Mature outcomes and prognostic indices in diffuse large B-cell lymphoma in Malawi: a prospective cohort.

Outcomes for diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa (SSA) are poorly described. We report mature data from one of the first prospective SSA cohorts. Patients aged ≥18 years with DLBCL were enrolled in Malawi 2013-2017. Participants were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy and concurrent antiretroviral therapy (ART) if positive for human immunodeficiency virus (HIV+). Eighty-six participants (mean age 47 years, standard deviation 13) were enrolled: 54 (63%) were male and 51 (59%) were HIV+, of whom 34 (67%) were on ART at DLBCL diagnosis. Median CD4 count was 0·113 cells × 109 /l (interquartile range [IQR] 0·062-0·227) and 25 (49%) had HIV viral load <400 copies/µl. Participants received median six cycles CHOP (IQR 4-6). No patients were lost to follow-up and the 2-year overall survival was 38% (95% confidence interval 28-49). In multivariable analyses, Eastern Cooperative Oncology Group performance status (PS) ≥2 and lactate dehydrogenase (LDH) >2× upper limit of normal (ULN) were associated with mortality. HIV status was not associated with mortality. A simplified prognostic model of LDH >2× ULN and PS ≥2 performed at least as well as the age-adjusted International Prognostic Index. DLBCL can be successfully treated in SSA and outcomes did not differ by HIV status. A simplified prognostic model prognosticates well and may be easier to use in resource-limited settings but requires validation.

Rosai-Dorfman disease in Malawi.

Rosai-Dorfman Disease (RDD) is a rare lymphoproliferative disease with limited cases reported in sub-Saharan Africa, potentially due to a lack of pathological services throughout the region. RDD diagnosis can be difficult, especially in resource-limited setting, as symptoms can be nearly identical to more common causes of lymphadenopathy.

Plasma Epstein-Barr virus DNA for pediatric Burkitt lymphoma diagnosis, prognosis and response assessment in Malawi.

Point-of-care tools are needed in sub-Saharan Africa (SSA) to improve pediatric Burkitt lymphoma (BL) diagnosis and treatment. We evaluated plasma Epstein-Barr virus (pEBV) DNA as a pediatric BL biomarker in Malawi. Prospectively enrolled children with BL were compared to classical Hodgkin lymphoma (cHL) and nonlymphoma diagnoses. Pediatric BL patients received standardized chemotherapy and supportive care. pEBV DNA was measured at baseline, mid-treatment, and treatment completion. Of 121 assessed children, pEBV DNA was detected in 76/88 (86%) with BL, 16/17 (94%) with cHL, and 2/16 (12%) with nonlymphoma, with proportions higher in BL versus nonlymphoma (p < 0.001) and similar in BL versus cHL (p = 0.69). If detected, median pEBV DNA was 6.1 log10 copies/mL for BL, 4.8 log10 copies/mL for cHL, and 3.4 log10 copies/mL for nonlymphoma, with higher levels in BL versus cHL (p = 0.029), and a trend toward higher levels in BL versus nonlymphoma (p = 0.062). pEBV DNA declined during treatment in the cohort overall and increased in several children before clinical relapse. Twelve-month overall survival was 40% in the cohort overall, and for children with baseline pEBV detected, survival was worse if baseline pEBV DNA was ≥6 log10 copies/mL versus <6 log10 copies/mL (p = 0.0002), and also if pEBV DNA was persistently detectable at mid-treatment versus undetectable (p = 0.041). Among children with baseline pEBV DNA detected, viremia was the only significant risk factor for death by 12 months in multivariate analyses (adjusted hazard ratio 1.35 per log10 copies/mL, 95% CI 1.04-1.75, p = 0.023). Quantitative pEBV DNA has potential utility for diagnosis, prognosis, and response assessment for pediatric BL in SSA.

Hodgkin lymphoma, HIV, and Epstein-Barr virus in Malawi: Longitudinal results from the Kamuzu Central Hospital Lymphoma study.

BACKGROUND: Contemporary descriptions of classical Hodgkin lymphoma (cHL) are lacking from sub-Saharan Africa where human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) are prevalent. METHODS: We describe a prospective cHL cohort in Malawi enrolled from 2013 to 2015. Patients received standardized treatment and evaluation, including HIV status and EBV testing of tumors and plasma. RESULTS: Among 31 patients with confirmed cHL, the median age was 19 years (range, 2-51 years) and 22 (71%) were male. Sixteen patients (52%) had stage III/IV, 25 (81%) B symptoms, and 16 (52%) performance status impairment. Twenty-three patients (74%) had symptoms >6 months, and 11 of 29 (38%) had received empiric antituberculosis treatment. Anemia was common with median hemoglobin 8.2 g/dL (range, 3.1-17.1 g/dL), which improved during treatment. No children and 5 of 15 adults (33%) were HIV+. All HIV+ patients were on antiretroviral therapy for a median 15 months (range, 2-137 months), with median CD4 count 138 cells/µL (range, 23-329 cells/µL) and four (80%) having undetectable HIV. EBV was present in 18 of 24 (75%) tumor specimens, including 14 of 20 (70%) HIV- and 4 of 4 (100%) HIV+. Baseline plasma EBV DNA was detected in 25 of 28 (89%) patients, with median viral load 4.7 (range, 2.0-6.7) log10 copies/mL, and subsequently declined in most patients. At 12 months, overall survival was 75% (95% confidence interval [CI], 55%-88%) and progression-free survival 65% (95% CI, 42%-81%). Baseline plasma EBV DNA and persistent viremia during treatment were associated with poorer outcomes. CONCLUSION: cHL in Malawi is characterized by delayed diagnosis and advanced disease. Most cases were EBV associated and one-third of adults were HIV+. Despite resource limitations, 12-month outcomes were good.

Accurate Real-Time Diagnosis of Lymphoproliferative Disorders in Malawi Through Clinicopathologic Teleconferences: A Model for Pathology Services in Sub-Saharan Africa.

OBJECTIVES: The incidence of lymphoproliferative disorders (LPDs) is increasing in sub-Saharan Africa (SSA) due to population growth, aging, and human immunodeficiency virus (HIV). Despite significant burden, resources for diagnosis and treatment of LPDs are limited, with little infrastructure to deliver modern pathology services. Diagnostic and therapeutic decisions are therefore frequently made without tissue confirmation, leading to high rates of misdiagnosis and inappropriate treatment. METHODS: We have established a laboratory in Malawi to support clinical and research efforts at a national teaching hospital. Consensus real-time diagnoses are rendered by local pathologists after weekly clinicopathologic teleconferences involving clinicians and pathologists from the United States and Malawi. Additional ancillary studies are then performed in the United States prior to final diagnosis. RESULTS: We report our first 2 years' experience and demonstrate high concordance between real-time diagnoses in Malawi and final diagnoses in the United States (5% major discordance rate for formalin-fixed, paraffin-embedded samples). In addition, we describe characteristics of pathologically confirmed LPDs in Malawi, highlighting differences by HIV status. CONCLUSIONS: Our multidisciplinary approach can be a model for strong pathology services that provide direct, real-time support to clinical care and research in SSA.

CHOP Chemotherapy for Aggressive Non-Hodgkin Lymphoma with and without HIV in the Antiretroviral Therapy Era in Malawi.

There are no prospective studies of aggressive non-Hodgkin lymphoma (NHL) treated with CHOP in sub-Saharan Africa. We enrolled adults with aggressive NHL in Malawi between June 2013 and May 2015. Chemotherapy and supportive care were standardized, and HIV+ patients received antiretroviral therapy (ART). Thirty-seven of 58 patients (64%) were HIV+. Median age was 47 years (IQR 39-56), and 35 (60%) were male. Thirty-five patients (60%) had stage III/IV, 43 (74%) B symptoms, and 28 (48%) performance status ≥ 2. B-cell NHL predominated among HIV+ patients, and all T-cell NHL occurred among HIV- individuals. Thirty-one HIV+ patients (84%) were on ART for a median 9.9 months (IQR 1.1-31.7) before NHL diagnosis, median CD4 was 121 cells/µL (IQR 61-244), and 43% had suppressed HIV RNA. HIV+ patients received a similar number of CHOP cycles compared to HIV- patients, but more frequently developed grade 3/4 neutropenia (84% vs 31%, p = 0.001), resulting in modestly lower cyclophosphamide and doxorubicin doses with longer intervals between cycles. Twelve-month overall survival (OS) was 45% (95% CI 31-57%). T-cell NHL (HR 3.90, p = 0.017), hemoglobin (HR 0.82 per g/dL, p = 0.017), albumin (HR 0.57 per g/dL, p = 0.019), and IPI (HR 2.02 per unit, p<0.001) were associated with mortality. HIV was not associated with mortality, and findings were similar among patients with diffuse large B-cell lymphoma. Twenty-three deaths were from NHL (12 HIV+, 11 HIV-), and 12 from CHOP (9 HIV+, 3 HIV-). CHOP can be safe, effective, and feasible for aggressive NHL in Malawi with and without HIV.

Outcomes for paediatric Burkitt lymphoma treated with anthracycline-based therapy in Malawi.

Burkitt lymphoma (BL) is the most common paediatric cancer in sub-Saharan Africa (SSA). Anthracyline-based treatment is standard in resource-rich settings, but has not been described in SSA. Children ≤18 years of age with newly diagnosed BL were prospectively enrolled from June 2013 to May 2015 in Malawi. Staging and supportive care were standardized, as was treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for six cycles. Among 73 children with BL, median age was 9·2 years (interquartile range 7·7-11·8), 48 (66%) were male and two were positive for human immunodeficiency virus. Twelve (16%) had stage I/II disease, 36 (49%) stage III and 25 (34%) stage IV. Grade 3/4 neutropenia occurred in 17 (25%), and grade 3/4 anaemia in 29 (42%) of 69 evaluable children. Eighteen-month overall survival was 29% (95% confidence interval [CI] 18-41%) overall. Mortality was associated with age >9 years [hazard ratio [HR] 2·13, 95% CI 1·15-3·94], female gender (HR 2·12, 95% CI 1·12-4·03), stage (HR 1·52 per unit, 95% CI 1·07-2·17), lactate dehydrogenase (HR 1·03 per 100 iu/l, 95% CI 1·01-1·05), albumin (HR 0·96 per g/l, 95% CI 0·93-0·99) and performance status (HR 0·78 per 10-point increase, 95% CI 0·69-0·89). CHOP did not improve outcomes in paediatric BL compared to less intensive regimens in Malawi.

Characteristics and survival for HIV-associated multicentric Castleman disease in Malawi.

INTRODUCTION: Clinical reports of multicentric Castleman disease (MCD) from sub-Saharan Africa (SSA) are scarce despite high prevalence of HIV and Kaposi sarcoma-associated herpesvirus (KSHV). Our objective is to describe characteristics and survival for HIV-associated MCD patients in Malawi. To our knowledge, this is the first HIV-associated MCD case series from the region. METHODS: We describe HIV-positive patients with MCD in Lilongwe, and compare them to HIV-associated lymph node Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) patients treated at our centre. All patients were enrolled into a prospective longitudinal cohort study at a national teaching hospital and cancer referral centre serving half of Malawi's 16 million people. We included adult patients≥18 years of age with HIV-associated MCD (n=6), lymph node KS (n=5) or NHL (n=31) enrolled between 1 June 2013 and 31 January 2015. RESULTS AND DISCUSSION: MCD patients had a median age of 42.4 years (range 37.2-51.8). All had diffuse lymphadenopathy and five had hepatosplenomegaly. Concurrent KS was present for one MCD patient, and four had performance status ≥3. MCD patients had lower median haemoglobin (6.4 g/dL, range 3.6-9.3) than KS (11.0 g/dL, range 9.1-12.0, p=0.011) or NHL (11.2 g/dL, range 4.5-15.1, p=0.0007). Median serum albumin was also lower for MCD (2.1 g/dL, range 1.7-3.2) than KS (3.7 g/dL, range 3.2-3.9, p=0.013) or NHL (3.4 g/dL, range 1.8-4.8, p=0.003). All six MCD patients were on antiretroviral therapy (ART) with median CD4 count 208 cells/µL (range 108-1146), and all with HIV RNA <400 copies/mL. Most KS and NHL patients were also on ART, although ART duration was longer for MCD (56.4 months, range 18.2-105.3) than KS (14.2 months, range 6.8-21.9, p=0.039) or NHL (13.8 months, range 0.2-98.8, p=0.017). Survival was poorer for MCD patients than lymph node KS or NHL. CONCLUSIONS: HIV-associated MCD occurs in Malawi, is diagnosed late and is associated with high mortality. Improvements in awareness, diagnostic facilities, treatment and supportive care are needed to address this likely under-recognized public health problem in SSA.

Gastric adenocarcinoma in common variable immunodeficiency: features of cancer and associated gastritis may be characteristic of the condition.

Common variable immunodeficiency (CVID) is associated with an increased risk of gastric cancer. The aim of the study was to determine the morphological features of CVID-associated gastric adenocarcinoma (CAGA) and of the background gastritis. The population of gastric cancer patients with CVID of Mayo Clinic in the period 2000-2010 was studied; 6 cases of CVID (2 males, 4 females, average age 47 years, age range 26-71 years) were found in 5793 patients with gastric cancer in the study period. Each patient underwent gastric resection for which histology slides were reviewed. Chronic gastritis variables, CVID-related findings, and features of the adenocarcinoma were recorded. CAGA was of intestinal type, with high number of intratumoral lymphocytes (ITLs). Cancer was diagnosed in younger patients than in the overall population of gastric cancer. Severe atrophic metaplastic pangastritis with extensive dysplasia was present in the background in 4 cases, with features of lymphocytic gastritis in 2 cases. Features of CVID (plasma cells paucity in 4 of 6 cases, lymphoid nodules prominent in four cases) could be detected. In summary, gastric adenocarcinoma at young age with ITLs, accompanied by atrophic metaplastic pangastritis, should alert the pathologist of the possibility of CAGA. It follows that, in presence of those characteristics, the search of CVID-associated abnormalities should be undertaken in the nonneoplastic tissues.

Histopathological changes in the gastrointestinal tract due to drugs: an update for the surgical pathologist (part I of II).

Abnormalities of the gastrointestinal (GI) tract due to drugs (AGIDs) are numerous and have significant impact. The aim of this narrative review is to help the practicing surgical pathologist recognize selected AGIDs. The adverse drug effects presented were chosen with an emphasis on recent and significant pathological and clinical contributions. The selection was based on a thorough review of the PUBMED-based literature and on the authors' opinions and experience. In the first part of the review, diagnostic abnormalities due to crystals (eg, iron, biphosphonates, nonsystemic drugs), mitosis arresting drugs (colchicine, taxanes), and biological agents, especially ipilimumab, are discussed. Some AGIDs' histopathologic features can be easily recognized. It is however the clinical correlation that in many cases of AGIDs will provide the necessary support for a drug effect diagnosis. The identification of AGIDs requires heightened awareness of the medical team in which close collaboration of pathologists and clinicians cannot be overemphasized.

Histopathological changes in the gastrointestinal tract due to medications: an update for the surgical pathologist (part II of II).

In keeping with the stated goal of providing the surgical pathologist with tools to recognize abnormalities of the gastrointestinal (GI) tract due to drugs (AGIDS), in part II of this review we embark in a more organ-based description of AGIDS. Adequate space is given to the numerous adverse gastrointestinal effects of nonsteroidal anti-inflammatory drugs. Pill esophagitis, esophagitis dissecans, proton pump inhibitors' effects, diaphragm disease, and the recently described effects of drugs such as olmesartan, mycophenolate, and of compounds such as yttrium-90 are highlighted among several others. The inclusion of drug effects in the differential diagnosis of "conventional" diseases (such as gastric antral vascular ectasia, graft-versus-host disease, ischemic colitis, acute colitis, collagenous enteritis, inflammatory bowel disease) is underscored to avoid sometimes significant diagnostic pitfalls. We reiterate the message of the necessary collaboration between pathologist and clinician in the recognition of these entities to provide the best patient care.

Inflammatory "Cap" Polyposis: A Case Report of a Rare Nonneoplastic Colonic Polyposis.

Inflammatory cap polyposis (ICP) is a rare nonneoplastic polyposis of the colon of unknown etiology that can be confused with prolapse-induced polyps and hyperplastic polyposis. We contribute a case of ICP from a 59-year-old woman who was affected by severe constipation and hematochezia. Numerous sessile and semipedunculated polyps were found in the colon, all with cap of whitish fibrin. Histology revealed erosion of the surface, superficial dilated crypts filled with mucoid inflammatory exudate, and minimal crypt serration, all findings typical of ICP. Only the largest polyps had smooth muscle in the mucosa. Ki-67 showed modest expansion and irregular distribution of the crypts proliferative areas. Low-degree positivity for p16, similar to that of hyperplastic polyps, was found. CK20 was expressed as in normal mucosa. Distinguishing between ICP and other polyposis is important because of difference in management.

Bizarre stromal cells in the esophagus: report of 2 cases and literature review.

A significant mimicker of malignancy in the esophagus is the presence of atypical/bizarre stromal cells (BSCs). Two patients, a 60-year-old woman and a 59-year-old man, with esophageal polyps at the gastroesophageal junction showed highly atypical/bizarre cells in the polyps' stroma. BSCs were admixed with inflammatory cells and had large atypical nuclei, prominent nucleoli, and variably abundant amphophilic cytoplasm. Immunohistochemical studies showed that BSCs expressed vimentin whereas S-100, CD68, HMB45, CD45, Pan-cytokeratin, CK5/6, p63, CD10, EMA, MART-1, desmin, smooth muscle actin, CD31, CD34, and CMV were negative. Ki-67 showed low proliferative rate (less than 1% positivity). No evidence of intracellular mucin was found after histochemical stains (AB/PAS and mucicarmine). Follow-up endoscopic mucosal resection was available in both cases and showed benign esophageal mucosa and submucosa with disappearance, in one case, or marked decrease of BSCs. Esophageal BSCs reports in the literature invariably locate them in distal esophagus polyps or masses. Awareness of BSCs, of their location and associations, may help to prevent misdiagnosis of malignancy. The literature of esophageal BSCs is reviewed and the approach to this abnormality is discussed.