Samir Dalia

Rosai-Dorfman Disease: Tumor Biology, Clinical Features, Pathology, and Treatment

BACKGROUND Rosai-Dorfman disease (RDD) is a rare, nonmalignant clinical entity characterized by a group of clinical symptoms and characteristic pathological features. METHODS Articles that reviewed tumor biology, clinical features, pathology, and treatment for RDD were identified in a search of the literature for the years 1990 to 2014. The results from this body of literature were reviewed and summarized. RESULTS Patients with RDD generally present with massive, painless cervical lymphadenopathy, fevers, and elevated inflammatory markers. Extranodal disease is typical, with the most common sites being the skin and the central nervous system. Rarely, the gastrointestinal tract is involved. Immunohistochemistry remains the mainstay of diagnosis with S100 and CD68 positive cells while CD1a will be negative of involved histiocytes. Histologically, the disease shows the classical characteristic finding of emperipolesis. Many patients do not require treatment; however, surgical resection remains the mainstay of treatment for symptomatic disease. The role of steroids, chemotherapy, and radiation therapy continue to be based on small case series and case reports. CONCLUSIONS RDD has a variable clinical presentation; therefore, a high degree of suspicion and a thorough pathological review are necessary to diagnose this rare clinical entity. Although some patients will experience spontaneous resolution, others may require surgical resection or steroid therapy and radiation or chemotherapy. Given the rarity of the disease and the lack of a clear therapeutic pathway, referring patients to a tertiary center is recommended for confirming the diagnosis and treatment considerations.

Diffuse Large B-Cell Lymphoma: Current Strategies and Future Directions

BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is the most common histology of non-Hodgkin lymphoma, representing 25% to 35% of new cases annually. The incidence of DLBCL has doubled in the past decades, highlighting the need for more effective treatment regimens. METHODS This article reviews the current protocols applicable to this aggressive lymphoma and discusses ongoing research that is focusing on molecular diagnostics, prognostic factors have also been defined for DLBCL. RESULTS Patients with DLBCL vary in clinical presentation, prognosis, and response to current therapies. While current therapy in the rituximab era has led to improved outcomes with reduced toxicity, novel treatment approaches for localized, advanced, and relapsed/refractory DLBCL are being pursued in clinical trials. Several studies have shown promise, such as trials involving proteasome inhibitors, lenalidomide, and antibody drug conjugates. CONCLUSIONS Recent discoveries in the spectrum of care for patients with DLBCL have prompted a renaissance for personalized cancer medicine and molecularly targeted therapy. Potential targets and novel drug combinations are undergoing continued study in the hope of achieving successful and personalized care of this disease.

Hepatitis B infection increases the risk of non-Hodgkin lymphoma: A meta-analysis of observational studies

Hepatitis B virus (HBV) infection is a major public health problem and the association between HBV infection and non-Hodgkin lymphoma (NHL) is unclear. The primary aim of our study was to evaluate the association between HBV infection assessed by a positive hepatitis B surface antigen (HBsAg) and the incidence of NHL and subtypes using a meta-analysis of epidemiological studies. The random effects model was used to calculate the outcome. Our search yielded 17 case-control and 5 cohort studies, including over 40,000 NHL cases. HBV infected individuals had an OR of 2.24 (95% CI 1.80-2.78; p ≤ 0.001) of developing NHL. In high HBV prevalent countries, there were increased odds of diffuse large B-cell lymphoma and a trend toward increased odds of developing follicular and T-cell lymphoma. Future research is needed to better understand the biological mechanisms responsible for lymphomagenesis in patients with HBV infection.

Dendritic cell and histiocytic neoplasms: biology, diagnosis, and treatment.

BACKGROUND Dendritic and histiocytic cell neoplasms are rare malignancies that make up less than 1% of all neoplasms arising in lymph nodes or soft tissues. These disorders have distinctive disease biology, clinical presentations, pathology, and unique treatment options. Morphology and immunohistochemistry evaluation by a hematopathologist remains key for differentiating between these neoplasms. In this review, we describe tumor biology, clinical features, pathology, and treatment of follicular dendritic cell sarcoma, interdigitating dendritic cell sarcoma, indeterminate dendritic cell sarcoma, histiocytic sarcoma, fibroblastic reticular cell tumors, and disseminated juvenile xanthogranuloma. METHODS A literature search for articles published between 1990 and 2013 was undertaken. Articles are reviewed and salient findings are systematically described. RESULTS Patients with dendritic cell and histiocytic neoplasms have distinct but variable clinical presentations; however, because many tumors have recently been recognized, their true incidence is uncertain. Although the clinical features can present in many organs, most occur in the lymph nodes or skin. Most cases are unifocal and solitary presentations have good prognoses with surgical resection. The role of adjuvant therapy in these disorders remains unclear. In cases with disseminated disease, prognosis is poor and data on treatment options are limited, although chemotherapy and referral to a tertiary care center should be considered. Excisional biopsy is the preferred method of specimen collection for tissue diagnosis, and immunohistochemistry is the most important diagnostic method for differentiating these disorders from other entities. CONCLUSIONS Dendritic cell and histiocytic cell neoplasms are rare hematological disorders with variable clinical presentations and prognoses. Immunohistochemistry remains important for diagnosis. Larger pooled analyses or clinical trials are needed to better understand optimal treatment options in these rare disorders. Whenever possible, patients should be referred to a tertiary care center for disease management.

Clinicopathologic Characteristics and Outcomes of Histiocytic and Dendritic Cell Neoplasms: The Moffitt Cancer Center Experience Over the Last Twenty Five Years

Neoplasms of histiocytic and dendritic cells are rare disorders of the lymph node and soft tissues. Because of this rarity, the corresponding biology, prognosis and terminologies are still being better defined and hence historically, these disorders pose clinical and diagnostic challenges. These disorders include Langerhans cell histiocytosis (LCH), histiocytic sarcoma (HS), follicular dendritic cell sarcoma (FDCS), interdigtating cell sarcoma (IDCS), indeterminate cell sarcoma (INDCS), and fibroblastic reticular cell tumors (FRCT). In order to gain a better understanding of the biology, diagnosis, and treatment in these rare disorders we reviewed our cases of these neoplasms over the last twenty five years and the pertinent literature in each of these rare neoplasms. Cases of histiocytic and dendritic cell neoplasms diagnosed between 1989–2014 were identified using our institutional database. Thirty two cases were included in this analysis and were comprised of the following: Langerhans cell histiocytosis (20/32), histiocytic sarcoma (6/32), follicular dendritic cell sarcoma (2/32), interdigitating dendritic cell sarcoma (2/32), indeterminate dendritic cell sarcoma (1/32), and fibroblastic reticular cell tumor (1/32). Median overall survival was not reached in cases with LCH and showed 52 months in cases with HS, 12 months in cases with FDCS, 58 months in cases with IDCS, 13 months in the case of INDCS, and 51 months in the case of FRCT. The majority of patients had surgical resection as initial treatment (n = 18). Five patients had recurrent disease. We conclude that histiocytic and dendritic cell neoplasms are very rare and perplexing disorders that should be diagnosed with a combination of judicious morphology review and a battery of immunohistochemistry to rule out mimics such as carcinoma, lymphoma, neuroendocrine tumors and to better sub-classify these difficult to diagnose lesions. The mainstay of treatment for localized disease remains surgical resection and the role of adjuvant therapy is unclear. In patients with multiple areas of involvement, treatment at tertiary care centers with multimodality treatment is likely needed. Accurate subset diagnosis will contribute to better data as well as treatment outcomes analysis of these rare disorders of adult patients in the future.

Meta-Analysis of the Association Between Cigarette Smoking and Incidence of Hodgkin's Lymphoma

INTRODUCTION Previous studies have suggested a relationship between smoking and Hodgkins lymphoma (HL). The main objective of this study was to evaluate this potential association with a meta-analysis of observational studies. PATIENTS AND METHODS A literature search was undertaken through December 2010 looking for observational studies evaluating the association between smoking and HL. From 714 articles, 17 were included in this study. Outcome was calculated and reported as odds ratio (OR). Heterogeneity was assessed by using the I(2) index. Publication bias was evaluated by trim-and-fill analysis. Quality assessment was performed with the Newcastle-Ottawa scale. RESULTS Our analysis showed an OR of developing HL of 1.35 (95% CI, 1.17 to 1.56; P < .001) in current smokers. Former smokers did not have an increased risk of HL. In subset analyses of current smokers, men and older individuals had ORs of HL of 1.78 (95% CI, 1.46 to 2.17; P < .001) and 1.77 (95% CI, 1.23 to 2.54; P = .002), respectively. In addition, the OR of HL was increased in individuals who smoke more than 20 cigarettes per day, have smoked more than 20 years, or have smoked more than 15 pack-years at 1.51 (95% CI, 1.16 to 1.98; P = .002), 1.84 (95% CI, 1.47 to 2.32; P < .001), and 1.97 (1.53 to 2.54; P < .001), respectively. Meta-regression analyses showed a relative OR of HL of 1.007 (95% CI, 1.001 to 1.013; P = .025) per cigarette per day and of 1.013 (95% CI, 1.006 to 1.019; P < .001) per year of smoking. CONCLUSION Smoking seems to increase the odds of developing HL in current smokers. The risk of HL is higher in men and older individuals and increases with higher intensity and longer duration of smoking.

Prognostic factors for advanced-stage human immunodeficiency virus-associated classical Hodgkin lymphoma treated with doxorubicin, bleomycin, vinblastine, and dacarbazine plus combined antiretroviral therapy: a multi-institutional retrospective study.

The treatment and outcomes of patients with human immunodeficiency virus (HIV)‐associated Hodgkin lymphoma (HL) continue to evolve. The International Prognostic Score (IPS) is used to predict the survival of patients with advanced‐stage HL, but it has not been validated in patients with HIV infection.

Obesity Is Associated With Increased Relative Risk of Diffuse Large B-Cell Lymphoma: A Meta-Analysis of Observational Studies

BACKGROUND The relation between body mass index (BMI) and incidence of diffuse large B-cell lymphoma (DLBCL) has been suggested, but no systematic review has been undertaken. MATERIAL AND METHODS We performed a literature search through December 2012. Meta-analyses were performed to quantify the relative risk (RR) of DLBCL incidence in overweight and obese persons compared with normal weight individuals using the random-effects model. Subset analyses were performed according to study design, sex, and geographic region. Overweight was defined as a BMI 25 to 29.9 kg/m(2), and obesity was defined as a BMI of 30 kg/m(2). Meta-regression, using an unrestricted maximum likelihood model, was performed to evaluate the linear association between BMI and odds of DLBCL. RESULTS Our study included 6 case-control and 10 cohort studies. The RR of DLBCL in overweight individuals was 1.14 (95% confidence interval [CI], 1.04-1.24; P = .004), and in obese individuals, RR was 1.29 (95% CI, 1.16-1.43; P < .001). The RR of DLBCL in overweight men and women was 1.22 and 1.27, respectively. In overweight individuals, both prospective and case-control studies showed an RR of 1.13. The RR of DLBCL in obese men and women was 1.40 and 1.34, respectively. In obese individuals, the RR in prospective studies was 1.25 and in case-control studies it was 1.33. Meta-regression analysis showed a 14% increase in DLBCL incidence for each 10 kg/m(2) increase in BMI. CONCLUSION An increased BMI is associated with higher RR of DLBCL regardless of sex. Also, there seems to be a linear association between BMI and DLBCL incidence.

Cigarette smoking is associated with a small increase in the incidence of non-Hodgkin lymphoma: a meta-analysis of 24 observational studies

Abstract Previous studies have evaluated the association between cigarette smoking and incidence of non-Hodgkin lymphoma (NHL) with inconclusive results. Our main objective was to evaluate this relationship using a meta-analysis of observational studies. A literature search was undertaken through October 2011 looking for pertinent studies. Seven prospective cohort and 17 case–control studies were included in this meta-analysis. Outcomes were calculated using the random-effects model and are reported as odds ratio (OR). Meta-regression was used to evaluate the dose–response of intensity and duration of smoking in NHL incidence. Our study found an OR of 1.40 (95% confidence interval [CI] 1.14–1.73; p = 0.001) in current female smokers seen only in case–control studies. No increased odds of NHL was seen in men. There was no association between smoking and the most common NHL subtypes, with the exception of a statistical trend toward a higher incidence of T-cell lymphoma. In conclusion, there appears to be an increase in the odds of NHL in current female smokers.

Results of a phase II study of lenalidomide and rituximab for refractory/relapsed chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is an incurable disease in need of new therapeutic strategies. The immunomodulatory agent, lenalidomide, has shown activity as salvage therapy for CLL. In this phase II trial, we combined lenalidomide with rituximab in 25 patients (range, 41-79) with refractory/relapsed CLL. Lenalidomide was administered orally on escalating doses, with cycle 1 doses of 2.5mg daily on days 1-7, 5mg on days 8-14, and 10mg on days 15-21 followed by 7days off. On cycle 2 and beyond, lenalidomide was administered at 20mg daily on days 1-21. Rituximab was administered at 375mg/m(2) intravenously on a weekly basis for the first cycle starting on day 15 for 4 doses, with each cycle being 28days. Treatment was continued until disease progression or toxicity. Overall response rate was 45.8% on intent-to-treat and 61.1% in evaluable patients (all partial responses). Median time to treatment failure was 14.3 months for evaluable patients, and median overall survival was not reached. The most common grade 3/4 toxicity was neutropenia (72% of patients). The most common nonhematologic toxicity was infection (29% of patients). Lenalidomide combined with rituximab showed activity in heavily treated refractory CLL with an acceptable toxicity profile.