Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells.

Aggressive natural killer-cell leukemia (ANKL) is a rare form of large granular lymphocyte leukemia, which is characterized by a systemic proliferation of NK cells. The clinical features of 22 ANKL cases were analyzed. Hepatomegaly (64%), splenomegaly (55%) and lymphadenopathy (41%) were also frequently observed. Leukemic cells were identified as CD1-, CD2+, surface CD3-, CD4-, CD5-, CD7+, CD8+/-, CD10-, CD11b+/-, CD13-, CD16+, CD19-, CD20-, CD25-, CD33(-), CD34-, CD38+, CD56+, CD122+, HLA-DR+ and TCR-. Two of the 16 cases examined for CD57 were positive and three of the seven cases examined for cytoplasmic CD3. Epstein-Barr virus was detected in the tumor cells of 11 of the 13 cases examined. No common cytogenetic abnormalities were identified and 6q anomaly was detected in only one. Three of 13 patients treated with chemotherapy containing anthracycline/anthraquinone attained complete remission, in contrast to none of the eight who were treated with regimens without anthracycline. Although the overall prognosis was poor with a median survival of 58 days, those who attained remission showed better prognosis (P=0.005). These findings suggest that ANKL is an entity of mature cytotoxic NK-cell neoplasms with distinct phenotype and disease presentations. Intensive treatment for ANKL may result in a better prognosis.     

侵袭性NK细胞白血病九例

 目的　提高对侵袭性NK细胞白血病（ANKL）的认识。方法　回顾分析2004年3月至2007年3月期间收治的9例ANKL患者的临床资料。结果　ANKL患者多有全身症状、肝脾大、淋巴结肿大、肝功能异常、贫血、中性粒细胞减少、血小板减少。大部分骨髓侵犯为轻、中度。肿瘤细胞免疫表型sCD-3、CD+56,可同时表达CD2、CD7、CD8、CD11b。3例患者有细胞遗传学异常,但未发现重现性染色体异常,TCR基因重排均为胚系构型。ANKL病程进展迅速,易发生多器官衰竭,中位生存时间9周。获得和未获得完全缓解（CR）患者生存时间分别为50周和3周。结论　ANKL为来源于成熟NK细胞的恶性肿瘤,具有独特的临床特征和免疫表型。病程呈侵袭性,对化疗不敏感,大部分患者短期内死亡。获得CR患者生存期明显延长,但难免复发,治愈率没有提高。     

Significance of chemokine receptor expression in aggressive NK cell leukemia.

Natural killer (NK) cell-type lymphoproliferative diseases of granular lymphocytes can be subdivided into aggressive NK cell leukemia (ANKL) and chronic NK cell lymphocytosis (CNKL). One reason for the poor outcome in ANKL is leukemic infiltration into multiple organs. The mechanisms of cell trafficking associated with the chemokine system have been investigated in NK cells. To clarify the mechanism of systemic migration of leukemic NK cells, we enrolled nine ANKL and six CNKL cases, and analyzed the expression profiles and functions of chemokine receptors by flowcytometry and chemotaxis assay. CXCR1 was detected on NK cells in all groups, and CCR5 was positive in all ANKL cells. Proliferating NK cells were simultaneously positive for CXCR1 and CCR5 in all ANKL patients examined, and NK cells with this phenotype did not expand in CNKL patients or healthy donors. ANKL cells showed enhanced chemotaxis toward the ligands of these receptors. These results indicated that the chemokine system might play an important role in the pathophysiology of ANKL and that chemokine receptor profiling might be a novel tool for discriminating ANKL cells from benign NK cells.     

Chemokine system and tissue infiltration in aggressive NK-cell leukemia

NK cell-type lymphoproliferative disease of granular lymphocytes can be subdivided into aggressive NK-cell leukemia (ANKL) and chronic NK-cell lymphocytosis (CNKL). Hepatosplenomegaly is observed in ANKL patients, and hepatic failure is a common cause of death. Significant numbers of ANKL cells were pathologically observed in sinusoidal and interlobular regions of the liver, and in the splenic red pulp. In our previous study, ANKL cells were simultaneously positive for CXCR1 and CCR5. So, in order to elucidate the mechanism in the systemic migration of ANKL cells, we investigated the expression of the corresponding chemokines in ANKL compared with CNKL. The serum level of IL-8, MIP-1alpha and MIP-1beta was significantly elevated in ANKL patients, and ANKL cells were highly positive for IL-8, RANTES, MIP-1alpha and MIP-1beta according to intracellular staining and RT-PCR. These chemokines were also positively stained in hepatocytes. The interaction between Fas and Fas ligand (FasL) is supposed to be one of the mechanisms for liver dysfunction in ANKL. The serum concentration of soluble FasL was significantly high in ANKL patients, and ANKL cells expressed FasL protein in the cytoplasm. These results suggest that the chemokine system plays an important role in the transmigration of FasL-expressing ANKL cells.     

流式细胞术在侵袭性NK细胞白血病诊断中的价值:一例报道并文献复习

 目的　分析侵袭性NK细胞白血病的临床特征及诊治方法,探讨流式细胞术（FCM）对其诊断的价值。方法　分析1例侵袭性NK细胞白血病患者的临床特征,并进行文献复习。结果　患者持续高热、肝脾进行性增大、血三系细胞减少,骨髓中可见不典型细胞,FCM检查示骨髓中NK细胞约占淋巴细胞的83.3 %,免疫表型为CD34-、CD2+、CD7+、CD3-、CyCD3+、CD5-、CD16+、CD56+、CD30-、CD4-、CD8-、CD117-、CD11c-、CD19-、CD45++、SSC+～++,TCR、IgH基因重排阴性,染色体正常,诊断为侵袭性NK细胞白血病。结论　侵袭性NK细胞白血病是一种少见的血液系统恶性疾病,临床表现多样、疾病进展迅速,早期容易误诊,FCM免疫分型结合骨髓细胞学涂片具有简便、快捷、可行、创伤性小的优势,在一些特殊情况下可作为首选检测手段。     

Characteristics and oncologic outcomes of patients with Ewing sarcoma of the scapula

Background and objectivesEwing sarcoma is the second most common bone sarcoma of childhood. Ewing sarcomas of the scapula are rare, with little known about their characteristics and outcomes. In this study, we describe the demographic characteristics, tumor characteristics, and oncologic outcomes of patients with Ewing sarcoma of the scapula.MethodsThis is a retrospective case series of thirty-four patients treated at three urban hospitals between 1993 and 2014 for Ewing sarcomas affecting the scapula. Their demographic data, tumor characteristics, and oncologic outcomes are reported and contrasted with data on Ewing sarcoma described in the literature.ResultsPatients in our case series were 59% male. The average age at diagnosis was 16 years. 44% of patients had metastatic disease at presentation. 26% of patients had a tumor size >8 cm in largest dimension at diagnosis. 9 patients in our series had the t (11; 22) translocation present. Patients had a survival rate of 68% at five years. No patients had local recurrence of disease. Compared with findings reported in the literature concerning Ewing sarcoma affecting other locations, patients with Ewing sarcoma of the scapula were slightly older at time of diagnosis, had a lower percentage of tumors with size > 8 cm in largest dimension at presentation, and more commonly had metastatic disease at presentation. Patients in our cohort had a 5-year survival rate of 68%, which is higher than the rate of approximately 55% as reported in the general literature.ConclusionsIn this study, we describe a retrospective case series of thirty-four patients with Ewing sarcomas of the scapula. This is the largest case series to date of Ewing sarcoma affecting this location to our knowledge. These results will contribute to the understanding of the clinical profile and oncologic behavior of Ewing sarcomas affecting the scapula.     

NK/T-Cell Lymphomas: Pathobiology, Prognosis and Treatment Paradigm

The current World Health Organization (WHO) classification includes two types of natural killer (NK)-cell lymphomas: extranodal NK/T-cell lymphoma, nasal type (ENKL), and aggressive NK-cell leukemia (ANKL). These diseases are mostly endemic to East Asia and Latin America. The Epstein-Barr virus (EBV) is usually detected in tumor cells, suggesting that EBV plays an important role in lymphomagenesis. At the site of origin, ENKL can be divided into two major subtypes: nasal and extranasal diseases. The advanced disease presentation, highly aggressive clinical course, and poor prognosis of the latter are analogous to ANKL. It is well known that P-glycoprotein, which is a product of the multi-drug resistance (MDR1) gene, is expressed on neoplastic cells of ENKL or ANKL. This is a major cause of the refractoriness of malignant lymphoma to conventional chemotherapeutic regimens containing anthracycline. Recent studies, however, have identified that L-asparaginase-containing regimens, such as SMILE (steroid, methotrexate, ifosfamide, L-asparaginase and etoposide), are effective for ENKL. Considering the myelotoxicity of SMILE, its use in the treatment of ANKL needs some modifications, but this treatment scheme is promising in improving the prognosis of NK-cell lymphomas.     

Retroviral expression screening of oncogenes in natural killer cell leukemia

Aggressive natural killer cell leukemia (ANKL) is an intractable malignancy that is characterized by the outgrowth of NK cells. To identify transforming genes in ANKL, we constructed a retroviral cDNA expression library from an ANKL cell line KHYG-1. Infection of 3T3 cells with recombinant retroviruses yielded 33 transformed foci. Nucleotide sequencing of the DNA inserts recovered from these foci revealed that 31 of them encoded KRAS2 with a glycine-to-alanine mutation at codon 12. Mutation-specific PCR analysis indicated that the KRAS mutation was present only in KHYG-1 cells, not in another ANKL cell line or in clinical specimens (n=8).     

侵袭性NK细胞白血病并发多器官衰竭一例并文献复习

 目的　提高对侵袭性NK细胞白血病（ANKL）及并发多器官功能衰竭（MOF）的认识。方法　报道1例罕见ANKL的诊断、治疗经过并结合文献复习讨论。结果　患者经骨髓、免疫表型等检查确诊ANKL,发病及治疗过程中并发MOF（肝、肾、心、肺等）、代谢性酸中毒、肿瘤溶解综合征、弥漫性血管内凝血（DIC）。予VP方案化疗和相应对症治疗曾一度好转,但很快死于呼吸、循环功能衰竭。结论　ANKL易发生髓外浸润,并发MOF,病情凶险,预后差。     

Central nervous system mesenchymal chondrosarcoma

Central nervous system mesenchymal chondrosarcomas are rare malignant tumors that constitute a separate entity from the classical chondrosarcoma and myxoid variant. Clinical behaviour of central nervous system chondrosarcomas is still unknown. We describe two rare examples of intracranial mesenchymal chondrosarcoma with a review of the literature, in an attempt to clarify the clinical characteristics, prognosis and treatment of choice of these unusual tumors. Among the 55 reported cases, 23 had postoperative radiotherapy. Although there is no statistical significance according to the Log-Rank test (p=0.7), the patients treated with radiation therapy seem to have a better chance of survival. Patients who had adjuvant chemotherapy (only 5) showed survival times similar to those patients who had none. Although clinical behaviour of central nervous system chondrosarcomas remains to be defined, data from our series as well as literature show that radical removal is the best therapeutic choice. In addition, patients treated with postoperative radiotherapy seem to show a trend toward increased survival.     

成年人疑似原发性噬血细胞综合征合并侵袭性自然杀伤细胞白血病一例并文献复习

目的:提高对成年人原发性噬血细胞综合征（HPS）合并侵袭性自然杀伤细胞白血病（ANKL）的认识。方法:回顾性分析南方医科大学南方医院惠桥医疗中心2017年10月收治的1例疑似原发性HPS合并ANKL成年病例的临床资料，并复习国内外相关文献。结果:患者，男性，21岁，持续发热，血细胞减少，脾大，纤维蛋白原低，铁蛋白显著升高，骨髓存在噬血细胞，自然杀伤（NK）细胞活性减低，可溶性CD25升高，流式细胞术检测NK细胞表达异常，存在家族性溶酶体转运调节因子（LYST）、UNC13D基因缺陷，疑似原发性HPS合并ANKL。给予4个疗程EPOCH+PEG-Asp（依托泊苷、地塞米松、长春地辛、环磷酰胺、多柔比星脂质体、培门冬酶）方案化疗，西达苯胺20 mg、2次/周维持治疗，无关全相合造血干细胞移植。随访35个月，疾病持续缓解。结论:成年人HPS即使存在继发性病因，仍有必要行相关基因筛查以避免误诊。HPS合并ANKL患者病情进展迅速，早期病死率高，确诊后宜尽早采用EPOCH+PEG-Asp方案诱导治疗及异基因造血干细胞移植。     

Aggressive natural killer cell leukemia: therapeutic potential of L-asparaginase and allogeneic hematopoietic stem cell transplantation

We conducted a retrospective Japan-Korea multicenter study to better elucidate the clinicopathologic features and therapeutic modalities for aggressive natural killer cell leukemia (ANKL). A total of 34 patients were analyzed. The median age of the patients was 40 years. Among the patients in the study, four had a history of Epstein-Barr virus-related disorders. Three types of ANKL cells were categorized according to their morphological features. Leukemic cells were below 20% in both peripheral blood and bone marrow of 11 patients. The clinical characteristics and prognoses of these 11 patients did not differ significantly from those of the others. As an initial therapy, l-asparaginase chemotherapy resulted in a better response. A total of six patients received allogeneic hematopoietic stem cell transplantation (HSCT) and two received autologous HSCT, with all in non-complete remission (CR). After HSCT, four with allogeneic and one with autologous HSCT reached CR. Median survival of all patients was 51 days. Median survival for the patients with and without HSCT were 266 and 36 days, respectively. A total of two patients with allogeneic HSCT were alive and in CR. All patients without HSCT died of ANKL. The use of L-asparaginase was indicated as a factor for longer survival (HR 0.33, 95% confidence interval; 0.13-0.83, P = 0.02). Early diagnosis of ANKL, l-asparaginase-based chemotherapy and allogeneic HSCT might lead to improved patient outcomes.     

Small cell carcinoma of the bladder. Report of five cases with immunohistochemistry and review of the literature with evaluation of prognosis according to stage

Five cases of small cell carcinoma (SCC) of the bladder are reported with pathologic and immunohistochemical findings and clinical follow-up. Sixteen additional cases reported in the literature are studied and staged according to depth of tumor infiltration of the bladder wall. In our series of five cases and those reviewed from the literature, survival appeared to be dependent on stage of the tumor, analogous to the more common transitional cell carcinoma (TCC). We report two of five patients with the longest recorded follow-up times in the literature who are alive with no evidence of disease at 4 and 6 years. Contrary to the belief that SCC of the bladder is an aggressive, rapidly disseminating tumor similar to SCC of the lung, our findings support the notion that this is a potentially curable neoplasm with a prognosis that appears to be dependent on stage and surgical resectability.     

Intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses. A clinicopathologic study of 6 cases

The clinical and pathologic features of 6 cases of intestinal-type adenocarcinoma of the sinonasal region are presented. These cases were collected in a 17 year period (1972-1988) and account for less than 4% of malignancies of this region in our records for this period. All of the patients were men aged 48 to 82 years (mean, 54 years). Previous exposure to wood dust was reported in 1 case. Radiographic studies, especially computerized tomography, were of critical importance to delineate the extent of tumors. Nasal obstruction was the most common complaint. Duration of symptoms prior to diagnosis is available in 5 cases and ranged from 5 to 36 months (mean 18 months). Surgical treatment was performed in 4 patients (of palliative type in 2) followed by radiotherapy in 3. Histopathology revealed tubulo-papillary (5 cases) and mucinous (1 case) patterns. Follow-up is available in all patients (range 0 to 108 months), 50% of whom are still alive. In our series, only 1 patient has survived more than 5 years. Data pooled from the literature reveal that 53% of patients have experienced local recurrences following therapy, and 60% have died of their disease. Of these deaths, 80% occurred within 5 years of diagnosis.     

A comparative analysis of clinicopathological features and survival among early adolescents/young adults and children with low-grade glioma: a report from the Children’s Oncology Group

Chordoid meningioma is a rare variant of meningioma, with a higher incidence in the young and a supposed association with Castleman’s syndrome. They have an aggressive clinical course, and are assigned as WHO grade II meningiomas. To the best of our knowledge, 284 chordoid meningiomas have been reported in the literature. This series reporting 33 cases is the third largest series in published literature from a single Institution. We reviewed Clinico-pathological characteristics of 33 patients diagnosed with chordoid meningioma between 2001 and 2015 in our institution. Forty-one specimens were available for review of histopathological and immunohistochemical characteristics. There were 15 men and 18 women with mean age of 36.8 years (median 36 years, range 9–62 years) at diagnosis with three cases occurring in pediatric age group. The majority were supratentorial in location with 11 convexity, 1 falcine, 5 parasagittal, 1 intraventricular, skull base involvement in 12 with 4 being petroclival location and 3 had spinal lesions. Lymphoplasmacytic infiltrates were seen in 23 cases with majority being T cells. MIB index varied from 1 to 14%. Five patients received radiotherapy for residual lesion. Two patients died (recurrence-1, post-operative complication-1). Three patients were lost to follow up after surgery. The mean post-operative follow up period for the remaining was 55.3 months. Seven patients had recurrence of which three had it twice. This study adds to the pool of available data for better understanding of this variant of meningioma. These meningiomas occur in middle age; spinal lesions and pediatric cases are not uncommon. We did not find any association between surgery, post-operative radiotherapy and histopathological features with recurrence and survival. Small number of cases may be responsible for this statistical insignificance.     

Metastatic tumors in the breast: a report of 5 cases and review of the literature

Breast cancer is the most common malignancy in women. However, metastases to the breast from nonmammary malignant neoplasms are rare and were detected at a rate of 0.28% in our series. Clinical and pathologic findings in 5 cases of metastatic tumors (malign mesenchymal tumor, squamous cell carcinoma of the tongue, non-Hodgkin lymphoma, and Sézary syndrome) in the breast are presented and discussed with respect to the literature. Detailed clinical history and a multidisciplinary approach are useful in establishing correct diagnosis and preventing unnecessary radical surgery.     

Multiple endocrine neoplasia type 1 syndrome: single centre experience from western India

Multiple endocrine neoplasia type 1 syndrome (MEN1) is a rare autosomal dominant familial cancer syndrome affecting multiple endocrine glands. Published literature on MEN1 from Indian subcontinent is scarce. We report here a case series of MEN1 patients (n = 18) from 14 unrelated families. Retrospective study describing the clinical profile of MEN1 patients from endocrine unit of a tertiary care hospital from western India. Additionally clinical profile of primary hyperparathyroidism (PHPT) in MEN1 patients was compared with that of apparently sporadic PHPT cohort from our centre. Eighteen patients (10 males, 8 females) diagnosed as MEN1 were included. Mean age at diagnosis was 31.5 ± 10.6 years (range 17–54). Incidence of primary hyperparathyroidism (PHPT), pituitary adenoma (PA), and gastro-entero-pancreatic neuroendocrine tumor (GEP-NET) was 94.4, 72.2, and 72.2 %, respectively. GEP-NET was the commonest presenting lesion (33.3 %), followed by PA (27.7 %), PHPT (16.6 %), thymic carcinoid (5.5 %), while 16.6 % cases were identified on family screening. PHPT manifestations (clinical and biochemical) in MEN1 were less severe as compared to those of sporadic PHPT. Contrast enhanced computed tomography (CECT) and ⁶⁸Ga-DOTANOC PET/CT were equally sensitive (64.7 vs. 63.5 %) in identifying multiglandular parathyroid disease. Non functioning tumors (NFT) were the most common GEP-NET, followed by insulinoma (5/13, two were metastatic). ⁶⁸Ga-DOTANOC PET/CT had higher sensitivity in detecting GEP-NET lesions than CECT (100 vs. 62.5 %). The most common pituitary lesion was prolactinoma, and all were cabergoline responsive. Genetic analysis was available in 13 patients and 11 patients showed mutation in MEN1 gene. The clinical profile of MEN1 in Asian Indian patients is largely comparable to that reported in other cohorts. Peculiar findings of our cohort are predominance of GEP-NET as a presenting manifestation and relatively higher prevalence of insulinoma with higher occurrence of metastatic insulinoma. Clinical and biochemical profile of MEN1 associated PHPT is less severe than that of our sporadic PHPT.     

Chemotherapy in alveolar soft part sarcomas. What do we know?

Alveolar soft part sarcoma (ASPS) is a rare tumour. Published series about treatment and outcome are scarce. Conclusive data about the response to chemotherapy are not available. The aim of this study was to analyse the efficacy of palliative chemotherapeutic treatment options and the incidence and mode of presentation of brain metastases. We retrospectively analysed our own sarcoma data-base and reviewed the literature. From our registry containing 757 patients, we identified 8 patients with ASPS. From the literature, 47 cases of adult patients and 13 children with sufficient data about chemotherapy were identified. Response to first-line chemotherapy in 68 patients was: complete remission (CR) 4%, partial remission (PR) 3%, stable disease (SD) 41%, progressive disease (PD) 51%. 285 patients with stage IV disease were evaluable for the analysis of metastatic sites. The incidence of brain metastases was 30.5% (87/285). Brain metastases were detected at a median interval of 48 months (range 0-396 months) after the primary diagnosis. Median survival after the diagnosis of brain metastases was 12 months. The median survival for patients with stage IV disease treated by chemotherapy was 36+ months (range 10-132 months) (31 patients evaluable) with a median follow-up of 46 months (range 10-135 months). ASPS shows a high incidence of brain metastases, at least 3 times higher than that of other soft tissue sarcomas. Chemotherapeutic regimens used for the treatment of other soft tissue sarcomas lack efficacy in ASPS. Staging investigations for ASPS should routinely include imaging of the brain. ASPS patients should not be treated with chemotherapy outside of controlled clinical trials. New targets for specific biologically-directed therapies need to be developed.     

Prognostic factors for mature natural killer (NK) cell neoplasms: aggressive NK cell leukemia and extranodal NK cell lymphoma,nasal type

Background: Patients with natural killer (NK) cell neoplasms, aggressive NK cell leukemia (ANKL) and extranodal NK cell lymphoma, nasal type (ENKL), have poor outcome. Both diseases show a spectrum and the boundary of them remains unclear. The purpose of this study is to draw a prognostic model of total NK cell neoplasms.Patients and methods: We retrospectively analyzed 172 patients (22 with ANKL and 150 with ENKL). The ENKLs consisted of 123 nasal and 27 extranasal (16 cutaneous, 9 hepatosplenic, 1 intestinal and 1 nodal) lymphomas.Results: Complete remission rate for ENKL was 73% in stage I, but 15% in stage IV, which was consistent with that for ANKL (18%). The prognosis of ENKL was better than that of ANKL (median survival 10 versus 1.9 months, P < 0.0001) but was comparable when restricted to stage IV cases (4.0 months, P = 0.16). Multivariate analysis showed that four factors (non-nasal type, stage, performance status and numbers of extranodal involvement) were significant prognostic factors. Using these four variables, an NK prognostic index was successfully constructed. Four-year overall survival of patients with zero, one, two and three or four adverse factors were 55%, 33%, 15% and 6%, respectively.Conclusion: The current prognostic model successfully stratified patients with NK cell neoplasms with different outcomes.