Lars Harbaum

Tumor necrosis is a new promising prognostic factor in colorectal cancer

The prognostic significance of tumor necrosis in colorectal cancer is unclear. Our study aimed to analyze the prognostic value of tumor necrosis with respect to progression-free and cancer-specific survival and to relate findings to expression of proteins involved in the control of cancer cell death, such as p53 and bcl-2. A total of 381 colorectal cancer specimens were retrospectively reevaluated. The extent of tumor necrosis was semiquantitatively assessed and recorded as either absent, focal (≤10% of the tumor area), moderate (10%-30%), or extensive (≥30%). Expression of p53 and bcl-2 was assessed immunohistochemically and recorded as either positive (using a cutoff value of 10%) or negative. In addition, mismatch repair protein status was assessed by immunohistochemistry using antibodies directed against hMLH1, hMSH2, and hMSH6. Tumor necrosis was observed in 365 (96%) cases, with 180 (47%) tumors showing focal necrosis, 119 (31%) moderate necrosis, and 66 (17%) extensive necrosis, respectively. Extent of necrosis was significantly associated with high T classification (P < .001), high N classification (P = .005), high International Union Against Cancer stage (P < .001), poor tumor differentiation (P < .001), large tumor size (P < .001), and blood vessel invasion (P = .01). No association of tumor necrosis with expression of p53, bcl-2, and mismatch repair protein status was observed. Tumor necrosis proved to be an independent prognostic variable with respect to progression-free and cancer-specific survival. In conclusion, tumor necrosis showed significant impact on prognosis of colorectal cancer patients. Its presence is readily assessable in hematoxylin and eosin-stained sections and should therefore routinely be commented upon in the pathology report.

Mucinous differentiation in colorectal cancer – indicator of poor prognosis?

Langner C, Harbaum L, Pollheimer M J, Kornprat P, Lindtner R A, Schlemmer A, Vieth M & Rehak P 
(2012) Histopathology 60, 1060–1072

Keratin 7 expression in colorectal cancer--freak of nature or significant finding?

Harbaum L, Pollheimer M J, Kornprat P, Lindtner R A, Schlemmer A, Rehak P & Langner C 
(2011) Histopathology59, 225–234

Clinicopathological significance of prolactin receptor expression in colorectal carcinoma and corresponding metastases

The role of human prolactin and its receptor, the prolactin receptor, in colorectal cancer is largely unknown. Our study aimed to assess the prevalence of prolactin receptor expression, its association with clinicopathological variables, as well as its prognostic value, comparing results of primary tissues with those of corresponding metastases. In all, 373 primary colorectal cancer and 171 corresponding metastases were evaluated for prolactin receptor expression by immunohistochemistry using a tissue microarray technique. Immunoreactivity was semiquantitatively scored as either focal (<10% of tumor cells positive), moderate (10–50%), or extensive (>50%). Prolactin receptor expression was related to clinicopathological parameters as well as patient outcome. To substantiate our findings, prolactin receptor expression was additionally assessed in HT-29 and SW-480 colorectal cancer cell lines using western blot. Prolactin receptor expression was observed in 360 out of 373 (97%) primary tumors, with 21 (6%) cases showing focal, 55 (15%) moderate, and 284 (76%) extensive expression, respectively. Extensive prolactin receptor expression was significantly associated with tumor size (P=0.002) and grade (P<0.001) as well as histological subtype (P<0.001). Somer’s D coefficients for concordance of primary tumors with corresponding lymph node and distant metastases were D=0.719 (P<0.001) and D=0.535 (P=0.001), respectively. Extensive prolactin receptor expression was significantly associated with disease progression (P=0.03) and cancer-specific survival (P=0.04) in patients with high-grade cancers. In conclusion, prolactin receptor expression is common in colorectal cancer, with high concordance between primary tumors and corresponding metastases. In view of evolving targeted therapy concepts in colorectal cancer, widespread prolactin receptor expression may offer a therapeutic perspective in affected patients.

The Endothelial ADMA/NO Pathway in Hypoxia-Related Chronic Respiratory Diseases

Since its discovery, many adhere to the view that asymmetric dimethylarginine (ADMA), as an inhibitor of the synthesis of nitric oxide (NO), contributes to the pathogenesis of various diseases. Particularly, this is evident in disease of the cardiovascular system, in which endothelial dysfunction results in an imbalance between vasoconstriction and vasodilatation. Even if increased ADMA concentrations are closely related to an endothelial dysfunction, several studies pointed to a potential beneficial effect of ADMA, mainly in the context of angioproliferative disease such as cancer and fibrosis. Antiproliferative properties of ADMA independent of NO have been identified in this context. In particular, the regulation of ADMA by its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) is the object of many studies. DDAH is discussed as a promising therapeutic target for the indirect regulation of NO. In hypoxia-related chronic respiratory diseases, this controversy discussion of ADMA and DDAH is particularly evident and is therefore subject of this review.

Peritumoral eosinophils predict recurrence in colorectal cancer.

In colorectal cancer, the presence and extent of eosinophil granulocyte infiltration may render important prognostic information. However, it remains unclear whether an increasing number of eosinophils might simply be linked to the overall inflammatory cell reaction or represent a self-contained, antitumoral mechanism that needs to be documented and promoted therapeutically. Peri- and intratumoral eosinophil counts were retrospectively assessed in 381 primary colorectal cancers from randomly selected patients. Tumors were diagnosed in American Joint Committee on Cancer (AJCC)/Union Internationale Contre le Cancer (UICC) stage I in 21%, stage II in 32%, stage III in 33%, and stage IV in 14%. Presence and extent of eosinophils was related to various histopathological parameters as well as patients’ outcome. Overall, peri- and intratumoral eosinophils were observed in 86 and 75% cancer specimens. The peritumoral eosinophil count correlated strongly with the intratumoral eosinophil count (R=0.69; P<0.001) and with the intensity of the overall inflammatory cell reaction (R=0.318; P<0.001). Both increasing peri- and intratumoral eosinophil counts were significantly associated with lower T and N classification, better tumor differentiation, absence of vascular invasion, as well as improved progression-free and cancer-specific survival. However, only peritumoral eosinophils, but not intratumoral, were an independent prognosticator of favorable progression-free (hazard ratio 0.75; 95% confidence interval 0.58–0.98; P=0.04) and cancer-specific survival (hazard ratio 0.7; 95% confidence interval 0.52–0.93; P=0.01)—independent of the intensity of overall inflammatory cell reaction. This was also found for patients with AJCC/UICC stage II disease, wherein the presence of peritumoral eosinophils was significantly associated with favorable outcome. In conclusion, the number of peritumoral eosinophils had a significant favorable impact on prognosis of colorectal cancer patients independent of the overall tumor-associated inflammatory response. Evaluation of peritumoral eosinophils represents a promising readily assessable tool and should therefore routinely be commented on in the pathology report.

Fibrinogen plasma concentration is an independent marker of haemodynamic impairment in chronic thromboembolic pulmonary hypertension

Fibrinogen has a crucial role in both inflammation and coagulation, two processes pivotal for the pathogenesis of pulmonary hypertension. We therefore aimed to investigate whether fibrinogen plasma concentrations a) are elevated in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) and b) may serve as a novel biomarker for haemodynamic impairment. In a dual-centre, retrospective analysis including 112 patients with PAH (n = 52), CTEPH (n = 49) and a control cohort of patients with suspected PAH ruled out by right heart catheterisation (n = 11), we found fibrinogen plasma concentrations to be increased in patients with PAH (4.1 ± 1.4 g/l) and CTEPH (4.3 ± 1.2 g/l) compared to control patients (3.4 ± 0.5 g/l, p = 0.0035 and p = 0.0004, respectively). In CTEPH patients but not in PAH patients fibrinogen was associated with haemodynamics (p < 0.036) and functional parameters (p < 0.041). Furthermore, fibrinogen was linked to disease severity (WHO functional class, p = 0.017) and independently predicted haemodynamic impairment specifically in CTEPH (p < 0.016). Therefore, fibrinogen seems to represent an important factor in CTEPH pathophysiology and may have the potential to guide clinical diagnosis and therapy.

N-Terminal Pro-Brain Natriuretic Peptide Is a Useful Prognostic Marker in Patients with Pre-Capillary Pulmonary Hypertension and Renal Insufficiency

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a routinely used prognostic parameter in patients with pre-capillary pulmonary hypertension (PH). As it accumulates in the presence of impaired renal function, the clinical utility of NT-proBNP in PH patients with concomitant renal insufficiency remains unclear. In a retrospective approach, patients with pre-capillary PH (group I or IV) and concomitant renal insufficiency at time of right heart catheterization (glomerular filtration rate (GFR) ≤60 ml/min/1.73 m2) were identified out of all prevalent pre-capillary PH patients treated at a single center. Forty patients with renal insufficiency (25.8%) were identified and matched regarding hemodynamic parameters with a control group of 56 PH patients with normal renal function (GFR >60 ml/min/1.73 m2). Correlations of NT-proBNP levels with hemodynamic and prognostic parameters (time to clinical worsening and overall survival) were assessed. Overall, GFR correlated inversely with NT-proBNP and had the strongest influence on NT-proBNP levels in a stepwise multiple linear regression model including hemodynamic parameters and age (r2 = 0.167). PH patients with renal insufficiency had significant higher levels of NT-proBNP (median: 1935 ng/l vs. 573 ng/l, p = 0.001). Nevertheless, NT-proBNP correlated with invasive hemodynamic parameters in these patients. Using higher cut-off values than in patients with preserved renal function, NT-proBNP levels were significantly associated with time to clinical worsening (>1660 ng/l, p = 0.001) and survival (>2212 ng/l, p = 0.047) in patients with renal insufficiency. Multivariate Cox’s proportional hazards analysis including established prognostic parameters, age and GFR confirmed NT-proBNP as an independent risk factor for clinical worsening in PH patients with renal insufficiency (hazard ratio 4.8, p = 0.007). Thus, in a retrospective analysis we showed that NT-proBNP levels correlated with hemodynamic parameters and outcome regardless of renal function. By using higher cut-off values, NT-proBNP seems to represent a valid clinical marker even in PH patients with renal insufficiency.

Tumor size, tumor location, and antitumor inflammatory response are associated with lymph node size in colorectal cancer patients

Lymph node size affects lymph node retrieval in surgical specimen and is used as criterion for pre-operative radiological estimation of metastatic disease. However, factors determining lymph node size remain to be established. Therefore, the association between lymph node size and presence of metastatic cancer deposits as well as different primary tumor characteristics was analyzed in a prospective cross-sectional study. Visible and palpable nodes were harvested, and conventional histology, immunohistochemistry, and molecular analysis were performed. The study cohort comprised 148 patients (median age 69 years, range 36–92). Lymph node dissection rendered 4167 nodes. Mean lymph node count was 28 (median 26, range 9–67). Metastatic disease was detected in 320 (8%) nodes and was associated with lymph node size (P<0.001). Positive nodes measuring ≤2 mm caused upstaging within the N category in one third of cases, but did not identify patients as node-positive as all patients also had positive larger nodes. Large tumor size (P=0.001), right tumor location (P<0.001), and deep tumor penetration (P=0.024) were all independently associated with lymph node size, whereas high lymphocytic antitumor reaction just missed statistical significance (P=0.053) in multivariable analysis. Microsatellite instability had no influence on lymph node size when analysis was restricted to right-sided tumors. In conclusion, analysis of small lymph nodes may lead to upstaging within the N category, but they do not identify a patient as node-positive and do therefore not influence clinical decision-making in the adjuvant setting. The majority of enlarged lymph nodes, including those measuring >1 cm, are not involved by cancer. Different tumor characteristics, such as large primary tumor size, right tumor location, and deep tumor penetration are independently associated with lymph node size and need to be considered when interpreting enlarged nodes detected by radiological imaging.

Tumour budding with and without admixed inflammation: two different sides of the same coin?

Background:Tumour budding is an adverse prognostic indicator in colorectal cancer (CRC). Marked overall peritumoural inflammation has been associated with favourable outcome and may lead to the presence of isolated cancer cells due to destruction of invading cancer cell islets.Methods:We assessed the prognostic significance of tumour budding and peritumoural inflammation in a cohort of 381 patients with CRC applying univariate and multivariate analyses.Results:Patients with high-grade budding and marked inflammation had a significantly better outcome compared with patients with high-grade budding and only mild inflammation. Outcome in these cases, however, was still worse compared with cases with low-grade budding, in which the extent of peritumoural inflammation had no further prognostic effect.Conclusions:Tumour budding proved to be a powerful prognostic variable in patients with CRC. Scattering of invading cancer cell islets by marked overall peritumoural inflammation seems to have a minor role.