Steroid and Xenobiotic Receptor (SXR) as a possible prognostic marker in epithelial ovarian cancer

We examined the expression of the steroid and xenobiotic receptor (SXR) and evaluated its clinical significance in human epithelial ovarian carcinoma. One hundred forty‐one cases were examined using immunohistochemistry for SXR with archival specimens. All cases were scored using a semi‐quantitative histological scoring (HSCORE) method. Specimens with an HSCORE > 60 were regarded as SXR‐positive. Various clinicopathologic variables were examined. SXR showed significant differences in age, histology, grade, ERα and PR. SXR was detected in 35 of 141 (24.8%) ovarian cancer tissues. There was a statistically significant negative correlation between SXR‐positive status and both disease‐free survival and overall survival (P= 0.0415 and 0.0316, respectively), independent of stage (P= 0.0167 and 0.021, respectively). In multivariate analysis, SXR was a statistically independent risk factor for both disease‐free survival and overall survival (P= 0.049 and 0.0354). Our results support an association of SXR between ERα and PR in epithelial ovarian cancers. Our data suggest that SXR is a prognostic factor in epithelial ovarian cancer and may represent a useful marker to identify patients at risk of recurrence or death.     

Colonic low‐grade endometrial stromal sarcoma and orthotopic endometrial stromal tumor with limited infiltration sharing the JAZF1‐SUZ12 gene fusion

Endometrial stromal tumors (ESTs) are composed of cells resembling endometrial stroma, and are divided into benign and malignant types based on morphology. Endometrial stromal nodule (ESN) is a benign localized tumor, and endometrial stromal sarcoma (ESS) is an infiltrative and potentially metastatic neoplasm. A series of genetic aberrations contribute to pathological diagnosis of ESTs. At present, subsets of ESN and ESS‐low grade (ESS‐LG) are characterized as JAZF1‐SUZ12/JJAZ1 gene fusion. The ESTs that show higher grade atypia but lack nuclear pleomorphism include YWHAE‐FAM22 ESS. Here we report an unusual case of ESTs. Sudden colonic perforation occurred to the patient, and emergency surgery was performed. Pathological findings suggested metastatic ESS. Thorough medical examination of the genital organs detected a 1 cm‐sized well‐demarcated uterine tumor. Microscopically, the tumor lacked infiltrative features, conforming to the definition of ESN. Both lesions demonstrated identical cytology and shared JAZF1‐SUZ12 gene fusion. Endometriosis was not found in any areas of the resected organs, strongly suggesting that the uterine orthotopic tumor metastasized. The current case uncovered the problems of differential diagnosis between ESN and ESS‐LG. We demonstrate detailed pathological features of the two lesions, and discuss the possibility of orthotopic EST with limited infiltration to develop into ESS‐LG.     

Mitotic Index is an Independent Predictor of Recurrence‐Free Survival in Meningioma

While World Health Organization (WHO) grading of meningioma stratifies patients according to recurrence risk overall, there is substantial within‐grade heterogeneity with respect to recurrence‐free survival (RFS). Most meningiomas are graded according to mitotic counts per unit area on hematoxylin and eosin sections, a method potentially confounded by tumor cellularity, as well as potential limitations of accurate mitotic figure detection on routine histology. To refine mitotic figure assessment, we evaluated 363 meningiomas with phospho‐histone H3 (Ser10) and determined the mitotic index (number of mitoses per 1000 tumor cells). The median mitotic indices among WHO grade I (n = 268), grade II (n = 84) and grade III (n = 11) tumors were 1, 4 and 12. Classification and regression tree analysis to categorize cut‐offs identified three subgroups defined by mitotic indices of 0–2, 3–4 and ≥5, which on univariate analysis were associated with RFS (P < 0.01). In multivariate analysis, mitotic index subgrouped in this manner was significantly associated with RFS (P < 0.01) after adjustment for Simpson grade, WHO grade and MIB‐1 index. Mitotic index was then examined within individual WHO grade, showing that for grade I and grade II meningiomas, mitotic index can add additional information to RFS risk. The results suggest that the use of a robust mitotic marker in meningioma could refine risk stratification.     

Do we truly see what we think we see? The role of cognitive bias in pathological interpretation

In the histomorphological grading of prostate carcinoma, pathologists have regularly assigned comparable scores for the architectural Gleason and the now‐obsolete nuclear World Health Organization (WHO) grading systems. Although both systems demonstrate good correspondence between grade and survival, they are based on fundamentally different biological criteria. We tested the hypothesis that this apparent concurrence between the two grading systems originates from an interpretation bias in the minds of diagnostic pathologists, rather than reflecting a biological reality. Three pathologists graded 178 prostatectomy specimens, assigning Gleason and WHO scores on glass slides and on digital images of nuclei isolated out of their architectural context. The results were analysed with respect to interdependencies among the grading systems, to tumour recurrence (PSA relapse > 0.1 ng/ml at 48 months) and robust nuclear morphometry, as assessed by computer‐assisted image analysis. WHO and Gleason grades were strongly correlated (r = 0.82) and demonstrated identical prognostic power. However, WHO grades correlated poorly with nuclear morphology (r = 0.19). Grading of nuclei isolated out of their architectural context significantly improved accuracy for nuclear morphology (r = 0.55), but the prognostic power was virtually lost. In conclusion, the architectural organization of a tumour, which the pathologist cannot avoid noticing during initial slide viewing at low magnification, unwittingly influences the subsequent nuclear grade assignment. In our study, the prognostic power of the WHO grading system was dependent on visual assessment of tumour growth pattern. We demonstrate for the first time the influence a cognitive bias can have in the generation of an error in diagnostic pathology and highlight a considerable problem in histopathological tumour grading. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The length of positive surgical margins correlates with biochemical recurrence after radical prostatectomy

van Oort I M, Bruins H M, Kiemeney L A L M, Knipscheer B C, Witjes J A & Hulsbergen‐van de Kaa C A
(2010) Histopathology 56 , 464–471 The length of positive surgical margins correlates with biochemical recurrence after radical prostatectomy Aims: To evaluate the prognostic role of the length of a positive surgical margin (+SM) for biochemical recurrence (BCR) after radical prostatectomy (RP) for prostatic cancer. Methods and results: Consecutive RP specimens (n = 267) with +SM were analysed. All RP specimens were sectioned at 4‐mm intervals and completely embedded. Data were analysed using Kaplan–Meier survival analysis and proportional hazards models. In 267 patients the length of +SM ranged from 0.4 to 174.5 mm (median 11.2 mm) and correlated with preoperative prostate specific antigen (PSA) (P < 0.001), pathological stage (P < 0.001), tumour volume (P = 0.001), number of +SM (P < 0.001), Gleason grade at +SM (P < 0.001) and Gleason score (P = 0.015). Patients with detectable postoperative PSA levels (n = 34) or adjuvant therapy (n = 59) were excluded from BCR analysis. In the remaining 174 patients the 5‐year risk of BCR was 29%; in patients with +SM ≤10 mm and >10 mm this was 21% and 39%, respectively. On multivariable analysis BCR was associated with an increasing length of +SM (≤10 mm versus >10 mm; hazard ratio 2.15; 95% confidence interval 1.12, 4.15; P = 0.022). Conclusions: The length of +SM is an independent prognostic factor for BCR in patients with undetectable PSA after RP.     

Increased staining for phosphorylated AKT and nuclear factor‐κB p65 and their relationship with prognosis in epithelial ovarian cancer

AKT plays an important role in malignant behavior of tumors. The purpose of the present study was to determine the expression of phosphorylated AKT (P‐AKT) and nuclear factor‐κB (NF‐κB) p65 and their association with clinicopathological parameters and prognosis in epithelial ovarian tumor. On immunohistochemistry 115 samples of ovarian tissue that included 68 specimens of epithelial ovarian cancer, 12 of borderline tumor, 24 of epithelial benign tumor and 11 of normal ovary, were evaluated. Sixty‐three patients with ovarian cancer were followed up from 7 to 68 months. The positive expression rate of P‐AKT and NF‐κB p65 were higher in epithelial ovarian cancer than in normal ovarian tissue (P < 0.01). Elevated P‐AKT or NF‐κB p65 expression was significantly correlated with late clinical stage (P < 0.05 and P < 0.01) and poor histological differentiation (both P < 0.01). P‐AKT expression was significantly correlated with NF‐κB p65 immunostaining (φ = 0.272, P < 0.05). Elevated expression of P‐AKT was negatively correlated with the survival of ovarian cancer patients, but it was not an independent prognostic factor after multivariate analysis. Overexpression of P‐AKT and NF‐κB p65 were involved in the carcinogenesis and metastasis of ovarian cancer. P‐AKT might contribute to the malignant transformation through NF‐κBp65 upregulation.     

Expression of classical NF‐κB pathway effectors in human ovarian carcinoma

Darb‐Esfahani S, Sinn B V, Weichert W, Budczies J, Lehmann A, Noske A, Buckendahl A‐C, Müller B M, Sehouli J, Koensgen D, Györffy B, Dietel M & Denkert C
(2010) Histopathology 56. 727–739
Expression of classical NF‐κB pathway effectors in human ovarian carcinoma Aims: Functional studies have demonstrated that nuclear factor (NF)‐κB promotes tumour progression in ovarian cancer cells. However, surprisingly little is known of the expression of effectors of the NF‐κB pathway in human ovarian cancer in vivo. Methods and results: Immunohistochemistry and in situ hybridization revealed that in a cohort of 85 primary ovarian carcinomas, total p65 expression was inversely correlated to nuclear and cytoplasmic phospho‐IκBα (P = 0.002 and P = 0.05, respectively), and IκBα mRNA expression (P = 0.032). In contrast, phospho‐p65 expression was paralleled by the expression of nuclear (P = 0.027) and cytoplasmic phospho‐IκBα (P = 0.01). Total p65 expression was an adverse prognostic factor for overall survival (P = 0.018). In contrast, total IκBα and phosphorylated nuclear and cytoplasmic IκBα expression were favourable prognostic markers (P = 0.001, P = 0.031, P = 0.001, respectively). Cytoplasmic phospho‐IκBα expression remained a significant prognostic factor on multivariate analysis (P = 0.010). In cultured, stimulated OVCAR‐3 ovarian cancer cells the cytoplasmic retranslocation of p65 was delayed by inhibition of the nuclear membrane transporter chromosomal region maintenance/exportin1 protein (CRM1). A positive association of p65 and CRM1 expression was demonstrated in ovarian cancer tissue (P < 0.0001). Conclusions: Total and phosphorylated IκBα protein expression might serve as markers for NF‐κB activation in human ovarian carcinoma. Cytoplasmic localization of p65 may be related to deregulated nucleocytoplasmic transport in carcinomas overexpressing CRM1.     

In lymph node-negative invasive breast carcinomas, specific chromosomal aberrations are strongly associated with high mitotic activity and predict outcome more accurately than grade, tumour diameter, and oestrogen receptor

The objectives of this study were to analyse whether specific chromosomal gains and losses in lymph node-negative breast cancer correlate with other features and to evaluate their prognostic value. Seventy-six lymph node-negative breast carcinomas (median follow-up 46 months; range 9-105 months) were used. Histological grade, tumour type, maximal tumour diameter, oestrogen/progesterone receptor (ER/PR), mitotic activity index (MAI), and mean nuclear area (MNA) were assessed. Whole genome DNA analysis was performed by comparative genomic hybridization (CGH). Chromosomal aberrations were compared with classical and other prognostic features. Kaplan-Meier curves and multivariate survival analysis (Cox model) were used to assess the prognostic value of the CGH and other data. Fifteen (21.4%) out of 70 patients (six cases were lost to follow-up) developed locoregional (n=3) or distant metastases (n=12). The following criteria were prognostic for (any) recurrence (in decreasing significance): 3q gain, simultaneous gain at 1q and 8q, MAI < versus > or =10, MNA < versus > or =63 microm. Loss of 1p occurred significantly more often in the large group of ductal breast carcinomas with a MAI > or =10 (n=38) than in cancers with a MAI<10. Moreover, 8/15 (53%) patients with recurrences had a gain at 3q, as opposed to three (5.5%) of the 55 recurrence-free patients. This association was even stronger in ductal carcinomas (hazard ratio=10.9, p<0.0001). Cox regression revealed that the 3q gain was the strongest prognostic factor; other features did not have additional prognostic value. In conclusion, loss of 1p is associated with a high MAI. A gain of 3q is a stronger predictor of recurrence than grade, MAI, and other features in invasive breast cancers.     

Osteopontin predicts the behaviour of atypical meningioma

Lin C‐K, Tsai W‐C, Lin Y‐C & Hueng D‐Y
(2012) Histopathology  60, 320–325
Osteopontin predicts the behaviour of atypical meningioma Aim: Although the World Health Organization (WHO) histological criteria distinguishing benign from atypical and malignant meningioma are clear, discerning benign from atypical meningioma is still somewhat difficult, leading to interobserver diagnostic variability. Osteopontin (OPN) and cortactin play important roles in tumorigenesis, invasion and metastasis of several human cancers. The aim of this study was to evaluate the usefulness of OPN and cortactin immunohistochemistry for distinguishing between benign, atypical and malignant meningioma and predicting their recurrence. Methods and results: Seventy‐five specimens (48 benign, 17 atypical and 10 malignant meningiomas) were investigated immunohistochemically. The mean immunohistochemical scoreimmunohistochemical score ± SE of the mean of both OPN and cortactin were significantly higher in grade II or grade III meningiomas than in grade I meningioma. Discriminant analysis of immunohistochemical OPN expression showed correct classification of 97.7% of WHO grade I meningiomas and 88.2% of WHO grade II meningiomas (95.4% accuracy). However, the same analysis of cortactin expression showed correct classification of 95.8% of WHO grade I meningiomas and only 23.5% of WHO grade II meningiomas (76.9% accuracy). A cut‐off for predicting grades I and II meningioma recurrence was determined for OPN (3.0) but not for cortactin. Finally, logistic regression identified both this cut‐off (P < 0.05) and WHO grade (P < 0.05) as independent risk factors for recurrence. Conclusions: OPN expression is a valuable marker for diagnosis of atypical meningioma and prediction of grades I and II meningioma recurrence.     

TERT promoter mutations in primary and secondary WHO grade III meningioma

Purpose: TERT promoter mutation (TERTp^Mut) has a strong association to recurrence and has been suggested to act as a driver mutation for malignant transformation of WHO grade I and II meningiomas. TERTp^Mut has been investigated in selected high‐grade meningioma samples. The existence of TERTp^Mut across recurrent tumors in a population‐based cohort needs to be investigated in order to identify when TERTp^Mut emerges across recurrent samples and to validate prognostic impact among WHO grade III tumors. Methods: We gathered material from a consecutive single‐center cohort of 40 patients with malignant meningioma (WHO grade III) treated between 2000 and 2018, including specimens from primary and secondary malignant meningiomas with the corresponding earlier benign specimens and later malignant recurrences. In total 107 tumor samples were studied by Sanger sequencing for TERT promoter mutational status. Results: Seven of 40 patients (17.5%) harbored TERTp^Mut thus validating the incidence of TERTp^Mut in previous non‐population‐based cohorts. In 6/7 patients, the TERTp^Mut was present at initial surgery (WHO grade I–III) while in one patient the TERTp^Mut was found de novo when the meningioma became malignant. The incidences were 2/1.000.000/year for TERTp^Mut WHO grade III meningioma and 8/1.000.000/year for TERTp^wt WHO grade III meningioma in our catchment area. We found a 1.7 times higher recurrence rate (CI 95% 0.65–4.44) and a 2.5 higher mortality rate per 10 person‐years (CI 95% 1.01–6.19) for TERTp^Mut compared to TERTp^wt. Conclusion: TERTp^Mut can occur independently of malignant progression in meningioma and was most often present from the first tumor sample across recurring tumors. TERTp^Mut in WHO grade III may represent a marker of an aggressive subset of tumors.     

Pathological significance of epidermal growth factor receptor expression and amplification in human gliomas

Zhao L‐l, Xu K‐l, Wang S‐w, Hu B‐l & Chen L‐r
(2012) Histopathology  61, 726–736 Pathological significance of epidermal growth factor receptor expression and amplification in human gliomas Aims: To investigate epidermal growth factor receptor (EGFR) expression and amplification in gliomas and to assess their association with survival. Methods and results: Immunohistochemistry and fluorescence in‐situ hybridization were performed to analyse EGFR status in 158 cases of primary glioma. Kaplan–Meier survival and Cox regression analyses were performed to analyse the prognosis of patients. Overexpression of EGFR and expression of EGFR variant III (EGFRvIII) were found in 102 cases (64.6%) and 47 cases (29.7%), respectively. Overexpression of EGFR was significantly correlated with World Health Organization (WHO) grade and Karnofsky performance score (KPS) (both P < 0.05). Expression of EGFRvIII was significantly correlated with WHO grade, gender, age, and KPS (all P < 0.05). EGFR amplification was found in 46 cases (29.1%), and was significantly correlated with WHO grade, age, KPS and EGFR overexpression (all P < 0.05). Cox multifactor analysis showed that EGFR amplification was an independent unfavourable prognostic factor for human gliomas at all ages, and EGFRvIII was an independent prognostic factor in patients older than 60 years. Conclusions: EGFR amplification and EGFRvIII expression were associated with an unfavourable prognosis for patients of all ages, and for those older than 60 years, respectively. The differing significance of EGFR status in young and old glioma patients and its impact on prognosis needs further study.     

The autophagy protein LC3A correlates with hypoxia and is a prognostic marker of patient survival in clear cell ovarian cancer

Clear cell ovarian cancer histotypes exhibit metabolic features associated with resistance to hypoxia and glucose deprivation‐induced cell death. This metabolic characteristic suggests that clear cell ovarian cancers activate survival mechanisms not typical of other epithelial ovarian cancers. Here we demonstrate that microtubule‐associated protein 1 light chain 3A (LC3A), a marker of autophagy, is related to hypoxia and poor prognosis in clear cell ovarian cancer. In 485 ovarian tumours, we found that LC3A was significantly associated with poor progression‐free (p = 0.0232), disease‐specific (p = 0.0011) and overall patient survival (p = 0.0013) in clear cell ovarian cancer patients, but not in other subtypes examined. LC3A was an independent prognostic marker of reduced disease‐specific [hazard ratio (HR): 2.55 (95% CI 1.21–5.37); p = 0.014] and overall survival [HR: 1.95 (95% CI 1.00–3.77); p = 0.049] in patients with clear cell ovarian carcinoma. We also found a strong link between autophagy and hypoxia as LC3A staining revealed a significant positive association with the hypoxia‐related proteins carbonic anhydrase‐IX and HIF‐1α. The functional link between hypoxia and autophagy was demonstrated using clear cell and high‐grade serous cell lines that were subjected to hypoxia or hypoxia + glucose deprivation. Clear cell carcinoma lines displayed greater autophagy induction and were subsequently more sensitive to inhibition of autophagy under hypoxia compared to the high‐grade serous lines. Together, our findings indicate that hypoxia‐induced autophagy may be crucial to the clinical pathology of clear cell ovarian cancer and is a potential explanation for histological subtype differences in patient disease progression and outcomes. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Genetic alterations detected by comparative genomic hybridization and recurrence rate in epithelial ovarian carcinoma

To assess the putative correlation between comparative genomic hybridization (CGH)-detectable genetic alterations in epithelial ovarian cancer and disease recurrence, conventional CGH was performed on 45 epithelial ovarian cancers: 26 tumors from sporadic, BRCA mutation noncarriers and 11 and 8 tumors from BRCA1 and BRCA2 mutation carriers, respectively. Relevant clinical data, including histology, grade, stage, size of residual tumor, recurrence, and survival, were obtained from outpatient and inpatient charts. Among the 45 cases, the most common regions involving gain of DNA copy number were 3q (n = 23; 51%), 8q (n = 21; 47%), and 1q (n = 14; 31%), and the most common regions with loss were 19 and 22 at 9 cases (20%) each, followed by 5q (n = 6; 13%). In multivariate analysis, the total number of genetic alterations was not associated with risk of recurrence, but gain in 5p was associated with a higher risk of recurrence (hazard ratio HR = 6.06, P = 0.0399), and gain in 1p as well as loss in 5q were associated with a significant decrease in recurrence (HR = 0.08, P = 0.0079, and HR = 0.10, P = 0.0143, respectively). Recurrence rate in patients with epithelial ovarian cancer is seemingly associated with specific genetic alterations detected by CGH, but the specific genes involved and the implications of these findings await further studies.     

Amplified in breast cancer 1 expression in breast cancer

Aims: The amplified in breast cancer 1 (AIB1), steroid receptor co‐activator family member, acts as an oestrogen receptor (ER) co‐activator. Acting with HER‐2, it is thought to play a role in endocrine resistance by facilitating ER–growth factor crosstalk. The aim was to analyse AIB1 expression by immunohistochemistry and study its correlations with other prognostic variables in breast cancer and its effect on survival. Methods: A tissue microarray comprising tumours from 438 patients with 15.4 years’ median follow‐up was used. Interpretable AIB1 expression obtained in 395 patients was analysed along with other prognostic factors in breast cancer. Results: AIB1 expression scores ranged from 0 to 30; positive AIB1 expression (score > 14) was seen in 146/395 breast cancers; it correlated negatively with ER (P = 0.003) and progesterone receptor (PR) (P = 0.007), and positively with HER‐2 (P = 0.005) and tumour grade (P = 0.014). It did not correlate with nodal status (P = 0.437). Among ER+ patients, AIB1 expression showed a trend towards loss of PR expression (29% versus 20%; P = 0.14). AIB1 did not predict survival on univariate or multivariate analysis. Conclusions: AIB1 expression correlates with HER‐2 expression in breast cancer and shows a trend of association with loss of PR expression in ER+ tumours. Our study supports the postulated role of AIB1 in ER–growth factor interactions.     

Granular cell astrocytoma: an aggressive IDH‐wildtype diffuse glioma with molecular genetic features of primary glioblastoma

Granular cell astrocytoma (GCA) is a rare adult infiltrating glioma subtype. We studied a series of 39 GCAs. Median age of presentation was 57.8 years and most cases developed in the frontal or temporal lobes. Tumors included grade II (n = 14), grade III (n = 11), and grade IV (n = 14) by WHO criteria. Granular cell morphology was diffuse in 31 (79%) cases and partial in eight (21%). Immunohistochemistry showed frequent positivity for GFAP (28 of 31), OLIG2 (16 of 16), and CD68 (27 of 30), but HAM56, CD163, and IBA‐1 histiocytic markers were all negative (22 of 22). IDH1(R132H) was negative in all the cases tested (16 of 16), while ATRX expression was retained (12 of 12). Cytogenetics demonstrated monosomy 10 (6 of 6) cases, +7 in 4 (of 6), ?13q in 4 of 6, and ?14 in 4 of 6. Next‐generation sequencing demonstrated mutations in PTEN/PIK3 genes in 6/13 (46%), NF1 in 3 of 10 (30%), TP53 in 3 of 13 (23%), PALB2 in 3 of 10 (30%), STAG2 in 3 of 10 (30%), EGFR mutation/amplification in 3 of 13 (23%), and AR in 2 of 10 (20%). CDKN2A/B deletion was identified in 5 of 13 (30%) cases (homozygous deletion in 4). The TERT C228T mutation was identified in 9 of 13 (69%). No mutations were encountered in IDH1, IDH2, CIC, FUBP1, H3F3A, BRAF or ATRX genes. The mean overall survival was 11.3 months. Patients >60 years old at diagnosis had a worse survival than patients <60 years (P = 0.001). There were no statistically significant differences in survival by WHO grade, extent of granular cell change, sex or MIB‐1 (P > 0.05). GCA is a variant of IDH‐wildtype diffuse glioma with aggressive behavior irrespective of grade and extent of granular cell morphology, and with molecular genetic features corresponding to primary glioblastoma.     

Overexpression of EGFR and absence of C-KIT expression correlate with poor prognosis in salivary gland carcinomas

Aims: To evaluate the prognostic impact of expression of receptor tyrosine kinases epidermal growth factor receptor (EGFR), HER2, and C‐KIT in relation to established clinicopathological parameters in salivary gland carcinomas. Methods and results:  Immunohistochemistry for EGFR, HER2, C‐KIT and the proliferation marker Ki67 was performed in 101 cases of salivary gland carcinoma and related to long‐term clinical follow‐up. Immunopositivity of C‐KIT was common in adenoid cystic carcinoma (92%). Lack of C‐KIT expression occurred in salivary duct carcinoma (P < 0.001) and was associated with high‐grade tumours (P = 0.002), positive lymph nodes (P = 0.002) and high expression of Ki67 (P = 0.001). HER2 was typically expressed in salivary duct carcinomas (83%), but was not associated with any other parameter. EGFR overexpression occurred independently of histological type and clinical parameters. On univariate survival analysis, overexpression of EGFR (P = 0.011) and lack of C‐KIT (P = 0.014) were associated with worse prognosis, whereas HER2 was of no prognostic significance. On multivariate analysis, the strongest negative predictor of survival was high proliferative activity measured by Ki67 (P = 0.002), followed by presence of residual tumour (P = 0.006), overexpression of EGFR (P = 0.026) and advanced tumour stage (P = 0.041). Conclusions: The expression of receptor tyrosine kinases confers additional prognostic impact on disease‐specific survival. EGFR overexpression is an independent negative prognostic factor.     

Expression of the potential cancer stem cell markers,CD133, CD44, ALDH1, and β‐catenin,in primary lung adenocarcinoma—their prognostic significance

The present study investigated expression profiles of the potential CSC markers including CD133, CD44, ALDH1, and β‐catenin, and evaluated their prognostic value in lung adenocarcinomas. One‐hundred‐and‐seventy‐seven tumors (stage I) were immunohistochemically examined for the expression of these markers, and thresholds to subdivide expression levels were determined using receiver operating characteristics curves. Tumors with high levels of CD133 (adjusted hazard ratio (HR) 4.55 (95% confidence interval (CI) 1.26–16.40, P = 0.021), CD44 (HR 3.73, 95% CI 1.20–11.58, P = 0.023) or ALDH1 (HR 3.61, 95% CI 1.09–12.3, P = 0.036), but not β‐catenin (HR 2.43, 95% CI 0.59–10.8, P = 0.220), showed a significantly higher risk of recurrence than the corresponding low expressers. In conclusion, levels of CD133, CD44, and ALDH1 had independent prognostic value to predict the recurrence of lung adenocarcinoma.