Low Mitotic Rate Research Articles

Dealing with complexity: prognostic implications of karyotype and mutations in chronic lymphocytic leukemia

Over the last 40 years, much progress has been made in defining and understanding the genetic factors underlying the heterogeneity in the clinical course of patients with chronic lymphocytic leukemia (CLL). The presence of acquired clonal genetic abnormalities in CLL has been recognized since the early 1980s. However, correlation of chromosomal alterations with prognosis was hampered by the low mitotic rate of CLL cells, which results in only 40–50% of CLL samples having detectable chromosomal abnormalities using conventional karyotyping. Over the last 25 years, two technologic innovations, interphase FISH and stimulated karyotyping, have allowed investigation into the effect of these genetic changes on disease biology, prognosis, and response to therapy. Testing for the presence of known chromosome abnormalities with prognostic significance in CLL is now considered standard of care (1) and is most commonly done via employment of CLL FISH panels. However, the time consuming, technical nature of the culturing step has largely limited stimulated karyotype testing to referral centers.

A Review of Sleeve Gastrectomy Specimen Histopathology

With the increasing popularity of sleeve gastrectomy, many stomach specimens are being evaluated. Understanding the significance and treatment for unexpected pathology is important. This study examines the incidence of relevant histopathology of sleeve gastrectomy specimens. It evaluates previous data for each histopathology and provides recommendations for treatment. In this study, a retrospective review was performed for 241 patients who underwent sleeve gastrectomy from 2009 to 2014 at a single institution. Of the specimens, 122 had no significant histopathology, 91 had gastritis, 13 had lymphoid aggregates, 5 had hyperplasia, 3 had intestinal metaplasia, 3 had gastrointestinal stromal tumors (GISTs), and 3 had gastric polyps. Of the GISTs all had a low mitotic rate and the size of the tumor ranged from 1.5 to 4.5 cm. The findings of metaplasia may be a marker for increased risk of malignancy and may require additional surveillance. The findings of GIST may warrant interval imaging to survey for recurrence, though the likelihood of recurrence for the tumors in this study is less than 2 per cent based on previous studies.

Microscopic gastrointestinal stromal tumours: a clinical and molecular study of 13 cases.

Recent literature suggests that clinically silent, microscopic gastrointestinal stromal tumours (micro-GISTs) are common incidental findings. The aim of this study was to examine the histological, immunohistochemical and molecular characteristics of these tumours, which we have defined as measuring ≤20 mm, in order to determine whether the rate and spectrum of mutations are similar to those of clinically symptomatic gastrointestinal stromal tumours (GISTs). Thirteen micro-GISTs identified as incidental findings in patients undergoing management of concomitant disease were tested for KIT/PDGFRA mutations. Ten micro-GISTs (77%) were located in the stomach, two (15%) in the duodenum, and one (8%) in the rectum. The mean tumour size was 9.3 mm (range 2-19 mm). All tumours were well-circumscribed lesions showing a predominantly spindle-cell morphology and a very low mitotic rate. Twelve of 13 (92%) tumours carried mutations in either KIT (83%) or PDGFRA (17%), a rate higher than in other published series. A high mutation rate (80%) was also seen in lesions measuring ≤5 mm. Our results suggest that KIT/PDGFRA mutation is a very common early event in GIST development, that tumour size does not reliably predict the presence of mutation, and that one or more subsequent mutations are required for clinical manifestation.

Golgi-Related Proteins GOLPH2 (GP73/GOLM1) and GOLPH3 (GOPP1/MIDAS) in Cutaneous Melanoma: Patterns of Expression and Prognostic Significance.

GOLPH2 and GOLPH3 are Golgi-related proteins associated with aggressiveness and progression of a number of cancers. Their prognostic significance in melanoma has not yet been analyzed. We performed immunohistochemical analysis for GOLPH2 and GOLPH3 in 20 normal skin, 30 benign nevi and 100 primary melanoma tissue samples and evaluated their expression in three compartments: cancer cells, tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). High levels of both proteins in melanoma cells were associated with characteristics of aggressive disease, and shorter disease-free survival (DFS) and cancer-specific overall survival (CSOS). On the contrary, increased numbers of GOLPH2-positive and GOLPH3-positive TAMs were observed in thinner, non-ulcerated tumors, with brisk lymphocytic reaction and absent lymphangioinvasion. Distant metastases were not observed among patients with high numbers of GOLPH2-positive TAMs. Increased expression of either protein in TAMs was related to prolonged CSOS and DFS. Similarly, GOLPH3-expressing CAFs were more frequent in thin melanomas with low mitotic rate, without ulceration and lymphangioinvasion. Moreover, increased GOLPH3-positive CAFs correlated with the absence of regional or distant metastases, and with longer CSOS and DFS. GOLPH2 expression was not observed in CAFs. Our results suggest that GOLPH2 and GOLPH3 play a role in melanoma progression and are potential targets for molecular-based therapies.

Gastrointestinal Stromal Tumor of Stomach: A Gentle Enemy of the Surgeon. Our Experience in Confronting the Disease.

Surgical resection is considered to be the best treatment for gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the gastrointestinal tract. Tumor size, mitotic rate, and anatomic locations are directly related to the potential malignancy, surgical approach, oncological treatment, and recurrence rate. This was a retrospective study of 40 patients who underwent surgical resection of histologically or immunohistochemistry-proven GIST of the stomach at the Rabin and Kaplan Medical Center between 2004 and 2013. Tumor size, location, margin status, pathologic characteristics, surgical approach, surgical outcome, and long-term follow-up were analyzed from hospital records. The most common presentation was upper gastrointestinal bleeding (40%), although 30% of cases were asymptomatic. A laparoscopic approach was the preferred technique whenever feasible; 85% of tumors were localized in the proximal stomach, with a median size of 5.6 cm. Most of the resected tumors revealed a low mitotic rate and thus had low-moderate risks of malignancy. All tumors were completely resected with free surgical margins. The median follow-up period was 40 months with 93% disease-free survival. Gastric GIST is a snake in the grass and its diagnosis is often incidental to endoscopy and computed tomographic scan. The most important technical point is to avoid tumor rupture during removal.

Interphase Molecular Cytogenetic Detection Rates of Chronic Lymphocytic Leukemia-Specific Aberrations Are Higher in Cultivated Cells Than in Blood or Bone Marrow Smears.

Banding cytogenetics is still the gold standard in many fields of leukemia diagnostics. However, in chronic lymphocytic leukemia (CLL), GTG-banding results are hampered by a low mitotic rate of the corresponding malignant lymphatic cells. Thus, interphase fluorescence in situ hybridization (iFISH) for the detection of specific cytogenetic aberrations is done nowadays as a supplement to or even instead of banding cytogenetics in many diagnostic laboratories. These iFISH studies can be performed on native blood or bone marrow smears or in nuclei after cultivation and stimulation by a suitable mitogen. As there are only few comparative studies with partially conflicting results for the detection rates of aberrations in cultivated and native cells, this question was studied in 38 CLL cases with known aberrations in 11q22.2, 11q22.3, 12, 13q14.3, 14q32.33, 17p13.1, or 18q21.32. The obtained results implicate that iFISH directly applied on smears is in general less efficient for the detection of CLL-specific genetic abnormalities than for cultivated cells. This also shows that applied cell culture conditions are well suited for malignant CLL cells. Thus, to detect malignant aberrant cells in CLL, cell cultivation and cytogenetic workup should be performed and the obtained material should be subjected to banding cytogenetics and iFISH.

Cellular Blue Nevomelanocytic Lesions: Analysis of Clinical, Histological, and Outcome Data in 37 Cases

Cellular blue nevomelanocytic lesions (CBNLs) frequently pose diagnostic problems to pathologists, and their biological potential may be difficult to establish. In this study, the authors have analyzed the clinical, histological, and outcome data of 37 cellular blue nevomelanocytic lesions and the molecular characteristics of 4 lesions. The cohort of cases comprised 8 cellular blue nevi (CBNs), 17 atypical cellular blue nevi (ACBNs), and 12 blue-nevus-like melanomas (BNLMs) with a mean follow-up of 5 years. The average age at diagnosis was 25.9 years for patients with ACBN, versus 30.4 years for CBN, and 44.6 years for BNLM. Both CBN and ACBN occurred most frequently on the trunk or extremities, whereas BNLM primarily involved the scalp. Histologically, CBN and ACBN were characterized by a mean diameter of <1 cm, absence of necrosis, low mitotic rate (mean: 1-2 mitotic figures/mm), little or no infiltrative properties, and usually low-grade cytologic atypia. In contrast, BNLM had a mean diameter of 1.6 cm, necrosis, tissue infiltration, greater mitotic activity (mean: 6 mitotic figures/mm), and high-grade cytologic atypia. ACBNs often were larger, more densely cellular, exhibited higher mitotic counts, and were cytologically more atypical than CBN. Seven CBN cases with follow-up had a benign clinical course (average follow-up of 4.7 years). Among 6 patients with ACBN who underwent sentinel lymph node (SLN) biopsy, 3 were positive, and a single additional case had 1 positive non-SLN (this patient did not have a SLN biopsy performed). All 14 cases of ACBN with follow-up were alive and without recurrence with mean follow-up of 5 years. Of the 9 melanoma cases with follow-up, 3 patients with SLN and non-SLN involvement died from their disease (average follow-up of 4.8 years). Array comparative genomic hybridization was performed on 2 ACBNs and 1 BNLM: One of the 2 ACBNs showed chromosomal aberrations and 1 BNLM showed multiple chromosomal gains and losses. Multiplex polymerase chain reaction was performed on 1 ACBN, and no mutations were found. From these results, the authors conclude that ACBN occupy an intermediate position within the spectrum of CBN and BNLM, yet many lesions cannot be reliably distinguished from either CBN or BNLM because of overlapping histologic features. However, in general, ACBNs seem to aggregate more closely with CBN in terms of clinical, histological, molecular profile (limited data), and biological behavior.

The clinical correlation of phosphatase and tensin homolog on chromosome 10, phosphorylation of AKT to an activated state, and odontogenic ameloblast–associated protein in gastrointestinal stromal tumors

BackgroundApproximately 15% of gastrointestinal stromal tumors (GISTs) will not respond to tyrosine kinase inhibitors and drug resistance can develop over time. For refractory tumors, additional therapies are needed. Odontogenic ameloblast–associated protein (ODAM) is expressed in some epithelial malignancies and can correlate with clinical outcomes. This study evaluated ODAM and its relationship to phosphatase and tensin homolog on chromosome 10 (PTEN) and phosphorylation of AKT to an activated state (pAKT) in GISTs. Materials and methodsNinety-five distinct tumor specimens from 79 patients were identified. Morphologic features and clinical data were recorded for all tumors. Risk of recurrence was calculated using the Memorial Sloan-Kettering nomogram. Immunohistochemistry was performed using antibodies to ODAM, PTEN, and pAKT. Immunoreactivity was assessed for both cytoplasmic and nuclear expression. Staining patterns were correlated with clinical outcomes. ResultsIncreasing cytoplasmic ODAM staining correlated with a lower recurrence score (P = 0.002), a lower mitotic rate (P = 0.0001), and smaller tumor size (P = 0.038). Increasing pAKT cytoplasmic staining correlated with a higher recurrence score (P = 0.037) and a higher mitotic rate (P = 0.036). ODAM and pAKT expression in the nucleus was associated with tumor origin. PTEN nuclear expression increased with increasing mitotic rate. pAKT expression increased in the cytoplasm and nucleus in high-risk tumors. ConclusionsRisk of recurrence correlated with cytoplasmic expression of ODAM and pAKT, whereas nuclear expression did not predict recurrence. The staining pattern for ODAM and pAKT in the cytoplasm may further clarify the risk of recurrence beyond the available nomograms. The increased expression of pAKT in the cytoplasm and nucleus of high-risk tumors suggests a potential target for systemic therapy.

Perivascular Epithelioid Cell Tumour with Intraorbital Location: Report of a Case and Review of the Literature

The Perivascular Epithelioid Cell tumours (PEComas) are rare mesenchymal neoplasms recognized as entity by the World Health Organization. The tumour cells have an uncertain origin and are characterized by distinctive histological and immunohistochemical features. We report a case of PEComa occurring as intraorbital lesion in a 47-year-old man. We found only two other cases described in the literature and we considered all three cases together in order of histology, immunohistochemistry, and clinical outcome. We found a strict histological overlapping and quite similar immunohistological results. All three cases showed a favourable clinical course probably related to small size of tumours (<5 cm), low mitotic rate (<2 mitoses in 50 HPF), and absence of necrosis.

Giant cavernous splenic haemangioma in a dog

Case history: a nine-year-old male German Shepherd Dog presented with a history of progressively enlarged abdomen, shallow breathing and uncoordinated gait. A large abdominal mass, causing huge pressure on the surrounding organs and abdominal distension, was observed on physical examination. Imaging findings: contrast-enhanced computed tomography (CECT) showed two isoattenuating masses originating from the tail of the spleen, depicting hypoattenuating cystic areas with enhancement of solid structures on contrast administration: a characteristic finding of cavernous splenic haemangioma. The dog underwent a successful complete splenectomy and was followed up for next six months. Histopathology findings: haematoxylin and eosin staining showed vascular channels lined by well-differentiated endothelial cells with a low mitotic rate, suggestive of cavernous haemangioma. Immunohistochemical (IHC) staining was performed for CD34, vimentin, HMB-45, AE1/AE3 and epithelial membrane antigen; the expression of CD34 and vimentin endothelial markers confirmed the diagnosis of splenic haemangioma. Diagnosis: cavernous haemangioma of the spleen. Clinical relevance: it is rare to have a massive lesion on the spleen presenting as a giant abdominal mass in dogs. The location and nature of such a mass is difficult to diagnose by radiography and ultrasonography owing to its large size. CECT was found to be reliable to characterise the mass morphologically, and CT played a significant role in diagnosis and surgical management. The diagnosis was confirmed by IHC.

High nevus counts confer a favorable prognosis in melanoma patients.

A high number of nevi is the most significant phenotypic risk factor for melanoma and is in part genetically determined. The number of nevi decreases from middle age onward but this senescence can be delayed in patients with melanoma. We investigated the effects of nevus number count on sentinel node status and melanoma survival in a large cohort of melanoma cases. Out of 2,184 melanoma cases, 684 (31.3%) had a high nevus count (>50). High nevus counts were associated with favorable prognostic factors such as lower Breslow thickness, less ulceration and lower mitotic rate, despite adjustment for age. Nevus count was not predictive of sentinel node status. The crude 5‐ and 10‐year melanoma‐specific survival rate was higher in melanomas cases with a high nevus count compared to those with a low nevus count (91.2 vs. 86.4% and 87.2 vs. 79%, respectively). The difference in survival remained significant after adjusting for all known melanoma prognostic factors (hazard ratio [HR] = 0.43, confidence interval [CI] = 0.21–0.89). The favorable prognostic value of a high nevus count was also seen within the positive sentinel node subgroup of patients (HR = 0.22, CI = 0.08–0.60). High nevus count is associated with a better melanoma survival, even in the subgroup of patients with positive sentinel lymph node. This suggests a different biological behavior of melanoma tumors in patients with an excess of nevi.

Progress toward the development of in vitro model system for chemical-induced developmental neurotoxicity: potential applicability of stem cells.

committed toward the neuronal lineage and are very similar to the fetal neural stem cells. In our so far published papers, we have successfully attempted to establish stem cell-based in vitro model systems for the study of the various aspects of DNT and have proven that human umbilical cord blood-derived stem cells (hUCBSCs) when differentiated into neurons serve as one of the classical tools for the same. These were employed to assess the developmental neurotoxicity potential of Monocrotophos (MCP), a known developmental neurotoxin. Differentiating cells were given MCP exposure at different stages of maturation, i.e., day 2, 4 and 8, and significant changes in the markers of differentiation, proliferation, injury and receptors were studied. Our group reported that there was a significant upregulation of the different MAPKs, apoptosis and neurogenesis markers and a down regulation in the various cell proliferation markers during the neuronal differentiation process. Expression analysis was done both at the transcriptional (RT-PCR) as well as translational levels (immunocytochemistry and Western blotting). As differentiation proceeded, there was a significant quantitative reduction in the expression of stems markers, i.e., CD133, MYC, NANOG, SHH, KLF4, SOX2, POU5F1 and FRAP1, whereas the differentiation marker expression was significantly increased except in case of NGF, CHRM2 and NR42A. The highest expression for differentiation markers, i.e., NFM, MBP, NFH, NCM, BDNF and STAT4, was seen on day 8. These results support that hUCBSCs successfully differentiated into the neuronal lineage. Post MCP exposure there was again a significant alteration in the various markers of apoptosis, oxidative stress, metabolism, etc. It was concurred from the results that MCP exposure leads to ROS generation, oxidative stress, depleted glutathione levels and even promoted apoptosis. Receptor studies further demonstrated that the Developmental neurotoxicity (DNT) has been the prime focus of our research group since it is one of the most crucial and significant parts of the neuroscience research arena. The restricted availability of live human fetal brain tissue and major ethical issues makes the field further challenging. So far, it has been best represented via the in vivo model systems; however, the inaccurate extrapolation of data to humans restricts its scope and applications. Therefore, there is a dire need for samples (cells and tissues) of human origin. Based on the OECD guidelines 426, rodent data are present for about 200 compounds, but there is a scarcity of data available for humans. The developing brain is highly vulnerable to even minute doses of substances which are otherwise harmless for a fully developed mature brain. This is primarily because of the poorly developed blood–brain barrier, low oxygen levels and high mitotic rates. The entire process of brain development is quite complex, and in order to generate DNT models in vitro, cells and tissues of human origin are needed. Stem cells with their inherent potential for pluripotency and unique ability for unlimited proliferation serve as one of the best tools. Stem cells can be made to differentiate into the neuronal lineages and can thereby sufficiently mimic cells of the developing brain. Human umbilical cord blood was employed for the isolation of stem cells as it is not only a rich source of stem cells, but also a waste material, therefore does not pose any major ethical dubious. CD34+ hematopoietic stem cells (HSCs)/non-hematopoietic stem cells (non-HSCs) derived from cord blood are greatly

Surgery for gastrointestinal stromal tumors (GISTs) of the stomach and small bowel: short- and long-term outcomes over three decades.

Many studies on gastrointestinal stromal tumors (GISTs) derive from tertiary referral centers, but few examine strictly population-based cohorts. Thus, we evaluated the clinical features, surgical treatments, clinical outcomes, and factors predicting the survival of patients with GISTs in a population-based series. Patients with GISTs diagnosed at Stavanger University Hospital over three decades (1980-2012) were analyzed. Data were retrieved from hospital records. Descriptive statistics and survival analyses (Kaplan-Meier) are presented. A limited number of colorectal GISTs (n = 6) restricted most analyses to those with a gastric or small bowel location. Among 66 patients surgically treated for GISTs, 60 patients (91 %) had either a gastric or a small bowel localization. Females comprised 61 %. The median age at diagnosis was 63 (range, 15-88) years. Clinical symptoms were recorded in 43 patients (65 %). Complete tumor resection was achieved in 85 % of the patients. During follow-up, 6 patients were surgically treated for local recurrence or metastatic disease. The median follow-up time was 6.1 years. At last follow-up, 30 patients (46 %) were deceased, 10 of whom died from GISTs. The median overall survival was 10.4 years. For GISTs with a gastric or small bowel location, a 1- and 5-year disease-specific survival of 100 and 96 %, and a relapse-free survival of 96 and 78 % were observed. Male gender, incidental diagnosis, smaller tumor size, a low mitotic rate, an intact pseudocapsule, low-risk categorization, and an early stage were significantly associated with improved outcomes. Surgery in a low-volume, population-based setting yields enhanced long-term disease and recurrence-free survival for patients with GISTs of the stomach or small bowel. Incidental diagnosis, complete tumor resection, and low-risk categorization are good predictors of long-term prognosis.

Prolapsed Gastric Gastrointestinal Stromal Tumor: A Rare Cause of Biliary Obstruction and Acute Pancreatitis

77-year-old woman presented with abdominal Apain and early satiety. Computed tomography of the abdomen (Figure A) showed a 6-cm submucosal mass (white arrow) on a stalk (black arrow) arising from the gastric fundus as well as several benignappearing liver lesions. Esophagogastroduodenoscopy (Figure B) demonstrated the same non-friable, nonobstructing gastric mass (white arrow) and its stalk (black arrow). While biopsy results were pending, the patient presented to the emergency department with acutely worsening abdominal pain, nausea, vomiting, and jaundice. Laboratory evaluation was significant for the following: alanine aminotransferase 83 U/L, aspartate aminotransferase 117 U/L, total bilirubin 4 mg/dL, and lipase 5315 U/L. Computed tomography imaging (Figure C) showed that the aforementioned mass had prolapsed into the duodenum (white arrow) and obstructed the ampulla of Vater, resulting in dilation of the common bile duct (white arrowhead), pancreatic duct (black arrow), and gallbladder. The mass was resected surgically, and microscopic evaluation (Figure D) revealed a low-grade spindle-cell neoplasm expressing CD117 (KIT), which is consistent with a gastrointestinal stromal tumor (GIST). The patient recovered well from surgery. Her serum bilirubin and lipase levels normalized, and postoperative imaging showed resolution of the pancreatobiliary ductal dilation. Because this GIST carried a low (<5%) risk for recurrence on the basis of its size (5–10 cm), location (stomach), and low mitotic rate ( 5 mitoses/50 high-power field), we did not recommend any adjuvant therapy. Comprising fewer than 1% of all gastrointestinal tumors, GISTs are intramucosal spindle-cell neoplasms that can arise throughout the gastrointestinal tract but are most commonly found in the stomach. Although they are frequently discovered incidentally, GISTs may cause early satiety, bloating, bleeding, pain, or frank bowel obstruction. Our patient presented with pancreatitis and biliary obstruction (manifested by elevated serum lipase and bilirubin levels and a radiographic “double-duct” sign) because of a prolapsed GIST obstructing the ampulla of Vater. Although gastric GISTs or polyps may infrequently prolapse through the pylorus into the duodenum, to our knowledge there are only 2 published case reports of gastric GIST causing pancreatitis and no published reports of gastric GIST causing both pancreatitis and biliary obstruction. After resection of a GIST, the consulting oncologist can assess recurrence risk on the basis of tumor size, mitotic rate, and anatomic location and, in turn, determine whether to recommend imatinib, which has been shown to improve recurrence-free survival in patients with resected intermediate or highrisk GIST.

Prognostic features in mucoepidermoid carcinoma of major salivary glands with emphasis on tumour histologic grading.

To compare the different grading systems of mucoepidermoid carcinoma (MEC) and identify the most reliable and objective histopathologic features predictive of outcome. Seventy-two cases diagnosed as MEC were subjected to a meticulous histopathologic re-review. 20 of 72 (28%) cases were originally misdiagnosed as MEC including 16 as high grade (HG). Among the 52 confirmed MEC, median follow up (FU) was 59months. Mitosis (≥4/10 High Power Fields), necrosis, pleomorphism, focal keratinization, desmoplasia, and lymph node metastasis were associated with adverse disease specific survival (DSS) and recurrence free survival (RFS) (P<0.002). In all grading systems, low and intermediate grade had similar DSS and RFS but much better outcome than HG (P<0.007). All patients with tumour harboring low mitotic rate and no necrosis did not recur except for one patient with a positive margin. All cases with high mitotic rate and necrosis died or recurred. The majority of previously diagnosed HG MEC cases are misclassified. There is no difference in outcome between low and intermediate grade in all grading schemes. Consideration should be given to stratify MEC based on relatively objective criteria such as mitosis and necrosis.

Benign multicystic peritoneal mesothelioma associated with partial spontaneous regression in an aged cow

This article describes a benign multicystic peritoneal mesothelioma presenting partial spontaneous regression in a 16-year-old Japanese Shorthorn cow, which exhibited innumerable fluid-filled cysts (<20 cm diameter) distributing throughout the serosal surface of the peritoneal cavity on postmortem examination. Each cyst was further subdivided into several daughter cysts. On histopathology, these cystic structures consisted of multiloculated irregular spaces that contained serous fluid positive for Alcian blue stain and periodic acid-Schiff (PAS) reaction and were lined by neoplastic mesothelial cells arranged in a single to multicell layers. In some places, neoplastic cells exhibited a tubular, papillary, villous-like, or peninsular growth pattern. Neoplastic cells exhibited mild anisocytosis and anisokaryosis with very low mitotic rate. Immunohistochemically, all or some of neoplastic cells were positive for cytokeratin or vimentin, respectively. Some smaller cysts represented abundant sclerotic stroma in association with fewer shrunken neoplastic cell-lined tubules enclosed by dense fibrocollagenous stroma, collagen fiber collapse, infiltrates of lymphocytes and macrophages disposing of collagen fiber debris, and many capillaries. These findings raised the likelihood that a specific process operating partial spontaneous regression might have been implicated in this tumor. The precise mechanism underlying this phenomenon remains uncertain, although the role of abundant sclerotic stroma was highlighted.

Pulmonary neuroendocrine neoplasms

The pulmonary neuroendocrine neoplasms originate from the enterochromaffin cells which are diffusely distributed in the body. The incidence of these tumors has increased significantly in recent decades due to the available diagnostics. They make up about 1-2% of all lung tumors and 20-30% of all neuroendocrine neoplasms. The current WHO classification from 2004 divides them into typical carcinoids (TC), atypical carcinoids (AC), large cell neuroendocrine carcinomas (LCNEC) and small cell carcinomas (SCLC). The major neuroendocrine biomarkers are chromogranin A, synaptophysin and CD56. TC have a low mitotic rate of <2 mitoses/2mm(2) (10 HPF), whereas the mitotic rate of the AC is 2-10 mitoses/2 mm(2) (10 HPF). The Ki-67 staining is helpful to distinguish typical and atypical carcinoids from the highly malignant LCNEC and SCLC. Clinically, the patient presents usually with cough, hemoptysis or bronchial obstruction. The occurrence of a carcinoid or Cushing's syndrome and a tumor-associated acromegaly are rare. Surgical resection with radical lymph node dissection is the treatment of choice for achieving long-term survival. Endoscopic resection of the endobronchial tumor growth is a good alternative for inoperable endobronchially localized tumors. Peptide receptor radionuclide therapy (PRRT) is a promising treatment option for patients with metastatic or unresectable pulmonary neuroendocrine tumors. New targeted therapies using angiogenesis inhibitors, mTOR inhibitors, and tyrosine kinase inhibitors are being tested for their effectiveness in many previous studies. Typical carcinoid tumors metastasize less frequently than AC, the 5-year survival rate of patients with TC being over 90%. Patients with AC have a 5-year survival rate between 35% and 87%. The highly malignant LCNEC and SCLC, on the other hand, have a 5-year survival rate between 15% and 57%, and <5% respectively. The increasing number of therapeutic options and diagnostic procedures requires a multidisciplinary approach and decision-making in multidisciplinary tumor conferences to ensure a personalized treatment approach. Therefore patients with a neuroendocrine neoplasm of the lung should be treated in specialized centers.

Treatment patterns, prescribing decision drivers, and predictors of complete response following disease recurrence in gastrointestinal stromal tumor patients-a chart extract-based approach.

The aim of this study was to investigate tumor characteristics, treatment patterns, and outcomes in recurrent KIT + GIST patients treated in a community practice setting. An online tool was used to retrieve data on 410 patients treated with adjuvant imatinib mesylate (IM) for primary resectable KIT + GIST, who discontinued, had a recurrence, and then restarted IM or initiated sunitinib. Tumor characteristics at recurrence, treatment patterns, and factors associated with post-recurrence complete response (CR) achievement were analyzed. About 72.7% of patients did not have surgery post-recurrence as majority of them had unresectable (45%), metastatic (40%), or multifocal tumors (62.4%). Following recurrence, 76.6% of patients were re-started on IM and 23.4% on sunitinib; patients were 7.37 times more likely to re-start IM if initial treatment duration was ≤18months (p < 0.001). Patients were also more likely to re-start IM if recurrence occurred >12months post-discontinuation, or they had a recurrence inside the GI system, lower or unknown Fletcher risk score at primary diagnosis, or lower mitotic rate, (odds ratio (OR) = 3.54, p < 0.001; OR = 2.64, p = 0.006; OR = 2.55, p = 0.007; and OR = 2.45, p = 0.002, respectively). About 22.4% achieved CR; patients were more likely to achieve CR if they had unifocal tumor at recurrence, inside the GI system, of ≤2cm, or had lower mitotic rate (OR = 2.61, p < 0.001; OR = 2.27, p = 0.036; OR = 2.16, p = 0.023, OR = 1.87, p = 0.017, respectively). IM treatment duration at primary diagnosis, time to develop recurrence after IM discontinuation, tumor location, and mitotic rate at recurrence were the main prescribing decision drivers. Tumor characteristics were the most important factor in achieving CR following c-KIT inhibitor retreatment.

Pleomorphic solid pseudopapillary neoplasm of the pancreas: degenerative change rather than high-grade malignant potential

Solid pseudopapillary neoplasms (SPNs) are rare tumors of the pancreas characterized by poorly cohesive uniform cells with solid and pseudopapillary growth patterns. Nuclear pleomorphism is not a well-recognized feature of SPNs and may complicate differentiation from other pancreatic neoplasms. We compared histologic, immunohistochemical, and clinical features of 18 pleomorphic SPNs with 121 conventional SPNs. The prevalence of pleomorphic SPN was 12.9% (18/139). Pleomorphic SPNs arose in older patients (median, 45 years versus 32 years; P < .001), but no differences were found in sex, tumor location, recurrence, and metastasis when compared with conventional SPNs. Except for pleomorphic nuclei, other cytologic and histologic features of pleomorphic SPNs, such as growth pattern, tumor size, infiltrative pattern, tumor extension, mitosis, and Ki-67 labeling index, were not different from those of conventional SPNs. Pleomorphic SPNs showed a significantly higher p53 protein expression (64.7% [11/17 cases]) than that of conventional SPNs (1.8% [2/112 cases], P < .001). However, immunoreactivity for β-catenin and E-cadherin was not different between pleomorphic and conventional SPNs. A TP53 gene mutation was observed in 2 of 3 p53-immunoreactive pleomorphic SPNs. In summary, nuclear pleomorphism occurs in a subset of SPNs. They are more often p53 immunoreactive than SPNs without pleomorphism, and some harbor TP53 gene mutations. However, pleomorphic SPNs do not appear to be more aggressive than conventional SPNs. Low mitotic rate and Ki-67 labeling index may suggest nuclear pleomorphisms as degenerative changes. Recognition of typical poorly cohesive tumor cells and immunohistochemical features could establish the correct diagnosis of SPNs.

Morphologic Characteristics and Immunohistochemical Profile of Diffuse Intrinsic Pontine Gliomas

Tumors of the central nervous system are the second most common malignancy in children. In particular, diffuse intrinsic pontine gliomas (DIPGs) are aggressive tumors with poor prognosis and account for 10% to 25% of pediatric brain tumors. The majority of DIPGs are astrocytic, infiltrative, and localized to the pons. Studies have shown median survival times of less than a year, with 90% of children dying within 2 years. We built multitissue arrays with 24 postmortem DIPG samples and analyzed the morphology and expression of several proteins (p53, EGFR, GFAP, MIB1, BMI1, β-catenin, p16, Nanog, Nestin, OCT4, OLIG2, SOX2) with the goal of identifying potential treatment targets and improving our understanding of the biology of these tumors. The majority of DIPGs were high-grade gliomas (22), with 18 cases having features of glioblastoma (World Health Organization [WHO] grade IV) and 4 cases with high-grade features consistent with anaplastic astrocytoma (WHO grade III). One case was low grade (WHO grade II), and 1 case showed intermediate features between a grade II and grade III glioma (low mitotic rate but increased cellularity and cell atypia), being difficult to grade precisely. The majority of the tumors were positive for GFAP (24/24), MIB1 (23/24), OLIG2 (22/24), p16 (20/24), p53 (20/24), SOX2 (19/24), EGFR (16/24), and BMI1 (9/24). Our results suggest that dysregulation of EGFR and p53 may play an important role in the development of DIPGs. The majority of DIPGs express stem cell markers such as SOX2 and OLIG2, consistent with a role for tumor stem cells in the origin and maintenance of these tumors. Targeted therapies against these proteins could be beneficial in treatment.