Low-dose steroid-induced tumor lysis syndrome in a hepatocellular carcinoma patient

Tumor lysis syndrome is rare in hepatocellular carcinoma (HCC), but it has been reported more frequently recently in response to treatments such as transcatheter arterial chemoembolization (TACE), radiofrequency thermal ablation (RFTA), and sorafenib. Tumor lysis syndrome induced by low-dose steroid appears to be very unusual in HCC. We report a patient with hepatitis-C-related liver cirrhosis and HCC in whom tumor lysis syndrome occurred due to low-dose steroid (10 mg of prednisolone). The patient was a 90-year-old male who presented at the emergency room of our hospital with general weakness and poor oral intake. He had started to take prednisolone to treat adrenal insufficiency 2 days previously. Laboratory results revealed hyperuricemia, hyperphosphatemia, and increased creatinine. These abnormalities fulfilled the criteria in the Cairo-Bishop definition of tumor lysis syndrome. Although the patient received adequate hydration, severe metabolic acidosis and acute kidney injury progressed unabated. He finally developed multiple organ failure, and died 3 days after admission. This was a case of tumor lysis syndrome caused by administration of low-dose steroid in a patient with HCC.     

Relationship between Tertiary Lymphoid Structure and the Prognosis and Clinicopathologic Characteristics in Solid Tumors

Background: An increasing number of studies had shown that tertiary lymphoid structure (TLS) plays an important role in tumor progression. However, the prognostic role of TLS in various tumors remains controversial. This meta-analysis aims to investigate the clinicopathological and prognostic values of TLS in solid tumors.Methods: A systematic search was conducted in PubMed, EMBASE and Cochrane Library undated to November 2, 2020. Odds ratios of clinical parameters, hazard ratio (HR) of overall survival (OS), relapse-free survival (RFS), disease-free survival (DFS) and relapse rate were calculated in order to evaluate the relationship between TLS expression and clinicopathological or prognostic values in different tumors.Result: 27 eligible studies including 6647 patients with different types of tumors were analyzed. High TLS expression was associated with a longer OS (HR = 0.66, 95% CI: 0.50 - 0.86, P = 0.002) and RFS (HR = 0.61, 95% CI: 0.47 - 0.79, P = 0.0001). Moreover, high TLS levels in tumor were associated with a low risk of recurrence (HR = 0.43, 95% CI: 0.32 - 0.57, P < 0.0001). However, there was no relationship between TLS expression and DFS. Meanwhile, high TLS expression was associated with smaller tumor size (P < 0.00001) and higher tumor infiltrating lymphocytes (TILs). Furthermore, the subgroup analysis showed high TLS expression that may be associated with a lower clinical grading and N stage in breast cancer and colorectal cancer.Conclusion: High TLS expression is associated with the longer OS and RFS in solid tumors, and a lower risk of cancer relapse. Meanwhile, high TLS expression is also associated with a smaller tumor size, higher infiltration of TILs, lower clinical grading and N stage in the tumor. Therefore, high TLS expression in the tumor is a favorable prognostic biomarker for solid tumor patients.     

Spurious elevation of automated platelet counts in secondary acute monocytic leukemia associated with tumor lysis syndrome.

The intent of this article is to describe the effect of tumor lysis on automated platelet counts in therapy-related, secondary acute monocytic leukemia. The first patient was a 69-year-old man with large cell carcinoma of the lung who developed acute monocytic leukemia 1(1/2) years after initiation of radiation and chemotherapy for his carcinoma. The second patient was a 72-year-old female with peripheral T-cell lymphoma who developed acute monocytic leukemia 1 year after initiation of chemotherapy for her lymphoma. Platelet counts were determined by the automated Coulter (STKS) counter. Both patients had clinical and laboratory evidences of tumor lysis syndrome and disseminated intravascular coagulation. The peripheral blood smears revealed numerous fragments of leukemic cells and apoptotic cells with pyknotic nuclei. The Coulter machine enumerated these cellular fragments as platelets, resulting in falsely elevated platelet counts. Awareness of this laboratory artifact in secondary acute monocytic leukemia with tumor lysis syndrome is important so that potential life-threatening thrombocytopenia is not overlooked.     

MEN1 gene mutations in sporadic neuroendocrine tumors of foregut derivation

Foregut-derived neuroendocrine (NE) tumors occur sporadically or in association with multiple endocrine neoplasia type 1 (MEN1) syndrome. Thirty-nine sporadic NE tumors of foregut derivation (six thymic, 21 bronchial, three gastric, and nine pancreatic tumors) as well as two hindgut-derived rectal carcinoids for somatic MEN1 gene mutation were analyzed by direct sequencing analysis. Five tumors showed mutations: nonsense mutations (Q393X and R98X) in thymic and pancreatic NE tumors, respectively, a 4 b.p. deletion (357del4) in a gastric NE carcinoma, and missense mutations (D172Y and S178Y) in pancreatic NE tumors. No mutation was identified in pulmonary or rectal NE tumors. In a patient with a pancreatic NE tumor (D172Y), the corresponding germline DNA showed the same mutation, suggesting that sporadic MEN1 syndrome was masked in this case. Somatic MEN1 gene mutations and deletions may play a crucial role in the tumorigenesis of a subset of foregut-derived NE tumors. Sporadic MEN1 syndrome may occur as a sporadic NE tumor of the pancreas.     

Germline PTPN11 missense mutation in a case of Noonan syndrome associated with mediastinal and retroperitoneal neuroblastic tumors

Noonan syndrome (NS) is an autosomal dominant disorder characterized by short stature, typical craniofacial dysmorphism, skeletal anomalies, congenital heart defects, and predisposition to malignant tumors. In approximately 50% of cases, the disease is caused by missense mutations in the PTPN11 gene. To date, solid tumors, and particularly brain tumors and rhabdomyosarcomas, have been documented in patients with NS; however, few cases of neuroblastoma associated with NS have been reported. Here we report an unusual case of neuroblastoma with mediastinal, retroperitoneal, and medullar locations associated in a NS patient carrying a PTPN11 germline missense mutation (p.G60A). This missense mutation occurs within the N-SH2 domain of the PTPN11 gene and has been reported to be associated with acute leukemia in NS patients. The association of this p.G60A PTPN11 mutation with neuroblastoma provides new evidence that gain of function PTPN11 mutations may play an important role in the pathogenesis of solid tumors associated with Noonan syndrome.     

Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout

Hyperuricemia is a feature of several pathologies and requires an appropriate and often early treatment, owing to the severe consequences that it may cause. A rapid and massive raise of uric acid, during tumor lysis syndrome (TLS), and also a lower and chronic hyperuricemia, as in gout, mainly damage the kidney. To prevent or treat these consequences, a new therapeutic option is represented by rasburicase, a recombinant form of an enzyme, urate oxidase. This enzyme converts hypoxanthine and xanthine into allantoin, a more soluble molecule, easily cleared by kidney. The several types of urate oxidase have followed each other, with progressive reduction of adverse reactions. The most important among them are allergenicity and the development of antibodies which compromise their effectiveness. Nevertheless, a limit of rasburicase's use remains its cost, which obliges to a judicious choice to prevent TLS in high risk patients with cancer and in case of allergy or impossibility to take allopurinol orally both in TLS and in gout. A large body of evidence confirms the efficacy and safety of rasburicase, even in comparison to the standard drugs used in the aforementioned pathologies.     

Elevated catecholamine metabolites in patients with Costello syndrome

Costello syndrome is a rare congenital anomaly syndrome with a predisposition to specific tumors, including neuroblastoma, rhabdomyosarcoma, and transitional cell carcinoma of the bladder. The increased risk for solid tumors led to the proposal of a tumor screening protocol. A screening test for neuroblastoma consists of measuring catecholamine metabolites in urine, an assay that may also be used for diagnostic confirmation of a suspected catecholamine secreting tumor. We report eight patients with Costello syndrome with elevated catecholamine metabolites, vanillylmandelic acid (VMA) and/or homovanillic acid (HVA), in urine. Each patient had additional laboratory and/or imaging studies. None of the patients was found to have a neuroblastoma or another catecholamine secreting tumor. In two cases, the assays were performed because the patients were symptomatic with diaphoresis and hypertension, respectively, and in the other six cases the assays were performed in order to screen for neuroblastoma. The pathophysiology for the catecholamine metabolite abnormality in these patients with Costello syndrome remains unclear. However, it appears that in this patient group an elevation above the normal limit, defined as 2 standard deviations (SD) above the mean for age, is more likely to be a variant, rather than a sign of a neuroblastoma. Thus, it may be prudent not to use this assay as a screening test, and to take the frequently elevated results into consideration when interpreting diagnostic assays.     

Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways

A specific subset of solid childhood tumors-Wilms' tumor, adrenocortical carcinoma, rhabdomyosarcoma, and hepatoblastoma-is characterized by its association with Beckwith-Wiedemann syndrome. Genetic abnormalities found in these tumors affect the same chromosome region (11p15), which has been implicated in the etiology of Beckwith-Wiedemann syndrome. This suggests that the development of these tumors occurs along a common genetic pathway involving chromosome 11. To search for additional common genetic pathways, this article reviews the genetic data published for these tumors. It was found that, up until now, the only genetic abnormalities detected in all four tumors affect chromosome band 11p15 and the TP53 gene. In addition, there are several aberrations that occur in two or three of the neoplasms. It is concluded that, of the four tumors, the genetic relationship is most evident between Wilms' tumor and rhabdomyosarcoma.     

Large mixed germ cell tumor in a young patient presenting as an intrapulmonary mass

We present the case of a 26-year-old man with a bland medical history, who presented to the general practitioner because of severe cough and dyspnea. The chest X-ray revealed a massive organ-displacing tumor in the right chest not delineable from the mediastinum. The subsequent needle core biopsy was diagnostic for a mixed germ cell tumor comprising immature teratoma and seminoma. After an initially good response to chemotherapy, tumor markers and tumor size were progressive. The right-sided pneumonectomy revealed an intrapulmonary tumor with cystic and solid components, hemorrhage, and necrosis with a tumor diameter of 18 cm. Histology confirmed a teratoma with mature and immature components accompanied by residual seminomatous tumor cells. Despite maximal intensive care, the patient died four weeks after surgery from acute respiratory distress syndrome. We describe this exceptional large intrapulmonary germ cell tumor and discuss the spectrum of such rare tumors.     

Activation of B cells in Tertiary Lymphoid Structures in cancer: Anti-tumor or anti-self?

Whereas T cells in the tumor microenvironment have been the main focus as cancer controlling cells and targets of immunotherapies, B cells have recently gained strong attention. Being associated to Tertiary Lymphoid Structures (TLS) located at the vicinity of tumor nests, the fate of B cell depends on TLS maturity. In immature TLS they may evolve as regulatory B cells producing immunosuppressive cytokines and promote tumor growth. In mature TLS with a germinal center, B cells are selected, amplified, undergo affinity maturation and isotypic switching, resulting in plasma cell generation and production of anti-tumor antibodies. In that case, they are associated with longer patient’s survival and therapeutic response to immunotherapy. Identification of tumor specific, or tumor overexpressed, antigens recognized by “in situ” produced antibodies and their discrimination from self-antigens induced by ICI treatments is a major challenge to develop novel antibody-based immunotherapies.     

Heparanase: a key enzyme in invasion and metastasis of gastric carcinoma.

Previous reports have shown that the biochemical activity of heparanase is significantly correlated with the invasion and metastasis of malignant cells in vitro. Recently, it was found that the human heparanase gene was cloned and highly expressed in malignant cell lines and human solid malignant tumors. In the present study, we investigated the heparanase mRNA expression by using in situ hybridization in 116 paraffin-embedded tissues of primary gastric carcinomas. To explore its clinicopathologic significance, it was detected in the various steps of tumor progression and then compared with prognostic indicators. As a result, the heparanase expression was more prevalent in late-stage rather than early-stage carcinomas (P <.0001) and was more frequent in tumors of large size (P =.0212). Expression also correlated with lymphatic (P =.0086) and venous (P =.0171) invasion and with negative prognostic factors such as lymph nodal (P <.0001) and distant (P =.0221) metastases. However, in a multivariate analysis, messenger RNA expression of heparanase was not an independent prognostic factor. It was concluded that heparanase might play an important role in the development of invasion and metastasis of the gastric cancer. It was indicated that patients with heparanase-positive gastric carcinoma would have a greater chance of metastasis with a poor prognosis.     

Malignant gastric neuroendocrinomas: Ultrastructural and biochemical characterization of their secretory activity

In two cases of malignant gastric tumors originally diagnosed as undifferentiated carcinomas electron microscopy revealed a neurosecretory type of granule. Subsequently tumor extracts were tested by biochemical methods and shown to have vanillylmandelic acid and 5-hydroxy-3-indoleacetic acid activity. Neither patient had signs or symptoms referable to the presence of these or related substances.These observations parallel those made in a variety of neuroendocrine tumors in which demonstration of neurosecretory granules or isolation of amine or peptide materials or their metabolites has not necessarily been reflected in clinical hormonal syndromes. Our findings indicate that regardless of clinically apparent hormonal activity or lack thereof, some undifferentiated gastric carcinomas may in fact derive from neuroendocrine APUD elements.     

胃肠道血管球瘤15例临床病理学分析

目的探讨胃肠道血管球瘤(GIGT)的组织病理学特征、诊断及鉴别诊断。方法收集郑州大学第一附属医院2011年1月至2018年6月诊断的15例GIGT,分析其临床病理特征、免疫表型、BRAF基因突变及预后,并复习相关文献。结果15例GIGT,男性7例,女性8例。14例发生于胃,1例发生于回肠。患者年龄37~59岁,中位年龄49岁,平均50岁。11例胃血管球瘤以间断腹痛、腹胀入院,另3例于体检时发现胃窦部占位入院;1例回肠血管球瘤以腹痛伴大便带血入院。影像学检查,胃血管球瘤位于黏膜下,边界清楚,动脉期强化明显;肠血管球瘤累及局部肠壁全层并堵塞管腔。大体检查:瘤体最大径1.5~3.0 cm不等,平均2.3 cm,切面实性。显微镜下观察:胃血管球瘤位于固有肌层间,富血管,与周围分界清楚,但均无明显包膜形成;瘤细胞大小一致,呈圆形或卵圆形,围绕血管周围呈血管外皮瘤样或实性巢团状排列;细胞形态温和,核圆形居中,染色质细腻,核仁不明显,核分裂象难见,无坏死,其中2例局部见小灶状钙化;2例见肿瘤侵入黏膜层;2例见脉管瘤栓;5例见神经侵犯。肠血管球瘤累及肠壁全层,细胞密度高,异型性明显,核分裂象热点区约(5~6)个/HPF。免疫组织化学显示,瘤细胞弥漫强表达平滑肌肌动蛋白(SMA)和Ⅳ型胶原,部分区域中等强度表达Caldesmon或Calponin,有12例局部弱表达突触素。胃血管球瘤的Ki-67阳性指数1%~30%不等,均值约6%。肠血管球瘤的Ki-67阳性指数约70%。15例GIGT均未检测到BRAF基因V600E位点突变。所有患者手术治疗后均未行放化疗。电话随访到13例患者,随访时间18~90个月,平均42个月,12例胃血管球瘤患者均健存,肠血管球瘤患者术后15个月出现肝转移。结论血管球瘤是胃肠道少见的间叶源性肿瘤,应与胃肠道间质瘤、神经内分泌肿瘤、平滑肌瘤、孤立性纤维性肿瘤及副节瘤等鉴别。多数GIGT生物学行为良善,预后良好,但尚需长期临床随访。     

Wilms tumor in a patient with 22q11.2 microdeletion

22q11.2 deletion syndrome is the most common microdeletion syndrome. Wilms tumor is one of the most common solid tumors in childhood yet 22q11.2 deletion and Wilms tumor only once have been reported in the same patient. Here we describe a young patient with subtle clinical findings suggestive of 22q11.2 at the time of diagnosis who subsequently developed Wilms tumor. We assert the importance of a low threshold for screening for 22q11.2 deletion and the associated phenotypes and maintaining vigilance in screening for common primary malignancies in patients with known 22q11.2 deletion.     

Primärer renaler Karzinoidtumor mit ausgedehnter lymphogener und hämatogener Metastasierung

Primary renal carcinoid tumors originating in normal kidney are extremely rare. We report a case of primary renal carcinoid tumor with an aggressive clinical course and multiple metastases in the paraaortal lymph nodes and the liver as well as a pulmonary metastasis, in a 30-year-old patient. A CT scan of the abdomen revealed a large mass in the right kidney and multiple tumor suspect areas in the liver and paraaortal lymph nodes. The patient did not have clinical manifestations of carcinoid syndrome. Histologically, the tumor was composed of trabecular, solid or anastomosing ribbon-like nests, identical to the features of neuroendocrine tumors from other locations. Immunohistochemical staining was positive for cytokeratin, neurospecific enolase, and chromogranin. Electron microscopically, tonofibrils, primitive desmosomes, and dense-core granules with a neuroendocrine appearance were present. The pathological features of this case are briefly reviewed in comparison with those of previously reportet in terms of certain clinical aspects, prognostic factors and the WHO-classification (2004) of this rare neoplasia.     

Pigmented adrenocortical carcinoma: Case report and review

Darkly pigmented adrenocortical neoplasms are rare tumors that are often referred to as “black adenomas,” indicative of both their pigmented nature and their invariably benign clinical behavior in previously reported cases. We herein describe an exceptional case of a malignant pigmented adrenocortical neoplasm, with late recurrence and metastasis. At age 53, this female patient was diagnosed with Cushing's syndrome and underwent a laparoscopic right adrenalectomy, revealing a 3 cm well-circumscribed, darkly pigmented adrenocortical tumor. The tumor exhibited several atypical histologic features and was diagnosed as an atypical pigmented adrenal cortical neoplasm of uncertain malignant potential. Eight years later, the patient developed clinical and biochemical evidence of recurrent Cushing's syndrome, and imaging studies revealed the presence of several masses in the right retroperitoneum. At subsequent exploratory laparotomy, three separate tumor nodules exhibiting varying degrees of pigmentation and ranging from 2.2 to 3.3 cm maximum dimension were excised. Histologically, the tumor nodules were consistent with local recurrence/metastasis of the patient's previously excised pigmented adrenocortical neoplasm.     

Characteristics of plasma DNA and its application for detection of K-ras gene mutation

DNA diagnosis is useful and significant for clinical oncology, but its use is limited due to a difficulty in preparing tumor-derived DNA materials. To overcome this problem, we investigated the characterization of plasma DNA and it application to successfully detecting K-ras mutation at codon 12 in normal persons, hematopoietic neoplasms, and solid tumors. The range of plasma DNA in each group was 15.8 +/- 5.2 ng/ml, 43.3 +/- 29.8 ng/ml, and 26.8 +/- 17.0 ng/ml, respectively. The ranges in patients with solid tumor were gradually decreased to the normal level of around 15 ng/ml in 3 weeks postoperatively. Plasma DNAs consisted of about 200 bp DNA fragmentation and were convenient for PCR amplification of K-ras gene. The mutation at codon 12 by PCR-RFLP analysis was detected in 13(27%) of 49 patients with solid tumors such as pancreatic cancer, breast cancer, colon cancer, and gastric cancer. The diagnostic specificity was 100%. Serial observations by the PCR-RFLP analysis revealed disappearance of the mutant K-ras about 7 days after successful curative surgery in a patient with gastric cancer.     

Hereditary aspects of gastric cancer

Although the etiology of gastric cancer and the mechanisms involved in its carcinogenesis are still poorly understood, dietary habits and life style as well as bacterial infections have been suggested to be important in the tumorigenic process. However, there is also an increasing evidence that a genetic predisposition in at least a subset of patients, plays an important role. Germline mutations in the E-cadherin gene have been described to be the molecular genetic cause of an hereditary diffuse type gastric cancer syndrome. In addition, gastric cancer is observed more frequently in association with some hereditary tumor syndromes which are mainly characterized by tumors in other organs. This article will summarize recent findings about the hereditary diffuse type gastric cancer syndrome and about gastric cancer in association with hereditary tumor syndromes with a known molecular genetic basis.