We postulated that lymph node (LN) harvest and LN size are influenced by immunologic effects.
To investigate this hypothesis, we performed a retrospective analysis of 170 node-negative colon cancer ...cases to evaluate the density of intratumoral T lymphocytes (ITLs). CD3- and CD8-positive T cells were counted using a digital system.
The ITL density was significantly increased in cases with sufficient LN harvest and high numbers of LNs larger than 5 mm (LN5). High ITL numbers were associated with improved cancer-specific survival. The analysis of the immune score revealed a significantly different cancer-specific outcome (P = .024), with no cancer-related death in the group with the highest score. The immune score and tumor budding were independently prognostic.
ITL density is independently prognostic and associated with LN harvest and LN size. The immune response is very likely the true explanation for the known prognostic effect of the LN harvest in colon cancer.
To date, the clinical value of lymph node size in colon cancer has been investigated only in a few studies. Only in radiological diagnosis is lymph node size routinely recognized, and nodes ≥10 mm in ...diameter are considered pathologic. However, the few studies regarding this topic suggest that lymph node size is not a reliable indicator of metastatic disease. Moreover, we hypothesized that increasing lymph node size is associated with favorable outcome. By performing a morphometric study, we investigated the clinical significance of lymph node size in colon cancer in terms of metastatic disease and prognosis. A cohort of 237 cases with excellent lymph node harvest (mean lymph node count: 33±17) was used. The size distribution in node-positive and -negative cases was almost identical. In all, 151 out of the 305 metastases detected (49.5%) were found in lymph nodes with diameters ≤5 mm. Only 25% of lymph nodes >10 mm showed metastases. Minute lymph nodes ≤1 mm were involved only very rarely (2 of 81 cases). In 67% of the cases, the largest positive lymph node was <10 mm. The prognostic relevance of lymph node size was investigated in a subset of 115 stage I/II cases. The occurrence of ≥7 lymph nodes that were >5 mm in diameter was significantly associated with better overall survival. Our data show that lymph node size is not a suitable factor for preoperative lymph node staging. Minute lymph nodes have virtually no role in correct histopathological lymph node staging. Finally, large lymph nodes in stage I/II disease might indicate a favorable outcome.
The outcome of prostate cancer is highly unpredictable. To assess the dynamics of systemic disease and to identify patients at high risk for early relapse we followed the fate of disseminated tumor ...cells in bone marrow for up to 10 years and genetically analyzed such cells isolated at various stages of disease.
Nine hundred bone marrow aspirates from 384 patients were stained using the monoclonal antibody A45-B/B3 directed against cytokeratins 8, 18, and 19. Log-rank statistics and Cox regression analysis were applied to determine the prognostic impact of positive cells detected before surgery (244 patients) and postoperatively (214 patients). Samples from primary tumors (n = 55) and single disseminated tumor cells (n = 100) were analyzed by comparative genomic hybridization.
Detection of cytokeratin-positive cells before surgery was the strongest independent risk factor for metastasis within 48 months (P < .001; relative risk RR, 5.5; 95% CI, 2.4 to 12.9). In contrast, cytokeratin-positive cells detected 6 months to 10 years after radical prostatectomy were consistently present in bone marrow with a prevalence of approximately 20% but had no influence on disease outcome. Characteristic genotypes of cytokeratin-positive cells were selected at manifestation of metastasis.
Cytokeratin-positive cells in the bone marrow of prostate cancer patients are only prognostically relevant when detected before surgery. Because we could not identify significant genetic differences between pre- and postoperatively isolated tumor cells before manifestation of metastasis, we postulate the existence of perioperative stimuli that activate disseminated tumor cells. Patients with cytokeratin-positive cells in bone marrow before surgery may therefore benefit from adjuvant therapies.
According to the present view, metastasis marks the end in a sequence of genomic changes underlying the progression of an epithelial cell to a lethal cancer. Here, we aimed to find out at what stage ...of tumor development transformed cells leave the primary tumor and whether a defined genotype corresponds to metastatic disease. To this end, we isolated single disseminated cancer cells from bone marrow of breast cancer patients and performed single-cell comparative genomic hybridization. We analyzed disseminated tumor cells from patients after curative resection of the primary tumor (stage M0), as presumptive progenitors of manifest metastasis, and from patients with manifest metastasis (stage M1). Their genomic data were compared with those from microdissected areas of matched primary tumors. Disseminated cells from M0-stage patients displayed significantly fewer chromosomal aberrations than primary tumors or cells from M1-stage patients (P < 0.008 and P < 0.0001, respectively), and their aberrations appeared to be randomly generated. In contrast, primary tumors and M1 cells harbored different and characteristic chromosomal imbalances. Moreover, applying machine-learning methods for the classification of the genotypes, we could correctly identify the presence or absence of metastatic disease in a patient on the basis of a single-cell genome. We suggest that in breast cancer, tumor cells may disseminate in a far less progressed genomic state than previously thought, and that they acquire genomic aberrations typical of metastatic cells thereafter. Thus, our data challenge the widely held view that the precursors of metastasis are derived from the most advanced clone within the primary tumor.
Lymph node staging is of paramount importance for prognosis estimation and therapy stratification in colorectal cancer. A high number of harvested lymph nodes is associated with an improved outcome. ...Methylene blue-assisted lymph node dissection effectively improves the lymph node harvest and ensures sufficient staging. Now, the effect on node positivity rate and stage-related outcome was investigated. The study cohort with advanced lymph node dissection consisted of 669 colorectal cancer cases of all stages, which were collected between 2007 and 2012. A historical collection of 663 cases investigated with conventional techniques between 2002 and 2004 served as control. Lymph node harvest was dramatically improved in the study group with mean lymph node numbers of 34 ± 17 vs 13 ± 5 (P<0.001) and sufficient staging rates of 98% vs 62% (P<0.001). However, neither the rate of nodal positive cases (37% vs 37%; P = 0.98) nor the rate of N2 cases differed between the two groups (14% vs 13%; P = 0.80). Furthermore, no differences were found concerning the outcome in both groups. The advanced lymph node dissection technique guarantees adequate histopathological lymph node staging in virtually all cases of colorectal cancer and is therefore extremely helpful. The hypothesis that it also provides a higher sensitivity in detecting metastases, however, could be not proved.
Fat-containing lesions of the thyroid are rare, encompassing several clinical-pathological conditions such adenolipomas, thyrolipomatosis and lipomotous tissue in case of amyloidosis. Furthermore, ...cases of papillary thyroid carcinoma have been identified in association with thyrolipomatosis. We report a case of 51 years old man referred to surgery for a multinodular goiter, showing multiple cystic and hemorrhagic nodules of up to 3 cm. One of these lesions showed features of papillary hyperplasia with focal cytological atypia and mature fat. Here, we describe and discuss the histological and immunophenotypical features of this rare lesion.
Pericolonic tumor deposits (PTDs) are associated with an adverse outcome in colorectal cancer. According to the International Union Against Cancer they are classified as N1 or V1/V2 depending on ...their shape. This recommendation, however, is not well supported by the literature. To elucidate the origin of PTDs, we performed a histomorphologic study of 69 PTDs, which were found in 7 of 21 colorectal specimens using the whole-mount step-section technique. Depending on the origin, the nodules were classified as venous invasions, lymphatic invasions, nerve sheath infiltrations, free PTDs, and continuous growth in 18 (26%), 3 (4%), 6 (9%), 34 (49%), and 8 (12%) of 69 PTDs, respectively. Polycyclic and oval-round shapes were identified in all categories. Continuous growth was found only within the inner third of the adhering fat, whereas the other morphologic features were found in all regions. The data of this study do not support PTD classification on the basis of their shape.
Tumor budding describes the presence of single tumor cells or small tumor cell clusters at the invasion front of carcinomas. It is currently thought to be the result of epithelial-mesenchymal ...transformation. Tumor budding can be appreciated histologically during routine evaluation of malignant polyps or surgical specimens of malignant tumors. Many studies have been published assessing cancers in all locations from the esophagus to the rectum, almost always reporting similar results. This seems especially remarkable as a generally accepted definition of how budding must be evaluated is still lacking. Regardless of the location, tumor budding generally is associated with nodal metastases and aggressive behavior, and it is mostly independent from other adverse factors. While the prognostic value of tumor budding is evident, especially in stage II colorectal cancers, it still has no therapeutic implications. This is owing to the heterogeneity of the performed studies and the lack of oncological studies, which are urgently needed.
Adequate lymph node assessment in colorectal cancer is crucial for prognosis estimation and further therapy stratification. However, there is still an ongoing debate on required minimum lymph node ...numbers and the necessity of advanced techniques such as immunohistochemistry or PCR. It has been proven in several studies that lymph node harvest is often inadequate under routine analysis. Lymph nodes smaller than 5 mm are especially concerning as they can carry the majority of metastases. These small, but affected lymph nodes may escape detection in routine analysis. Therefore, fat-clearing protocols and sentinel techniques have been developed to improve accuracy of lymph node staging. We describe a novel and simple method of ex vivo methylene blue injection into the superior rectal artery of rectal cancer specimens, which highlights lymph nodes and makes them easy to detect during manual dissection. Initially, this method was developed for proving accuracy of total mesorectal excision. We performed a retrospective study comparing lymph node recovery of 12 methylene blue stained and an equal number of unstained cases. Lymph node recovery differed significantly with average lymph node numbers of 27+/-7 and 14+/-4 (P<0.001) for the methylene blue and the unstained group, respectively. The largest difference was found in size groups between 1 and 4 mm causing a shift in size distribution toward smaller nodes. Metastases were confirmed in 21 and 19 lymph nodes occurring in five and four cases, respectively. Hence, we conclude that methylene blue injection technique improves accuracy of lymph node staging by heightening the lymph node harvest in rectal resections. In our experience, it is a very simple time and cost effective method that can be easily established under routine circumstances.
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