italian rheumatologic centers.

OBJECTIVES: The minor salivary gland biopsy (MSGB) is widely considered an important component of the diagnostic algorithm of primary Sjögren's syndrome (pSS) and is mentioned in all the classification criteria sets for the disease. The aim of this study, coordinated by the Italian Society of Rheumatology, was to verify the inter-observer agreement on the evaluation of MSGB among different experienced Italian rheumatologic centres, in order to better standardise the diagnostic methodology. METHODS: Seven centres participated in the study, providing a total of 50 MSGB samples. Each center blindly classified all the samples according to the Chisholm and Mason (CM) grading. The results were collected and analysed. RESULTS: The inter-observer agreement was satisfactory when the samples were stratified as consistent and non-consistent with the final diagnosis of pSS (median κ =0.75; mean κ =0.70). Nonetheless, significant discrepancies in the histopathologic evaluation of MSGB emerged when the agreement was assessed on the single scores. Considering the modal CM grading for each sample as the correct grading, upon re-examination, a potential bias in the final clinical diagnosis was detected in 7 out of 50 samples. CONCLUSIONS: This study has shown significant discrepancies in the evaluation of MSGB among different rheumatologic centres in the same country. Greater standardisation of the procedure is clearly necessary, both to improve the diagnostic performance and scientific communication.

Sudden death due to spontaneous rupture in splenic artery atypical dissection with features of vasculitis: case report and review of the literature.

A case of sudden death in a 45-year-old man due to splenic artery dissection and rupture diagnosed at a medico-legal autopsy is described. The examination of the splenic artery revealed macroscopically the features of a ruptured intramural haematoma (no intimal tear, no lumen dilation) and histologically the characteristics of a lymphoplasmacytic vasculitis of the vasa vasorum associated with fibrinoid degeneration. The patient died at home after having been discharged from hospital where he had presented for modest abdominal pain with no evidence of the true nature of the disease found using echography. The Authors discuss the literature relative to splenic artery dissection (13 cases of which only one diagnosed in vivo), the present case being the only one due to vasculitis of the vasa vasorum and the forensic implications (autopsy was ordered to examine the causes of death, to verify whether diagnosis could have been reached during hospitalization with consequences on the outcome and if a hypothesis of malpractice could be prospected).

Isolated polyarteritis nodosa of the genitourinary tract presenting with severe erectile dysfunction: a case report with long-term follow-up.

INTRODUCTION: Polyarteritis nodosa (PAN) is a rare necrotizing vasculitis affecting small- and medium-sized arteries of multiple organs. Spreading to the genitourinary tract is very common, with invariable involvement of kidneys or testes, but its impact on erectile function remains undetermined. AIM: We describe a case of isolated PAN of the genitourinary tract diagnosed in a young man presenting with severe erectile dysfunction (ED), debate the critical issues of the differential diagnosis, and provide the long-term follow-up outcome. METHODS: The case report profiled a 36-year-old man who presented with progressively worsening erectile function and was incidentally found to suffer from genitourinary PAN. Extensive clinical, laboratory, and instrumental investigations, including brachial artery dilation test, suggested an arteriogenic etiology for ED and excluded a systemic involvement by PAN. Management featured use of a long-term, on-demand phosphodiesterase type 5 (PDE5) inhibitor regimen for ED, and close surveillance with no immunosuppressive therapy for PAN. MAIN OUTCOME MEASURES: Clinical history data, brachial artery dilation test, response to PDE5 inhibitor therapy. RESULTS: After 12 months of PDE5 inhibitor therapy, the patient recovered a normal erectile function, paralleled by restored endothelial function as assessed with brachial artery dilation test. At a 5-year clinical follow-up, he continued to have full erectile ability with only occasional use of PDE5 inhibitor, and no evidence of progressive PAN was documented. CONCLUSIONS: We propose PAN as a novel cause of arteriogenic ED, report the effective therapy with PDE5 inhibitor, and confirm the good long-term prognosis of isolated genitourinary PAN without immunosuppressive treatment.

Are PSA density and PSA density of the transition zone more accurate than PSA in predicting the pathological stage of clinically localized prostate cancer?

PURPOSE: To assess whether PSA density (PSAD) and PSA density of the transition zone (PSADTZ) are more accurate than PSA alone in predicting the pathological stage of prostate cancer. MATERIALS AND METHODS: One hundred and nine consecutive patients with clinically localized prostate cancer and preoperative PSA values over the whole range, treated with radical retropubic prostatectomy and limited pelvic lymph node dissection were included in this prospective study. Total prostate and transition zone volumes were measured by transrectal ultrasound using the prolate ellipsoid method. PSA, PSAD, and PSADTZ were compared to percentage of positive biopsy cores (% PC), biopsy and surgical Gleason score, and pathological stage, using univariate and multivariate analysis. RESULTS: Pathological stage was pT2a, pT2b, pT3a, and pT3b in 25.6%, 37.7%, 25.6%, and 11.1% of patients, respectively. Lymph node metastases were found in 4.6% of patients. PSA, PSAD, and PSADTZ were significantly related to % PC, biopsy, and surgical Gleason score and pathological stage (P < 0.001), and were equally able to predict higher pathological stage, i.e., seminal vesicle invasion and lymph node metastases. Only by adding % PC in multivariate analysis was it possible to discriminate intra- from extracapsular tumors. CONCLUSIONS: The results of the present study demonstrate that PSAD and PSADTZ failed to outperform PSA in preoperative stage prediction of prostate cancer, possibly because the formula used to calculate them does not eliminate the contribution to total PSA of the nonmalignant portion of the gland.

Pigmentatio maculosa eruptiva idiopathica: a case report and review of the literature.

BACKGROUND: Pigmentatio maculosa eruptiva idiopathica is a rare pediatric disease characterized by asymptomatic, brownish macules involving the neck and trunk with no preceding inflammatory process or history of drug exposure. METHODS: A 9-year-old girl presented with brown-gray, nonconfluent, asymptomatic macules on the trunk, neck, and limbs, ranging from 5 to 30 mm in diameter. The macules appeared suddenly with no lesions preceding their occurrence. Histopathologic examination showed basal cell layer hyperpigmentation, and abundant melanophages with a mild perivascular lymphohistiocytic infiltrate in the papillary dermis. RESULTS: The lesions disappeared spontaneously 1.5 years later with no therapy. No relapse occurred. CONCLUSION: Pigmentatio maculosa eruptiva idiopathica must be differentiated from other skin disorders with hyperpigmentation in pediatric practice in order to avoid unnecessary treatment, as spontaneous resolution is expected. Following a literature review, we underline the importance of spontaneous regression as an additional clinical feature for this disease.

Hepatocyte growth factor and transforming growth factor beta1 ratio at baseline can predict early response to cyclophosphamide in systemic lupus erythematosus nephritis.

OBJECTIVE: To determine whether the ratio of hepatocyte growth factor (HGF) to transforming growth factor beta1 (TGFbeta1) in systemic lupus erythematosus (SLE) nephritis could be a prognostic factor for response to therapy with cyclophosphamide (CYC) and steroids at 6 months, and to examine whether the molecular ratio of HGF to TGFbeta1 correlates with the activity index (AI) and chronicity index (CI) and has predictive value for remission at the sixth month. METHODS: Thirty-six SLE patients with new-onset nephritis, 25 of whom were treated with CYC and steroids, entered into a prospective observational cohort trial at a tertiary university referral center. Renal biopsy findings and clinical parameters were recorded for all patients. Histopathologic, clinical, and immunohistochemical data at baseline served to define the predictive value for the outcome at 6 months. RESULTS: AI and CI at baseline did not distinguish patients who had achieved remission from those who had not achieved remission after receiving CYC plus steroids. HGF and TGFbeta1 were expressed in the tubuli, not in the glomeruli. The CI correlated directly with the TGFbeta1 extension score (TGFbeta1-ES) (r = 0.43, P = 0.008), but correlated indirectly with the HGF intensity score (HGF-IS) (r = -0.39, P = 0.02) and the HGF-ES (r = -0.45, P = 0.006). An HGF-ES:TGFbeta1-ES ratio of >or=1 at baseline distinguished patients who had achieved remission from those who had not achieved remission, with a predictive value of 94%. CONCLUSION: These findings indicate that baseline expression of renal HGF and TGFbeta1 predicts short-term renal outcome after therapy with CYC and steroids.

Cystic endometriosis of the epididymis.

Endometriosis of the male genitourinary tract is an exceedingly rare entity, with only 6 cases reported to date involving the bladder, prostate, lower abdominal wall, and paratesticular region. We present what we believe to be the first case of cystic endometriosis of the epididymis in a 27-year-old man with scrotal pain, describe its pathologic and immunohistochemical features, and discuss its pathogenesis.

Atypical lymphoproliferation progressing into B-cell lymphoma in rheumatoid arthritis treated with different biological agents: clinical course and molecular characterization.

A patient with rheumatoid arthritis (RA) developed an atypical lymphoproliferative disorder (LPD) after methotrexate and cyclosporine A, which regressed after suspension of both drugs. After subsequent treatment with rituximab, the LPD was still undetectable. Anti-tumor necrosis factor a therapy was used when the arthritis relapsed, but an aggressive B-cell non Hodgkin's lymphoma developed. Molecular analyses showed an oligoclonal B-cell expansion at the LPD step. A minor clone with significant sequence homology to B-cell lymphomas arising in Sjogren's syndrome and mixed cryoglobulinemia syndrome, given rise to the non-Hodgkin's lymphoma. Treatment of rheumatoid arthritis associated with lymphoproliferation represents a clinical challenge, and common pathogenetic pathways to lymphoma may occur in different autoimmune diseases.

Carcinosarcoma arising in a patient with multiple cylindromas.

Familial cylindromatosis (Brooke-Spiegler syndrome) is a rare autosomal dominant inherited disease characterized by the development of adnexal tumors, mostly cylindromas, but also trichoepitheliomas and spiradenomas. Malignant tumors may occur, usually with the features of a cylindrocarcinoma. The authors describe the case of a 75-year-old woman with the Brooke-Spiegler syndrome who presented with multiple nodules of the scalp, face, and trunk. In 1997 she underwent surgical excision of the entire forehead and scalp with skin grafting. Histologic examination revealed multiple cylindromas, some with areas of spiradenoma and one with an extensive adenomatous component; some trichoepitheliomas were also evident. In 2002, a nodule of the trunk suddenly increased in size and became painful. The lesion was excised and histologic and immunohistochemical evaluation revealed a malignant cutaneous biphasic tumor extending into the subcutis, consisting of a major portion with the features of an adnexal carcinoma and of a minor one of atypical spindle cells. Biphasic malignant skin tumors are rare and only a limited number have been described, none in association with the Brooke-Spiegler syndrome. The authors discuss the morphogenesis of the folliculosebaceous-apocrine unit from which the tumors in this syndrome derive, and the pivotal role of mesenchymal cells in determining the process. Since the Brooke-Spiegler syndrome is characterized by a germline mutation in the CYLD oncosuppressor gene, a biphasic tumor in this setting may represent a true carcinosarcoma.

Systemic connective tissue disease complicated by Castleman's disease: report of a case and review of the literature.

Castleman's disease is an atypical lymphoproliferative disorder characterized by the prevalence of B CD5-positive cells in the marginal zone. Autoimmune manifestations have often been reported, but the association of Castleman's disease with systemic autoimmune syndromes has been rarely described. However, many authors stress the difficulties in distinguishing between connective tissue disease and Castleman's disease in most cases. To clarify this issue, we describe a patient and review the literature reports of all cases of Castleman's disease associated with a connective tissue disease. A 19-year old woman presented with autoimmune thyroiditis and polymyositis. Seven years after the onset she developed a systemic inflammatory flare and a burst of autoimmunity, followed by generalized lymphoadenopathy. A mediastinal lymph node biopsy led to the diagnosis of Castleman disease of mixed type. Chemotherapy was given, with rapid response of the lymphoproliferative disorder but persistence of the underlying autoimmune disorder. The plasma concentration of B-lymphocyte stimulator (BLyS) was high (13.3 ng/mL) at the diagnosis of Castleman's disease. It fell dramatically after chemotherapy (4.97 ng/mL), even though it remained just above the mean BLyS value found in healthy blood donors (3.37+/-0.78 ng/mL).Castleman's disease can present autoimmune traits. In our patient, Castleman's disease complicated the course of a connective tissue disorder several years after the onset. We hypothesize that chronic stimulation of B-cell clones, particularly CD5+, by BLyS could favor the development of both autoimmune diseases and a broad range of lymphoproliferative disorders (such as Castleman's disease). This is the first report of increased BLyS levels in a patient with Castleman's disease, supporting a possible pathogenetic role of BLyS in the development of an autoimmune disorder and of a B lymphoproliferative disorder years later.

Extrasalivary lymphoma development in Sjögren's syndrome: clonal evolution from parotid gland lymphoproliferation and role of local triggering.

OBJECTIVE: To characterize Sjögren's syndrome (SS)-related B cell lymphoproliferation at the premalignant stage and during the evolution to B cell lymphoma, and to better understand the pathobiologic mechanisms associated with clonal expansion and the possible influence of different microenvironments on neoplastic transformation. METHODS: We analyzed sequential parotid and lung biopsy specimens that were obtained from a single patient with SS at multiple time points over a 7-year period. Polymerase chain reaction DNA amplification, cloning, and sequencing of the immunoglobulin heavy chain variable region showed clonality, somatic mutations, intraclonal heterogeneity, and genealogic relationships of the B cell clones in the different biopsy specimens. RESULTS: The evolution of a nonmalignant B cell clone that was present in the parotid gland and evolved into a B cell lymphoma was documented. During such a process, one subclone was selected that accumulated somatic mutations in a pattern consistent with the preservation of antigen receptor functionality, possibly attributable to continued hypermutation and selection. Intraclonal diversity indicated the presence of local triggers in both the parotid and lung microenvironments. CONCLUSION: Molecular followup of B cell lymphoproliferation in SS, from nonmalignant stage to overt B cell lymphoma, indicated a role for B cell receptor engagement in clonal survival. The outgrowth of one subclone, with malignant transformation in the lung, a target organ different from the initial site of the lymphoproliferative process (the parotid gland), indicates that resident stimuli in different microenvironments may locally sustain ongoing lymphoproliferation and B cell transformation.

Desmoplastic melanoma of the nail.

Desmoplastic melanoma represents a variant of melanoma that is difficult to diagnose because 71% of patients have amelanotic skin lesions. In the acral region of the limbs, the clinical diagnosis is more difficult, especially in cases in which there are not clear, rapidly growing, pigmented nail streaks. Histopathological identification of desmoplastic melanoma is confusing because of the intense fibrous reaction in the dermis and minimal, atypical melanocytic proliferation at the dermal-epidermal junction. For these reasons, it is still misdiagnosed unfortunately as a variety of entities, including simple scar, fibrohistiocytic neoplasms, neural tumors, and superficial fibromatoses-with potentially devastating consequences. In equivocal cases, the use of immunohistochemistry (in particular S-100 and neuron-specific enolase) may be helpful in establishing the diagnosis. Because of the high local recurrence rate for desmoplastic melanoma of the finger, amputation is recommended in an effort to gain effective tumor control. Lymph node dissection may be reserved for patients with positive axillary nodes.