Detection of KRAS gene mutation and its clinical significance in colorectal adenocarcinoma / 中华病理学杂志

<p><b>OBJECTIVE</b>To explore the clinical significance of KRAS mutation detection in colorectal adenocarcinoma.</p><p><b>METHODS</b>Paraffin-embedded tissue specimens were obtained from 440 patients with colorectal adenocarcinoma. The genomic DNA was extracted. Mutations of exon 2 of KRAS gene were examined by PCR and direct sequencing.</p><p><b>RESULTS</b>Somatic mutations of KRAS gene were identified in 146 cases, with the mutation rate of 33.2% (146/440). Among these 146 patients, KRAS mutation involved codon 12 in 118 patients, including 35G > A (Gly12Asp, 62 cases), 35G > T (Gly12Val, 35 cases), 34G > T (Gly12Cys, 9 cases), 34G > A (Gly12Ser, 6 cases), 35G > C (Gly12Ala, 5 cases), and 34G > C (Gly12Arg, 1 case); in 27 patients the mutation involved codon 13, including 38G > A (Gly13Asp, 25 cases), 38G > C (Gly13 Val, 1 case) and 37G > T (Gly13 Cys, 1 case); and in one patient, the mutation involved codon 14 with 40G > A (Val14Ile). The status of KRAS or codon 12 mutations in colorectal adenocarcinoma was related to patients' gender (P = 0.021 and P = 0.030, respectively), and this significant correlation to females was conserved in clinical stage III (P = 0.007 and P = 0.003, respectively), but not in stages I, II, and IV. The status of KRAS or codon 12 mutations was also related to tumor stage. Between stage II and stage IV, the mutation rate of KRAS and codon 12 showed significant difference (P = 0.028 and 0.034, respectively). Between stage III and stage IV, only the codon 12 mutation rate showed significant difference (P = 0.011). Codon 13 mutation was not related to tumor stage.</p><p><b>CONCLUSION</b>About one third of patients with colorectal adenocarcinoma have KRAS gene mutation, which might be related to patients' gender; and could be consistently detected by PCR and direct sequencing.</p>

Staging and histologic grading of gastrointestinal stromal tumors / 中华病理学杂志

<p><b>OBJECTIVE</b>To investigate the clinical stage and histological grade of gastrointestinal stromal tumors.</p><p><b>METHODS</b>Twelve clinical and pathological parameters were assessed in 613 patients with follow-up information. These parameters were classified into two gross spread parameters including liver metastasis and peritoneal dissemination, five microscopic spread parameters including lymph node metastasis, vascular, fat, nerve and mucosal infiltration, and five histological parameters including mitotic count ≥ 10 per 50 high-power fields, muscularis propria infiltration, coagulative necrosis, perivascular pattern and severe nuclear atypia.</p><p><b>RESULTS</b>The accumulated 5-year disease-free survival (DFS) and overall survival (OS) of 293 patients without any of these predictive parameters of malignancy were 99.3% and 100.0%, respectively. They were regarded as nonmalignant and further evaluations on the stage and grade of these tumors were not performed. At least one and at most seven predictive parameters of malignancy were identified in 320 patients. For these patients, the accumulated 5-year DFS and OS rates were 43.9% (mean 6.7 years) and 59.7% (mean 9.3 years), respectively. The DFS showed significant difference between patients with and without gross spread (P < 0.01), with and without microscopic spread (P = 0.001). DFS and OS were associated with the number of predictive parameters of malignancy in patients without gross spread (P < 0.01 for both DFS and OS), but not in patients with gross spread (P = 0.882 and 0.441, respectively).</p><p><b>CONCLUSIONS</b>Malignant GIST could be divided into clinical stages I and II based on the absence and presence of gross spread, respectively. The degree of malignancy of patients in clinical stage I could be graded according to the number of predictive parameters of malignancy. Patients in clinical stage II were of the highest degree of malignancy regardless of the number of parameters. The staging and grading of gastrointestinal stromal tumors in this study are strongly associated with prognosis.</p>

Focal nodular hyperplasia of liver: a clinicopathologic study of 238 patients / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the clinicopathologic features of focal nodular hyperplasia (FNH) of liver.</p><p><b>METHODS</b>The clinical, radiologic, pathologic findings and follow-up data of 238 cases of FNH were retrospectively analyzed.</p><p><b>RESULTS</b>The patients included 93 females and 145 males. The age of the patients ranged from 11 to 77 years (median = 39.1 years). Amongst the 233 patients who had clinical information available, 188 were asymptomatic, 216 had no history of hepatitis B and/or C infection and 232 had negative serum alpha-fetoprotein level. Amongst the 185 patients who had undergone radiologic examination, 123 (66.5%) were accurately diagnosed as such. Macroscopically, of the 284 lesions from 238 patients, the average diameter was 3.7 cm. Two hundred and fifteen cases (90.3%) were solitary, 172 cases were located in the right lobe and 115(40.5%) had central stellate fibrotic scars or lobulated cut surface. Histologically, 229 lesions belonged to classic type and 9 lesions were of non-classic type. The latter was further classified as the telangiectatic form (6 lesions) and the mixed hyperplastic and adenomatous form (3 lesions). There was no evidence of significant cytologic atypia. Follow-up data were available in 173 patients (72.7%). None of them died of the disease and 2 patients suffered from relapses after 2 and 4 years, respectively.</p><p><b>CONCLUSIONS</b>FNH is a hyperplastic response of normal liver cells to local blood flow anomalies. It has no obvious sex predilection and more than 66% can be diagnosed accurately with radiologic examination. The lesions in the current study show no cytologic atypia.</p>

Study on clinicopathologic parameters of malignant behavior in gastrointestinal stromal tumors / 中华病理学杂志

<p><b>OBJECTIVE</b>To determinate the clinicopathologic parameters in predicting the malignant behavior of gastrointestinal stromal tumor (GIST).</p><p><b>METHODS</b>Eight hundred and forty cases of GIST were retrospectively reviewed. The tumors were classified as malignant if they met any of the following criteria: evidence of gross dissemination (including liver metastasis and/or peritoneal spread), evidence of microscopic dissemination (including lymph node metastasis, infiltration to vessels, fat tissue, nerves and/or mucosal tissue), or disease relapse. The remaining cases were provisionally classified as tumors of uncertain biologic behavior. A number of morphologic parameters were then evaluated under light microscopy and univariate and multivariate analyses were adopted for this study.</p><p><b>RESULTS</b>Histologic findings correlated with evidences of the following morphologic parameters were considered in accord with the criteria of the malignant behavior: mitotic count>or=10 per 50 high-power fields (P<0.01), muscle infiltration (P<0.01), coagulative necrosis (P<0.01), perivascular growth pattern (P=0.005) and remarkable nuclear atypia (P=0.014). Basing on the above criterion, 485 cases were re-classified as "malignant" and 355 cases "non-malignant". Follow-up data showed that the five-year disease-free survival and overall survival in the "non-malignant" group were 99.3% and 100% respectively, in contrast to 43.9% and 59.7% respectively in the "malignant" group (P<0.01).</p><p><b>CONCLUSIONS</b>The set of clinicopathologic parameters is useful in predicting the malignant behavior of GIST and prognosis.</p>

Clinical and pathological studies of borderline gastrointestinal stromal tumors / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Borderline gastrointestinal stromal tumors (GISTs) are intermediate tumors between benign and malignant variants; however, the clinical and pathological features of borderline GISTs remain poorly defined. This study aimed to characterize GISTs and to identify a set of borderline criteria for practical use.</p><p><b>METHODS</b>Medical records and specimens of 840 patients from 12 hospitals were retrospectively examined. Totally 485 and 76 patients with any of the parameters predictive of either malignant or benign tumors were excluded. The Kaplan-Meier method was used to calculate disease-free survival and overall survival rates.</p><p><b>RESULTS</b>Among the remaining 279 borderline GIST patients, 223 were followed up for 1 to 31.48 years. Two patients developed local recurrence, and both were cured by subsequent operations alone. The 5-year disease-free survival and overall survival rates were 99% and 100%, respectively. Morphologically, borderline GISTs typically exhibited moderate cellularity, and subsets of them also showed moderate atypia, low mitotic activities, or large tumor size. According to the National Institutes of Health (NIH) consensus criteria, the risk levels of the 279 GISTs were classified to be very low to high. However, the disease-free survival rates were not significantly different among these risk groups (P = 0.681).</p><p><b>CONCLUSIONS</b>The proposed borderline GIST criteria in the current study may complement the existing NIH criteria, based primarily on tumor size and mitotic count, in the evaluation of the biological behaviors of GISTs. Since a subset of borderline GISTs with high risk level showed favorable outcome, the introduction of the borderline GIST system may avoid overdiagnosis and over therapy.</p>

Study on the mechanism of imatinib-induced resistance in gastrointestinal stromal tumors / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the mechanism of imatinib mesylate (IM) induced-resistance in the patients with gastrointestinal stromal tumors (GISTs) and treated with imatinib.</p><p><b>METHODS</b>Eight patients with GIST treated with IM developed secondary IM resistance. A total of 16 tumor samples (pre-IM therapy) and 11 tumor samples (post-IM treatment) were available. Exon 9, 11, 13, and 17 of c-kit gene as well as exon 12 and exon 18 of PDGFRA gene were sequenced.</p><p><b>RESULTS</b>In addition to the changes of baseline genotype, the IM-induced gene changes were concentrated in the kinase domain of c-kit gene in all 8 patients, 2 of them were located in the exon 13 of c-kit gene presenting with V654A, while 6 in exon 17 involving 816 and 820 to 823 codons.</p><p><b>CONCLUSION</b>The mechanism of imatinib mesylate resistance after initial treatment with this agent in gastrointestinal stromal tumors is a novel mutation development in kinase domain of c-kit.</p>

Clinical and histopathological alterations of lymphangioleiomyomatosis in 14 Chinese patients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Lymphangioleiomyomatosis (LAM) is a rare disease that predominantly affects young females. It is considered as an "orphan" life-threatening disease of unknown etiology, with uncertain clinical prognosis, and no effective treatment. LAM can arise sporadically or in association with tuberous sclerosis complex (TSC), an autosomal inherited syndrome characterized by hamartoma-like tumor growth and pathologic features that are distinct from manifestations of pulmonary LAM. The clinical course of LAM is characterized by progressive dyspnea on exertion, recurrent pneumothorax, and chylous fluid collections.</p><p><b>METHODS</b>Fourteen cases of LAM from Zhongshan Hospital, Fudan University are reviewed, twelve were confirmed by lung biopsy, one by retroperitoneal lymphangioleiomyoma resection, and one by autopsy.</p><p><b>RESULTS</b>All 14 patients were women, aged 18 to 69 years (mean 43.3 years, median 46.5 years). Haemoptysis (57.1%) and chylothorax (35.7%) were more frequent than those described in previous case series. Extrapulmonary findings such as renal angiomyolipoma (AML), enlarged abdominal lymph nodes, liver AML and retroperitoneal lymphangioleiomyoma were seen in 21.4%, 14.3%, 7.14% and 7.14% in 14 cases respectively, which is remarkably lower than in the previously reported. Abnormal smooth muscle cells (LAM cells) were found to line the airways, bronchioles, lymphatics and blood vessels leading to airflow obstruction and replacement of the lung parenchyma by cysts. There were some surprises in the autopsy case as several LAM cell emboli were found in the veins of mediastinum lymph nodes; LAM cells were found to be disseminated in soft tissues adjacent to the ilium.</p><p><b>CONCLUSIONS</b>Women with unexplained recurrent pneumothorax, tuberous sclerosis, or a diagnosis of primary spontaneous pneumothorax or emphysema in the setting of limited or absent tobacco use should undergo high-resolution computed tomography (HRCT) scan screening for LAM. Routine abdominal and pelvic imaging examinations should be performed to detect extrapulmonary involvement. The autopsy studies histologically suggested that LAM could be a multisystemic disease and LAM cells might possess metastatic potential.</p>

Chondroblastoma occurring in atypical sites / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the clinical, pathologic and radiologic features of chondroblastoma occurring in sites other than epiphysis and apophysis of long bones, and to investigate possible reasons for misdiagnosis.</p><p><b>METHODS</b>The clinical, pathologic and radiologic data of 18 chondroblastoma cases occurring in atypical sites were collected from 5 major hospitals in Shanghai during the past 12 years. S-100 immunostaining was performed to confirm the cartilaginous differentiation of the tumor cells.</p><p><b>RESULTS</b>Chondroblastoma occurred in small bones of feet in 10 of the 18 cases (55.6%) studied, being commonest in the talus and calcaneus bones. Mean age of the patients was 27.8 years, with 55.6% over 25 years of age. Radiologic examination revealed expansive, multilocular and well-demarcated radiolucent lesions in most cases. There was local cortical destruction in 5 cases (28%) and soft tissue infiltration in 1 case. In 10 cases (55.6%), the tumor was associated with aneurismal bone cyst or simple bone cyst formation. None of the cases studied was accurately diagnosed clinically before the operation. In 2 cases, the pathology was also misdiagnosed, often being diagnosed as aneurismal bone cyst or giant cell tumor.</p><p><b>CONCLUSIONS</b>Chondroblastoma occurring in atypical sites are often associated with atypical age, radiologic features and pathologic findings at presentation. Thorough understanding of the potential pitfalls is essential in order to avoid misdiagnosis.</p>