High Mitotic Activity Research Articles

Decreased expression of gastric gland mucin-specific glycan α1,4-linked N-acetylglucosamine on its scaffold mucin 6 is associated with malignant potential of pyloric gland adenoma of the stomach.

Pyloric gland adenoma (PGA) is a unique gastric neoplasm expressing mucin 6 (MUC6), and is often associated with high-grade dysplasia and/or adenocarcinoma. MUC6 secreted from the gastric gland mucous cells, such as pyloric gland cells, carries unique O-glycans with terminal α1,4-linked N-acetylglucosamine (αGlcNAc) residues on its molecule. As we recently demonstrated that αGlcNAc serves as a tumour suppressor for gastric adenocarcinoma, this study aimed to investigate the significance of αGlcNAc expression in PGA. Eighteen patients with PGA were examined with immunohistochemistry for αGlcNAc and MUC6. αGlcNAc and MUC6 were coexpressed in 12 of 18 PGAs. However, reduced αGlcNAc expression relative to MUC6 expression was observed in six cases. When the MIB-1 labelling index (LI) of tumour cells was examined with respect to reduced αGlcNAc expression, the MIB-1 LI was significantly higher in PGAs showing decreased αGlcNAc expression relative to MUC6 expression than in PGAs with unchanged αGlcNAc expression (P = 0.023). The present study indicates that coexpression of αGlcNAc and MUC6 in PGA suggests the presence of fully glycosylated MUC6 on tumour cells, consistent with pyloric gland differentiation. However, the decreased glycosylation of αGlcNAc on MUC6 is associated with high mitotic activity of tumour cells, indicative of malignant potential of PGA.

WHO Grade IV Gliofibroma: A Grading Label Denoting Malignancy for an Otherwise Commonly Misinterpreted Neoplasm.

We report a 50-year-old woman with no relevant clinical history who presented with headache and loss of memory. Magnetic resonance imaging showed a left parieto-temporal mass with annular enhancement after contrast media administration, rendering a radiological diagnosis of high-grade astrocytic neoplasm. Tumour sampling was performed but the patient ultimately died as a result of disease. Microscopically, the lesion had areas of glioblastoma mixed with a benign mesenchymal constituent; the former showed hypercellularity, endothelial proliferation, high mitotic activity and necrosis, while the latter showed fascicles of long spindle cells surrounded by collagen and reticulin fibers. With approximately 40 previously reported cases, gliofibroma is a rare neoplasm defined as either glio-desmoplastic or glial/benign mesenchymal. As shown in our case, its prognosis is apparently determined by the degree of anaplasia of the glial component.

Primary small cell neuroendocrine carcinoma of the oral cavity: A case report and review of the literature.

Small cell neuroendocrine carcinoma (SNEC) of the oral cavity is a rare and distinctive tumor with aggressive clinical behavior. Thus far, only a small number of cases have been reported and no definitive standard treatment strategy has been determined. The current study reports a case of oral SNEC arising in the lower gingiva in a 73-year-old male. Computed tomography displayed a relatively well-defined mass measuring 2.8×2×1.4 cm in size. The mass was located in the buccal side of the right mandibular posterior gingiva and exhibited no bony involvement. Histopathological examination revealed a proliferation of small cells with ovoid- to spindle-shaped nuclei, fine granular chromatin, inconspicuous nucleoli, scant cytoplasm and high mitotic activity. Immunohistochemically, the tumor cells were positive for cytokeratin AE1/AE3, chromogranin A, synaptophysin and neuron-specific enolase. Surgical resection and radical neck dissection were performed prior to the administration of adjuvant chemotherapy with a combination of cisplatin and etoposide. No evidence of local recurrence or metastasis was observed at 14 months post-surgery.

A case of unusual histology of infantile lipoblastoma confirmed by PLAG1 rearrangement.

Lipoblastoma, a relatively rare benign adipose neoplasm, predominantly affects children younger than 3 years of age. We herein report the case of a 7-month-old girl with an unusual myxomatous histology of lipoblastoma. A rapidly growing mass was detected in the subcutaneous area of the left buttock. Histologically, the tumor consisted of abundant myxoid stroma exhibiting cellular atypia and a high mitotic activity. Although the histological findings were unusual, the tumor was diagnosed as a lipoblastoma according to both PLAG1 immunohistochemistry and the presence of PLAG1 rearrangement on fluorescence in situ hybridization.

Üst gastrointestinal sistem stromal tümörlerinin endosonografik ve histopatolojik özelliklerinin karşılaştırılması: Tek merkez deneyimi

Background and Aims: Gastrointestinal stromal tumors are mesenchymal tumors mostly prevalent at middle ages. Since endoscopy is insufficient for evaluation of gastrointestinal stromal tumors, endoscopic ultrasound is preferred and mostly used imaging technique. Gastrointestinal stromal tumor lesions with high mitotic activity and large tumor size are usually considered to have a malign potential. We aimed to investigate the correlation between the endoscopic ultrasound findings and histopathologic characteristics of gastrointestinal stromal tumors. Materials and methods: Twenty five patients who underwent endoscopic ultrasound fort he suspicion of gastrointestinal stromal tumor and have the definitive diagnosis of gastrointestinal stromal tumor histopathologically were included to the study (13M, 12F, mean age 52.1±16.3). Results: All gastrointestinal stromal tumors were located in the stomach; five of them in the fundus, 17 in the corpus and 3 in the antrum. There were ulcerations on 10 (%40) gastrointestinal stromal tumor lesions. Mean diameter of the gastrointestinal stromal tumors measured during endoscopic ultrasound evaluation (51.59±20.37mm) was highly correlated with the real tumor size (54.30±24.86 mm, r: 0.817, p

A rare case of cutaneous leiomyosarcoma in budgerigar (Melopsittacus undulatus).

Leiomyosarcoma in birds is relatively rare. This tumor as a muscle neoplasm was reported in captive and free ranging birds. Smooth muscle cells may develop to the leiomyosracoma, but splenic smooth muscle trabeculae is most common site of the tumor growth. Although budgerigars have an incidence of neoplastic diseases but smooth muscle tumors were rarely reported in this species. To the best of our knowledge, present case is the first report of cutaneous leiomyosarcoma in budgerigar. The bird was referred with a history of growing mass in subcutaneous tissue of abdomen. First bird was suspected to the egg impaction, but necropsy confirmed a firm, creamy structure that suspected to the tumor mass. No invasion was observed to the other organs. After excision of the mass, routine histopathologic evaluation and immunohisochemistry investogation were performed for desmin and smooth muscle actin (SMA). Histopathologic examination revealed spindle-shaped cell with cigar-shaped, round, or oval nuclei with cytologic criteria of malignancy including marked pleomorphism and high mitotic activity. These findings were consistent with immunohistochemistry profile of our case and thus confirmed as cutanous liomyosarcoma.

Carbonic Anhydrase Expression in TNBC Breast Cancer Cells and Human Tumor Grafts

Carbonic anhydrase IX (CAIX) has emerged as a potential target for triple negative breast cancer (TNBC). Our goal is to utilize the tumor graft model to demonstrate the efficacy of carbonic anhydrase (CA) inhibitors in reducing tumor load and metastasis. Here, we compare the expression of CAIX in TNBC human breast cancer cell lines with a bank of tumor tissues generated from subject‐derived breast tumor grafts in mice that retain characteristics of the original patient samples (Dr. Alana Welm). In our sampling of TNBC cell lines, CAIX expression was observed in four of the five lines. Two showed exclusive expression of CAIX relative to other cell surface CA family members, allowing us to evaluate catalytic activity. We observed that CAIX activity, measured by 18O exchange between H216O and H13C18O3−, was related to the level of CAIX expressed and inhibited by an impermeant sulfonamide (N‐3500). We then analyzed CAIX expression in tumor‐grafted tissue. Thirteen samples were available and represented the three major breast cancer phenotypes: estrogen and progesterone receptor‐positive (ER/PR), HER2‐positive, and TNBC. Of the six TNBC tissues, four expressed CAIX. No carbonic anhydrase XII (CAXII) was observed. Cryogenically preserved TNBC tissue was used to develop orthotopic tumors in nude mice. Immunohistochemistry showed high mitotic activity with CAIX expression adjacent to necrotic tissue. The tissue was negative for ER/PR and CAXII. These observations demonstrate that the tumor graft model will be useful in evaluating the efficacy of CA inhibitors for potential clinical use. We gratefully acknowledge funding from NIH (GM25253‐DNS and CA165284‐SCF), the UF Cancer Center (SCF), and the CSCRB, Inc (SCF).

Adult white New Zealand rabbit as suitable model for corneal endothelial engineering.

BackgroundCorneal endothelium engineering is focused in producing transplantable cell sheets to overcome the shortage of corneal graft tissue donors for the treatment of corneal blindness. For this purpose, the use of a proper animal model plays a key role. Corneal parameters of White New Zealand rabbits such as endothelial cell density, central corneal thickness, and corneal diameter decrease with age, similarly as in humans. However, as opposed to humans, they retain the ability to restore their corneal endothelium after injury. Therefore, they are considered as an inappropriate corneal endothelial wound healing model.FindingsHere we analyze the corneal endothelium mitotic ability of White New Zealand rabbits aged 3, 6, 12 and 18 months, 36 and 72 hours after thermal injury. The highest mitotic activity was observed in the 3-month rabbits 36 h after wounding. Rabbits of 12 months registered decreased mitotic activity and those of 18 months did not show mitotic activity 72 h after injury.ConclusionsThese results propose that rabbits of 18 months represent a suitable model for human corneal endothelium engineering research.

Inflammatory Myofibroblastic Tumor of the Uterus

Inflammatory myofibroblastic tumor is currently regarded as a neoplasm with intermediate biological potential and a wide anatomic distribution. Inflammatory myofibroblastic tumors of the female genital tract are rare, and to date reported cases behaved indolently. We describe, herein, 10 cases of uterine inflammatory myofibroblastic tumor, 3 of which had an aggressive clinical course. Subject age ranged from 29 to 73 years. Tumors were composed of spindle and epithelioid myofibroblastic cells admixed with lymphoplasmacytic infiltrates in a variably myxoid stroma. Two growth patterns, myxoid and fascicular (leiomyoma-like), were noted. All tumors were positive for ALK expression by immunohistochemistry, which was stronger in the myxoid areas. Smooth muscle marker and CD10 expression was variable in extent, but typically positive. Fluorescence in situ hybridization for ALK rearrangements was positive in both fascicular and myxoid areas in all 8 cases tested. Three subjects showed clinical evidence of tumor aggressiveness as defined by extrauterine spread, local recurrence, or distant metastasis. Aggressive tumors were larger, had a higher proportion of myxoid stroma, and higher mitotic activity than indolent tumors. Tumor cell necrosis was seen only in cases with adverse outcome. This is the first report to describe aggressive biological behavior in uterine inflammatory myofibroblastic tumor. This diagnosis is often underappreciated and merits inclusion in the differential diagnosis of myxoid mesenchymal lesions of the uterus, particularly because patients with an aggressive course may benefit from targeted therapy.

Evaluation of biologic potential and risk stratification for predicting disease-free survival after resection of primary gastrointestinal stromal tumor: A multivariate clinicopathological study.

Gastrointestinal stromal tumor (GIST) is mesenchymal neoplasms of the gastrointestinal tract, which express CD117, a c-kit proto-oncogene protein and show gain of function mutation of c-kit gene. Apart from the presence of metastasis, the criteria to differentiate benign and malignant GISTs are not well-defined. Although a variety of prognostic factors have been investigated, no method has yet proven sufficient to enable reliable determination of malignancy in all cases. This study was planned to risk stratify the GIST cases with respect to the various clinicopathological features and to identify prognostic factors in GIST. n histological and immunohistochemical analysis, 121 cases of GIST were identified. MIB-1 (Ki-67) labeling index (LI) was performed in 60 cases. Follow-up data was available for 93 patients. A P < 0.05 was taken as significant. Larger tumor size, high mitotic activity and Ki-67 LI of >10% were identified as significant predictors of disease-free survival in univariate analysis (P < 0.0001). Other factors of statistically significant value were a high cellularity (P < 0.0027), nuclear pleomorphism (P = 0.0002), epithelioid cell type (P = 0.0098), presence of tumor necrosis (P < 0.01), presence of skeinoid fibers (P = 0.042), S-100 negativity (P = 0.025). Extra-gastrointestinal GIST and metastasis were more frequently associated with progressive disease (PD) as compared with GIST (P < 0.0004), (P < 0.0001). On multivariate analysis size (P = 0.0025), Ki-67 labeling index (P = 0.0186) and mitotic count (P = 0.0375) emerged as independent prognostic predictors of PD. This study suggests that GIST in Asian population may have a different phenotype with some predilection to nodal metastasis. Of all the features studied, tumor size and mitotic index are the best prognosticators in GIST with the addition of Ki-67 LI, wherever available.

Uveal melanoma: estimating prognosis.

Uveal melanoma is the most common primary malignant tumor of the eye in adults, predominantly found in Caucasians. Local tumor control of uveal melanoma is excellent, yet this malignancy is associated with relatively high mortality secondary to metastasis. Various clinical, histopathological, cytogenetic features and gene expression features help in estimating the prognosis of uveal melanoma. The clinical features associated with poor prognosis in patients with uveal melanoma include older age at presentation, male gender, larger tumor basal diameter and thickness, ciliary body location, diffuse tumor configuration, association with ocular/oculodermal melanocytosis, extraocular tumor extension, and advanced tumor staging by American Joint Committee on Cancer classification. Histopathological features suggestive of poor prognosis include epithelioid cell type, high mitotic activity, higher values of mean diameter of ten largest nucleoli, higher microvascular density, extravascular matrix patterns, tumor-infiltrating lymphocytes, tumor-infiltrating macrophages, higher expression of insulin-like growth factor-1 receptor, and higher expression of human leukocyte antigen Class I and II. Monosomy 3, 1p loss, 6q loss, and 8q and those classified as Class II by gene expression are predictive of poor prognosis of uveal melanoma. In this review, we discuss the prognostic factors of uveal melanoma. A database search was performed on PubMed, using the terms “uvea,” “iris,” “ciliary body,” “choroid,” “melanoma,” “uveal melanoma” and “prognosis,” “metastasis,” “genetic testing,” “gene expression profiling.” Relevant English language articles were extracted, reviewed, and referenced appropriately.

Immunohistochemical Analysis of p16 Expression in Uterine Smooth Muscle Tumors

Objective: Immunohistochemistry with p16 antibody is used as a diagnostic marker in several gynecologic pathologies. The purpose of the present study was to evaluate the diagnostic and prognostic significance of p16 immunohistochemistry in various uterine smooth muscle tumors. Methods: Tissue specimens, including 29 leiomyomas, 13 smooth muscle tumors of uncertain malignant potential (STUMP), and 17 leiomyosarcomas, were obtained from 59 patients with uterine smooth muscle tumors. The prevalence of p16 expression in various uterine smooth muscle tumors was examined using immunohistochemistry methods and we investigated the association between p16 expression and various clinicopathologic parameters, including prognosis of leiomyosarcomas. Results: The prevalence of p16 expression of leiomyomas, STUMP, and leiomyosarcomas tumors was 10.3%, 38.4%, and 76.4%, respectively. The prevalence and immunohistochemistry scores of p16 were significantly higher in the leiomyosarcomas group than in the leiomyomas or STUMP tumor groups. In the leiomyosarcomas groups, p16 immunohistochemistry scores were significantly higher in the groups with more advanced stage, higher mitotic activity, and recurrence. The relationship among p16 immunohistochemistry scores and age, tumor size, extent of necrosis, and degree of myometrial invasion was not significant. High expression of p16 in leiomyosarcomas was linked to shorter disease-free and overall survival. Conclusions: The use of p16 immunohisitochemistry is a useful marker in differential diagnosis in various uterine smooth muscle tumors. Moreover, p16 overexpression possibly plays an important role in tumor progression and we demonstrate that p16 may be a predictor of overall survival in patients with leiomyosarcoma tumors.

Guaiazulene biochemical activity and cytotoxic and genotoxic effects on rat neuron and N2a neuroblastom cells.

Aim:Neuroblastoma (NB)cells are often used in cancer researches such as glioblastoma cells since they have the potential of high mitotic activity, nuclear pleomorphism, and tumor necrosis. Guaiazulene (GYZ 1,4-dimethyl-7-isopropylazulene)is present in several essential oils of medicinal and aromatic plants. Many studies have reported the cytotoxic effect of GYZ; however, there are no studies that compare such effects between cancer cell lines and normal human cells after treatment with GYZ.Materials and Methods:In this study, we aimed to describe in vitro antiproliferative and/or cytotoxic properties (by 3-[4,5 dimetylthiazol -2-yl]-2,5 diphenlytetrazolium bromide [MTT] test), oxidative effects (by total antioxidant capacity [TAC] and total oxidative stress [TOS] analysis)and genotoxic damage potentials (by single cell gel electrophoresis)of GYZ.Result:The results indicated that GYZ have anti-proliferative activity suppressing the proliferation of neuron and N2a-NB cells at high doses. In addition, GYZ treatments at higher doses led to decreases of TAC levels and increases of TOS levels in neuron and N2a-NB cells. On the other hand, the mean values of the total scores of cells showing DNA damage were not found different from the control values.Conclusion:From this study, it is observed that GYZ has in vitro cytotoxic activity against neuron and N2a-NB cells.

Pathomorphology of colonic mucosa in patients with chronic post-parasitic colitis

Aim. To identify pathologic features of the colonic mucosa in patients with chronic post-parasitic colitis. Methods. Under the observation were 80 patients aged 38-42 years (38 men and 42 women) 1.5-2 years after undergoing parasitic diseases (amebiasis, giardiasis, diphyllobothriasis). In 19 patients due to the presence of dyspeptic phenomena colon mucosa was evaluated by morphometric parameters using grid of Avtandilov. The control group consisted of 6 patients with adaptive norm, in which by complex evaluation (bacteriology, parasitology, endoscopic, histologic) the pathology has not been revealed. Biopsies of colon mucosa were fixed in 10% neutral formalin solution and embedded in paraffin. Histological sections were stained with 1% aqueous solution of Alcian blue, Mayer’s hematoxylin and eosin; for morphometric analysis of 24 objective indicators - azure II-eosin by Romanovsky, with eosin methylene blue and thionine by Nicolas. Results. It was found that the mucosa in chronic post-parasitic colitis in all cases different from the normal colonic mucosa by registered parameters: the amebiasis - in 50% of cases, giardiasis - in 54.1%, with difillobotriosis - in 70.8%. In post-difillobotriosis colitis the number of fibroblasts in the lamina propria was reduced. Post-lyambliotic colitis characterized by hypertrophy of the surface epithelium and a high mitotic activity of the epithelium of intestinal glands. Conclusion. After undergoing parasitic diseases, in the colon mucosa preserved histological changes corresponding to chronic ulcerative colitis; post-amebiasis chronic colitis characterized by catarrhal-haemorrhagic inflammation, chronic post-lyambliotic - catarrhal-follicular, post-difillobotriosis - catarrhal-haemorrhagic inflammation with high activity of the pathological process and moderate atrophy of the intestinal glands.

Analiza wczesnych wyników leczenia chorych na czerniaka skóry poddanych biopsji węzła wartowniczego

Introduction. Surgery is the main treatment option for skin melanoma and the treatment results depend on stage. Most melanomas diagnosed in Poland are &gt; pT1a and therefore sentinel node biopsy (SNB) is needed for accurate allows for accurate regional (nodal) staging. The aim of this work was to assess early treatment results in skin melanomapatients undergoing SNB. Material and methods. From 2010 to 2012 in the Department of Surgical Oncology, Cancer Center in Kraków,115 skin melanoma patients underwent SNB (72 females and 43 males). Selected parameters potentially influencing survival were analyzed. Results. In 15 (13%) patients SN was positive. In patients with positive SN melanomas were thicker compared to SN negative patients (5.16 versus 3.87 mm, p = 0.08). In 23 patients the disease relapsed: distant metastases (n = 17) or locoregional recurrence (n = 6). In the group with positive SN, recurrence was noted in 8 cases (53%); in the group with negative SN, recurrence was seen in 15 patients (15%). Recurrent patients were characterised by thicker melanomas (7.1 versus 3.53 mm, p = 0.03). No evidence of disease survival (Kaplan-Meier) curves were significantly separated for positive and negative SN groups. Cox analysis was used for prognostic parameters. SN status and mitotic index were shown to independently influence survival time with no evidence of disease (p = 0.001). Conclusions. SNB effectively identifies melanoma patients with microscopic regional node metastases. Melanoma thickness (Breslow) significantly influences the risk for nodal metastases. Presence of nodal metastasis in SN and high mitotic activity significantly increased the risk of relapse.

Symplastic Leiomyomas of the Scrotum

Smooth muscle tumors of the scrotum are very uncommon, and those with degenerative-appearing atypia, variably designated as "atypical," "symplastic," or "bizarre" leiomyomas, are extremely rare with only 11 cases in the literature. Given their rarity, the diagnostic criteria and prognosis of symplastic leiomyomas are not well established. We describe 9 cases of scrotal symplastic leiomyomas and compare their histopathologic characteristics to 10 usual leiomyomas and 5 leiomyosarcomas of the scrotum. The preoperative diagnosis was scrotal tumor or cyst in all cases. The mean age was 46 years (range, 32 to 60 y) for usual, 59 (range, 48 to 79) for symplastic leiomyomas, and 57 (range, 49 to 65) for leiomyosarcoma. Submitting diagnoses for symplastic leiomyomas were: atypical spindle cell lesion (n=3); probably leiomyosarcoma (n=1); leiomyosarcoma (n=1); and none given (n=4). Symplastic leiomyomas were diagnosed when there was moderate-severe cytologic atypia, yet was degenerative-appearing with multinucleation or smudged chromatin in the setting of low nuclear/cytoplasmic ratio, low cellularity, and no mitotic activity. The mean size was 1.0 cm for usual leiomyomas, 1.0 cm for symplastic leiomyomas, and 2.0 cm for leiomyosarcomas. Leiomyosarcomas had high nuclear/cytoplasmic ratio, high cellularity, nuclear pleomorphism, and hyperchromasia. Five of 10 usual and 3/9 symplastic leiomyomas showed at least 1 ill-defined border simulating infiltrative growth. Three leiomyosarcomas were grade 1, and 2/5 were grade 2. Resection margins were positive in 5/10 usual and 3/9 symplastic leiomyomas and in 1/5 leiomyosarcoma. Ki67 labeling in usual leiomyomas was on average 2.4% (range, 1% to 5%) and in symplastic leiomyomas was 1.8% (range, 1% to 5%). Mitoses were absent in all cases of usual and symplastic leiomyomas. Mitotic figures averaged 4.7 (range, 1 to 7) and 13.5 (range, 7 to 20) per 10 HPF for the grade 1 and 2 leiomyosarcomas, respectively. None of the symplastic leiomyomas recurred after a median follow-up of 27 months. The 2 patients with grade 2 leiomyosarcoma had no evidence of metastases at 6 and 7 months follow-up, respectively. Scrotal symplastic leiomyomas may have an ill-defined infiltrative border, which along with their atypia mimic malignancy. Ki67 is low in symplastic leiomyomas, which along with their favorable follow-up and experience in other organs justifies a benign diagnosis. High cellularity and high mitotic activity are the most reliable features for the diagnosis of scrotal leiomyosarcoma.

Abstract 246: Mammary cancer preventive activity of an extract of withania somnifera roots

Abstract Mammary cancer preventive activity of an alcoholic extract of Withania somnifera (WS) roots was examined in female ErbB2+/- (MMTV/Neu) mice. The WS root extract was mixed with feed at a concentration of 750 mg/kg of diet. Mice treated with the root extract developed fewer mammary tumors relative to mice in the untreated group; after 310 days, mice in the treated group had an average of 1.62 tumors, and mice in the control group had 2.48, a reduction of 33% (p=0.1). Representative samples of the mammary tumors were examined histologically after staining with hematoxylin and eosin (H&amp;E) and for proliferation (Ki67 and PCNA). For mammary tumors of control mice, sections stained with H&amp;E showed high mitotic activity, whereas in tumors from treated mice, there was low mitotic activity. Labeling indices for Ki67 and PCNA markers in cancers of treated mice were 35% and 30% lower, respectively, than those of the control group. Expression of the cytokine CCL2 was 50% lower in cancers of the treated group. These results indicate that the root extract of WS reduces mammary tumor formation and tumor cell proliferation. Supported by grant U54 CA118948. Citation Format: kamel F. Khazal, Donald Hill, Clinton J. Grubbs. Mammary cancer preventive activity of an extract of withania somnifera roots. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 246. doi:10.1158/1538-7445.AM2014-246

Multiple chest wall swellings in adult Burkitt's lymphoma

A 64-year-old male farmer presented to our hospital in April, 2013, with a 3 month history of painless, progressive swelling of his chest wall and lower jaw, and 10 kg unintentional weight loss. On examination he had multiple lumps about 3 × 1⋅5 cm around the angle of the mandible, and multiple 10 × 8 cm lumps at the mid sternal region and of the left lower anterior chest wall (fi gure). These lumps were non-tender to palpation, hard, and tethered, with irregular contours, no tempertature changes or overlying skin changes. Blood tests were normal and HIV serology was negative. CT Chest showed a soft tissue mass 8 × 10⋅6 × 8 cm encasing and eroding the body of sternum with presternal and retrosternal soft tissue components (appendix), and whole-body PET CT fusion showed increased 18F-fl uorodeoxyglucose (18F-FDG) uptake (appendix). Histological and immunohistochemical examination of a biopsy specimen from the chest wall swelling showed tightly-packed small round cells with high mitotic activity infi ltrating fat and starry sky appearance (fi gure), positive for CD20, Bcl-2, Mum-1, and Bcl-6, and negative for CD10, CD3, Cyclin-D1, and TdT, with Ki-67 nearly 100%. Conventional cytogenetics showed complex structural and numerical abnormalities including characteristic t (8;14) (appendix). We diagnosed high risk group adult Burkitt lymphoma stage IV, and started treatment with modifi ed Magrath regimen of four alternating cycles of R-CODOX-M and R-IMVAC chemotherapy. The patient achieved complete remission with disappearance of sternal swellings, normal peripheral blood counts, normal bone marrow aspirate, and no evidence of 18FDG uptake on repeat PET scan. He remained in remission at last 3 month follow-up in December, 2013. Lancet 2014; 384: 2244

Successful multimodal therapy for undifferentiated carcinoma with neuroendocrine differentiation in the clival region

Carcinomas with neuroendocrine differentiation include tumor components with characteristics of neuroendocrine tumors of carcinomas of the lung, gastrointestinal tract, prostate, and breast. No clear definition or treatment has been established. A 66-year-old female was admitted to our hospital for a sore throat and otalgia. Magnetic resonance imaging showed a locally invasive tumor with a diameter of 45 mm in the clival region. Histopathological examination revealed that the tumor consisted of densely packed undifferentiated tumor cells with high mitotic activity. Two cellular components were present: one proliferating in solid nests that were immunopositive for cytokeratin, and the other that was diffusely proliferating and immunopositive for neuroendocrine markers. The tumor was thus diagnosed as undifferentiated carcinoma with neuroendocrine differentiation. The patient was treated with four cycles of cisplatin and etoposide and a total of 70 Gy radiotherapy. A complete response was achieved and maintained without therapy for 16 months. Metastasis to the lymph nodes, liver, and bone then appeared, and a lymphadenectomy revealed undifferentiated carcinoma without neuroendocrine differentiation. The patient died because of the tumor 36 months after the initial diagnosis. Because undifferentiated carcinomas with neuroendocrine differentiation in the skull are exceedingly rare, we report this case in which the tumor was controlled with chemoradiotherapy.

CDKN2A LOSS IS ASSOCIATED WITH SHORTENED SURVIVAL IN INFILTRATING ASTROCYTOMAS BUT NOT OLIGODENDROGLIOMAS OR MIXED OLIGOASTROCYTOMAS

BACKGROUND: Infiltrating WHO grade II and III gliomas are devastating and difficult to treat neoplasms classified as astrocytoma (A2), oligodendroglioma (O2), oligoastrocytoma (OA2), or anaplastic astrocytoma (A3), oligodendroglioma (O3), and oligoastrocytoma (OA3). Anaplastic grade is critically dependent on the presence of mitoses (astrocytomas) or high mitotic activity (oligodendroglial tumors), with CDKN2A deletion considered the most common mechanism for associated cell cycle dysregulation. We therefore sought to determine if p16 loss by immunohistochemistry (IHC) or CDKN2A gene by fluorescence in situ hybridization (FISH) are associated with patient survival across histologic groupings after controlling for age, grade, and other molecular markers. METHODS: Adults (18 years of age) with infiltrating gliomas (grades II or III) were selected from the UCSF Adult Glioma Study (N = 157). The population consisted of 90 males (average age = 43.2) and 67 females (average age = 40.7). Isocitrate dehydrogenase (IDH) status (IDH1 and IDH2) was known for all cases. Histology and grade were as follows: 53 O2, 33 A2, 29 OA2, 20 O3, 15 A3, 7 OA3. CDKN2A FISH was performed using commercial probes and immunostains for p16 and MIB1 (Ki-67) were similarly performed using commercial antibodies. The end point for the analysis was overall survival, analyzed using Cox proportional hazards, stratified by tumor histology and with adjustment for sex, age, grade, and various tumor markers. A total of 61 events (deaths) were observed, and median follow-up time across all subjects was 6.4 years. RESULTS: After controlling for age, sex, and grade, CDKN2A deletion was associated with decreased survival in astrocytoma patients (P = 0.045; HR = 3.1; 95%CI = 1.03-9.2) but not in oligodendroglioma or oligoastrocytoma patients (P = 0.57 and P = 0.67, respectively). A strong inverse association between IDH mutation and CDKN2A deletion was observed in astrocytomas, and the association of CDKN2A deletion with survival was attenuated after controlling for IDH status (P = 0.34). Interestingly, CDKN2A loss was observed in 83% of IDH wild-type versus 33% of IDH-mutant astrocytomas (P = 0.029). CDKN2A loss was only weakly associated with decreased p16 expression (p = 0.09), and the p16 labeling index (LI) was not associated with outcome. There was also no clear association between CDKN2A deletion and MIB1 LI (P = 0.92). CONCLUSIONS: CDKN2A deletion by FISH is associated with shortened survival in astrocytoma patients, but not in patients with oligodendroglial tumors. The strong inverse association between IDH mutation and CDKN2A deletion suggests that CDKN2A status may have prognostic value in the clinical work-up of grade II and III astrocytoma patients. SECONDARY CATEGORY: n/a.