Early invasive colorectal carcinomas metastatic to the lymph node with attention to their nonpolypoid development

Clinicopathologic study of six cases of early invasive colorectal carcinoma metastatic to lymph node was performed in order to elucidate possible characteristics relating to the risk of metastasis, with particular attention to the growth pattern of the primary tumor. All of the cases had at least one of the well-known risk factors for lymph node metastasis, including moderately or poorly differentiated histologic characteristics, considerable degree of submucosal invasion, and lymphatic invasion. An interesting finding of the present study was the identification of a nonpolypoid growth pattern with no concomitant adenomatous tissue, which seemed to be different from that of "malignant polyps" of previously reported cases showing adenoma-carcinoma sequence. This unique growth feature was found in all of the cases. Therefore, in addition to the accepted risk factors, nonpolypoid growth pattern and absence of adenomatous component may be risk factors predictive of nodal metastasis in patients with early invasive colorectal carcinoma.     

Establishment of a highly differentiated thyroid cancer cell line of Hürthle cell origin

Hürthle cell carcinomas (HCC) of the thyroid are a variant of follicular thyroid tumors. In contrast to follicular thyroid carcinoma, HCC rarely take up radioiodine and frequently metastasize to the lymph nodes. Histologically they are indistinguishable from Hürthle cell adenomas except for evidence of invasion and metastasis. How these carcinomas develop and why they behave differently than other follicular tumors is not known. Although some differentiated thyroid cancer cell lines exist, none are from Hürthle cell tumors. We have established a well-differentiated thyroid cancer cell line from a metastasis of a HCC, designated XTC.UC1. In vitro, XTC cells display epitheloid morphology, grow with a population doubling time of 4.3 +/- 0.3 days, migrate, and invade through reconstituted basement membranes. The cells are immunoreactive for and release thyroglobulin, respond to thyrotropin (TSH) with increase of intracellular cyclic adenosine monophosphate (cAMP), proliferation, and invasion of reconstituted basement membrane, thus exhibiting characteristics of well-differentiated thyroid carcinoma. In vivo, xenografted XTC cells grow with a doubling time of 9.8 +/- 0.8 days. Tumors spontaneously metastasize to the lymph nodes and less frequently to the lungs and the liver. The cells retained their differentiated function in vivo as assessed by human thyroglobulin (hTG) secretion and immunohistochemistry. This is a first report of the establishment of a unique, highly differentiated thyroid carcinoma cell line derived from an HCC. Based on the ability to invade through reconstituted basement membrane in vitro and the potential to metastasize in vivo, this cell line may provide a unique model to study invasion and metastazation of well-differentiated thyroid cancer.     

Endoscopic treatment of submucosal invasive colorectal carcinoma with special reference to risk factors for lymph node metastasis

A clinicopathological analysis of the risk factors for lymph node metastasis was performed in 177 patients with submucosal invasive colorectal carcinoma (CRC). The submucosal deepest invasive portion was histologically subclassified as well (W), moderately (M), or poorly (Por) differentiated. M type was further subdivided into moderately-well (Mw) and moderately-poorly (Mp) differentiated. The pattern of tumor growth was classified as polypoid growth (PG) and non-polypoid growth (NPG). Lymph node metastasis was detected in 21 (12%) of the 177 patients. Macroscopically, type IIc and IIa + IIc lesions showed a significantly higher incidence of lymph node metastasis (44% and 30%) than type IIa and I (4% and 8%). Regarding the histologic subclassification, Por and Mp lesions showed a significantly higher incidence of lymph node metastasis (67% and 37%) than W and Mw lesions (4% and 14%). NPG tumors showed a significantly higher incidence of lymph node metastasis (29%) than PG tumors (7%). The depth of submucosal invasion and lymphatic invasion (ly) were also significantly correlated with the incidence of lymph node metastasis (submucosal scanty (sm-s) invasion 4%, massive invasion 20%; ly(+) 23%, ly(-) 5%). None of the lesions with both sm-s invasion and of W or Mw type showed lymph node metastasis. These results indicate that submucosal invasive CRC with both sm-s invasion and of W or Mw type, which shows no ly, is the appropriate indication for endoscopic curative treatment.     

MUC-1 expression as a predictor of the curative endoscopic treatment of submucosally invasive colorectal carcinoma

PURPOSE: This study was undertaken to clarify the clinical significance of MUC-1 expression in the endoscopic treatment of colorectal carcinoma with submucosal invasion. METHODS: One hundred eighty-four colorectal carcinomas with submucosal invasion were examined. The depth of submucosal invasion was classified as scanty or massive. The histologic subclassification at the deepest invasive portion was defined as well-differentiated, moderately well-differentiated, moderately to poorly differentiated, poorly differentiated, or mucinous adenocarcinoma. MUC-1 expression was examined immunohistochemically at the deepest invasive portion. In addition, the Ki67 labeling index was also examined immunohistochemically. RESULTS: Lymph node metastases were detected in 28 (15.2 percent) of 184 lesions. Lesions with both scanty submucosal invasion and well-differentiated or moderately well-differentiated adenocarcinomas had no lymph node metastases. MUC-1 expression was detected in 88 (47.8 percent) of 184 lesions and correlated significantly with the presence of lymph node metastases. The Ki67 labeling index also correlated significantly with lymph node metastases. Furthermore, lesions with both MUC-1-negative and low Ki67 labeling index showed no lymph node metastases, even in lesions with massive submucosal invasion. Multivariate analysis indicated that MUC-1 expression was one of the most important risk factors for lymph node metastases and histologic grade among the clinicopathologic factors usually examined. CONCLUSION: MUC-1 expression is one of the accurate predictors of the presence of lymph node metastases among the clinicopathologic factors commonly used. Combined analysis of MUC-1 expression and Ki67 labeling index may be a useful indicator of lymph node metastases and may broaden the indications for the curative endoscopic treatment of carcinoma with massive submucosal invasion.     

The expression of invasive behavior of differentiated squamous carcinoma cell line evaluated by an in vitro invasion model

In order to elucidate the factors contributory to the expression of invasiveness of oral squamous cell carcinoma, we conducted biochemical and morphological comparisons of well differentiated squamous carcinoma cell line OSC-19 (oral squamous cell carcinoma) and undifferentiated carcinoma cell line KB, both cultured on 3T3 cell-embedded collagen gel (in vitro invasion model). OSC-19 cells invaded 3T3 cell-embedded collagen gel, while KB cells and OSC-19 cells on 3T3 cell-free gel matrix were less invasive. Cultured OSC-19 cells were characterized by lower proliferating activity, lower secretion of laminin and higher secretion of fibronectin than those of KB cells. Although the basement membrane with deposition of laminin and type IV collagen was formed, it was discontinuous at the invasion front. Gelatin zymography and western blotting showed matrix metalloproteinases (MMP), i.e., 72 kDa gelatinase (MMP-2) and 92 kDa gelatinase (MMP-9). Gelatinolytic activity was assayed, and was higher in OSC-19 cells than in KB cells or OSC-19 cells of the 3T3 cell-free model. By immunohistochemical analysis, MMP-2-positive cells were found scattered in both cell lines without any preferential localization, and the positivity for MMP-9 was localized in the invasion front of OSC-19 cells. These results strongly suggest that the invasiveness of squamous cell carcinoma is well correlated with cell-matrix adhesion by fibronectin and with focal elaboration of metalloproteinases, especially MMP-9, which play a major role in degrading the extracellular matrix components.     

Dural puncture and activated protein C resistance: risk factors for cerebral venous sinus thrombosis

BACKGROUND: The biologic aggressiveness of squamous cell carcinoma of the oral cavity is reflected in its ability to metastasize to regional cervical lymph nodes. Patients with clinically negative cervical lymph nodes are believed to have a good prognosis; however, the prognosis of patients with lymph node metastasis occurring after excision or radiotherapy of the primary tumor is poor. METHODS: Univariate and multivariate analyses for occult lymph node metastasis (ONM) in 172 patients with clinically negative cervical lymph nodes were performed by the authors to elucidate the clinical and histologic tumor risk factors to enhance their ability to predict ONM. A multivariate Cox proportional hazards model and Hayashi's quantification theory type II were used to analyze prognostic factors and to determine the probability of ONM. RESULTS: Using Cox's proportional regression model, the factors linked to cancer specific survival were selected: tumor differentiation (P = 0.0330), mode of carcinoma invasion (P = 0.0175), and ONM (P = 0.0433). Pathologically identified metastatic lymph nodes were found in 21.5% of the cases studied (37 of 172 cases). The 5-year cancer specific survival was 94.0% for patients without lymph node metastasis, and 51.0% for patients with ONM (P < 0.0001, log rank test). The most significant predictors for ONM of each of the clinical and histologic factors, in descending order, were: mode of carcinoma invasion, intensity of lymphocytic infiltration, degree of differentiation, number of mitotic figures, and type of growth by means of Hayashi's quantification theory type II. The presence or absence of ONM in 147 of 172 patients (85.5%) was correctly predicted by the score at the point of intersection of the two curves, which was -0.03. Further investigation revealed that 28 of 32 new cases were differentiated accurately by means of this diagnostic system. CONCLUSIONS: The results of the current study suggest that this method of analysis can establish a reliable predictor of ONM, thereby facilitating correct choices for surgical procedures to enhance the survival rates of patients with clinically negative cervical lymph nodes.     

Radiofrequency capacitive hyperthermia for unresectable hepatic cancers

To determine the involvement of proteinases with hydrolytic activity towards extracellular matrix and basement membrane, in invasion and metastasis of tumour cells, the expression of cathepsin D, an aspartic proteinase, and cathepsin B, a cysteine proteinase, was studied. Formalin-fixed paraffin-embedded specimens from 13 patients who had squamous cell carcinomas (SCC) with local recurrence, skin and/or lymph node metastasis were examined. Cathepsin D stained intensely as a granular pattern (mature enzyme) in tumour cells of 69% of primary lesions and all the secondary lesions of the patients with SCC. Cathepsin B stained more intensely in SCC cells of all of the primary and secondary lesions than in normal epidermis; staining patterns were almost diffuse (procathepsin B). Granular and diffuse patterns (mature enzyme of cathepsin D and procathepsin B, respectively) appeared in the outer and inner parts of tumour islands, respectively. The presence of the active mature form of cathepsin D and procathepsin B in metastatic skin lesions of SCC was confirmed by Western blotting analysis. The presence and localization of the active mature form of cathepsin D suggests that activated cathepsin D may be involved in the invasion and metastasis of SCC.     

Gastric carcinoma resected 95 months after being diagnosed: report of a case

It is usually assumed that patients with gastric carcinoma will almost certainly die within 5 years if they do not receive treatment. We report herein a rare case of curative gastrectomy being performed 95 months after gastric carcinoma was diagnosed. A 37-year-old Japanese man had an upper gastrointestinal endoscopy with biopsy which revealed moderately differentiated adenocarcinoma of the stomach. This was diagnosed as type IIc early gastric carcinoma with ulceration but he refused surgery. At 45 years of age, 95 months later, he presented to our hospital with melena, at which time lesions in an identical location had enlarged to Borrmann type 3 advanced gastric carcinoma. Thus, a total gastrectomy with regional lymph node dissection was performed. Although there was no liver or peritoneal metastasis, the regional lymph nodes were involved; however, the patient recovered well and is still alive without any further recurrence roughly 4 years postoperatively. The natural history of gastric carcinoma and the malignant cycle are discussed following the presentation of this case.     

Lupus vulgaris complicated by metastatic squamous cell carcinoma

A 47-year-old Bedouin man presented with an ulcerated nodule of several months' duration on the nape of the neck. The nodule developed on an asymptomatic, slowly growing plaque which appeared during childhood. Physical examination revealed two erythematous plaques covering the posterior and right lateral aspects of the neck. The border of the plaques was soft, circinate, with a reddish-brown color, while the center was slightly erythematous and atrophic. An ulcerated nodule measuring 2 cm was seen on one of the plaques. Physical examination was unremarkable with no lymphadenopathy. Laboratory tests, including complete blood cell count, erythrocyte sedimentation rate (ESR), and routine chemistry tests, were all within normal limits. Chest X-ray showed a small calcified perihilar lymph node. The Mantoux test was positive with erythema and induration of 15 mm after 48 h. Biopsy from a plaque showed extensive diffuse granulomatous infiltration throughout the dermis with epithelioid and Langhans giant cells surrounded by mononuclear inflammatory cells. No caseation necrosis was present. Ziehl-Neelsen, periodic acid-Schiff (PAS), and Giemsa stains were negative. Polymerase chain reaction (PCR) for the detection of Mycobacterium tuberculosis and atypical mycobacteria from a skin sample was also negative. Fresh tissue cultures yielded M. tuberculosis after 6 weeks. A biopsy specimen from the ulcerated nodule demonstrated islands of atypical malignant squamous cells invading the dermis, which were compatible with moderately differentiated squamous cell carcinoma (SCC). The ulcerated nodule was completely excised, and treatment for tuberculosis was initiated with a combination of isoniazid, rifampicin, and pyrazinamide. Within 3 months of therapy, the patient's lesions resolved, leaving only slightly atrophic hypopigmented scars. A month after the treatment's initiation, an enlarged cervical lymph node was noted showing metastatic SCC on histologic examination. The patient underwent neck dissection and radiation therapy without evidence of any further metastases.     

NDPK/nm23 expression and its correlation with lymph node metastasis in human lung cancer

Using labelled streptavidin-biotin (LSAB) method, we examined the expression of nucleoside diphosphate kinase(NDPK), the product of metastasis suppressor gene nm23, in human lung cancer. Of 88 patients tested, 48 (54.5%) showed positive staining. The positive staining rate was higher in adenocarcinoma (28/42, 66.7%) than in squamous cell carcinoma (20/46, 43.5%; P < 0.05). Higher incidence of positive staining was also found in squamous cell carcinoma without hilar or mediastinal lymph node metastasis (16/27, 59.3%) than in that with hilar or mediastinal lymph node involvement (4/19, 21.1%; P < 0.05). NDPK/nm23 was equally expressed in adenocarcinoma irrespective of lymph node status. In both cell types of carcinoma, expression of NDPK/nm23 was not correlated with tumor cell differentiation, nor was it correlated with the P-TNM staging. Our results suggest that NDPK/nm23 may play different roles in the pathogenesis and metastasis of human pulmonary squamous cell carcinoma and adenocarcinoma. Its expression levels are inversely correlated with lymph node metastasis in squamous cell carcinoma.     

p53 expression in skin carcinogenesis and its relationship to cell proliferation and tumour growth

The immunoreactivity of p53 protein was studied in relation to tumour development, histopathological characteristics, cell proliferation, and basement membrane organisation following the induction of skin carcinogenesis in tumour-sensitive and -resistant mouse strains by ultraviolet (UV) irradiation or 7,12-dimethylbenz(a)anthracene (DMBA). In non-neoplastic skin exposed to UV irradiation or DMBA, p53 immunoreactivity was observed in nearly 50% of the basal layer cells. These cells were morphologically and histochemically indistinguishable from the p53-negative cells, occurring similarly in the tumour-producing and the tumour-negative mouse strains and regardless of subsequent tumour formation. In induced epidermal hyperplasia and in benign tumours, p53-positive and proliferating cells constituted 40-50% of all cells in the basal layer, while superficial cells were p53 negative. In dysplastic epidermis, p53-positive cells and proliferating cells were seen in all cell layers. In the case of squamous cell carcinomas, p53-positive proliferating cells in differentiated neoplasms were localised close to the basement membrane and, more frequently, in border areas showing invasion and basement membrane destruction. In horn cysts, centrally located cells were non-proliferating and p53 negative. In moderately differentiated neoplasms, proliferating cells were located closer to the basement membrane, while p53-positive cells were distributed diffusely in the neoplasm. In poorly differentiated neoplasms, p53-positive cells were more common than proliferating cells and were arranged in a diffuse pattern. The results showed that the number and location of p53-positive cells depended upon histology, with a close relationship to tumour type and degree of malignancy, but not on the mode of induction, nor on the animal strain or the relationship to subsequent tumour formation.     

Multiple melanoma in xeroderma pigmentosum

Xeroderma pigmentosum comprises a heterogeneous group of autosomal recessive hereditary diseases, which are characterized by a number of clinical characteristics and an abnormal DNA repair mechanism. Patients affected show a high frequency of mucocutaneous malignant tumors, especially squamous cell carcinomas and basal cell carcinomas. We report on a 65-year-old patient who successively developed a total of 15 malignant melanomas, 1 squamous cell carcinoma and 1 lymph node metastasis of a malignant melanoma. The clinical diagnosis of xeroderma pigmentosum was confirmed by the complementation analysis, which defined our patient as xeroderma pigmentosum of the complementation group D.     

alpha3beta1 Integrin is required for normal development of the epidermal basement membrane

Integrins alpha3beta1 and alpha6beta4 are abundant receptors on keratinocytes for laminin-5, a major component of the basement membrane between the epidermis and the dermis in skin. These integrins are recruited to distinct adhesion structures within keratinocytes; alpha6beta4 is present in hemidesmosomes, while alpha3beta1 is recruited into focal contacts in cultured cells. To determine whether differences in localization reflect distinct functions of these integrins in the epidermis, we studied skin development in alpha3beta1-deficient mice. Examination of extracellular matrix by immunofluorescence microscopy and electron microscopy revealed regions of disorganized basement membrane in alpha3beta1-deficient skin. Disorganized matrix was first detected by day 15.5 of embryonic development and became progressively more extensive as development proceeded. In neonatal skin, matrix disorganization was frequently accompanied by blistering at the dermal-epidermal junction. Laminin-5 and other matrix proteins remained associated with both the dermal and epidermal sides of blisters, suggesting rupture of the basement membrane itself, rather than detachment of the epidermis from the basement membrane as occurs in some blistering disorders such as epidermolysis bullosa. Consistent with this notion, primary keratinocytes from alpha3beta1-deficient skin adhered to laminin-5 through alpha6 integrins. However, alpha3beta1-deficient keratinocytes spread poorly compared with wild-type cells on laminin-5, demonstrating a postattachment requirement for alpha3beta1 and indicating distinct roles for alpha3beta1 and alpha6beta4. Our findings support a novel role for alpha3beta1 in establishment and/or maintenance of basement membrane integrity, while alpha6beta4 is required for stable adhesion of the epidermis to the basement membrane through hemidesmosomes.     

Para-aortic lymph node metastasis in carcinoma of the distal bile duct

BACKGROUND/AIMS: Lymph node dissection plays an important role in radical surgery for pancreaticoduodenal carcinomas. The aim of this study was to identify the critical areas of lymph node dissection in carcinoma of the distal bile duct. METHODOLOGY: Between January 1995 and December 1996, 20 consecutive patients with distal bile duct cancer underwent pancreaticoduodenectomy with extended lymph node dissection (including the para-aortic nodes). Histopathologic findings were examined with special reference to lymph node metastasis. RESULTS: Histological evidence of lymph node metastasis was found in 11 patients (55%). The areas with frequent metastases were the posterior pancreaticoduodenal lymph nodes (35%), and the nodes around the hepatoduodenal ligament (35%) and around the common hepatic artery (30%). Para-aortic lymph node involvement was identified in 5 patients (25%). Most of these existed in the inter-aorticocaval space. Pancreatic parenchymal invasion was present in 10 patients. Half of the patients with pancreatic invasion had para-aortic nodal involvement. Para-aortic lymph node metastasis was significantly associated with pancreatic parenchymal invasion (p<0.05). CONCLUSIONS: In carcinoma of the distal bile duct with pancreatic parenchymal invasion, extended lymph node dissection (including para-aortic nodes) should be undertaken because of the relatively high incidence of metastasis.     

Establishment and characterization of a novel human myoepithelial cell line and matrix-producing xenograft from a parotid basal cell adenocarcinoma

Myoepithelial cells exert important paracrine effects on epithelial morphogenesis and mitogenesis through direct cell-cell interactions and through synthesis of a basement membrane extracellular matrix. To study these effects further, this study established the first immortalized human myoepithelial cell line, HMS-1, and transplantable xenograft, HMS-X, from the rare parotid basal cell adenocarcinoma. The cell line exhibited a fully differentiated myoepithelial phenotype and the xenograft exhibited the rare property of accumulating an abundant extracellular matrix composed of both basement membrane and nonbasement membrane components with the latter predominating. With HMS-1 as a feeder layer, dramatic and specific induction of epithelial morphogenesis (spheroid formation) occurred with selected normal epithelial and primary carcinoma target cells. HMS-1 and HMS-X provide distinct advantages over the conventional murine matrices in existence. They will be invaluable in future studies of human tumor-myoepithelial and matrix interactions important for tumor cell growth, invasion, and metastasis.     

Prediction of axillary lymph node involvement of women with invasive breast carcinoma: a multivariate analysis

BACKGROUND: The increasing use of systemic therapy for women with lymph node negative breast carcinoma and earlier stage of disease at mammographic detection raises questions regarding the need for routine axillary lymph node dissection. Predictive modeling for lymph node involvement may be one way to reduce the need for axillary lymph node dissection and its morbidity. METHODS: A multivariate analysis of 12 factors predictive of axillary lymph node involvement was conducted in a population-based cohort of 4312 women with invasive breast carcinoma diagnosed between January 1, 1993 and December 31, 1996. RESULTS: Clinical palpability, lymphatic or vascular invasion, lesion size, margin status, histology, and patient age were independent predictors of axillary lymph node involvement. The model correctly identified lymph node status in 76.6% of cases. Model accuracy and fit were equally high when applied to randomly selected halves of the study subjects. Approximately 32.0% of the patients in the study sample (1363/4312) were identified as having an extremely high (91%; n = 1102) or low (10%; n = 261) risk of lymph node involvement. In a second analysis, a clinically useable, three-variable model identified a very low risk group of patients (n = 147) with a 4.8% risk of lymph node metastasis and a high risk group of patients (n = 1008) with a 74.2% risk of lymph node metastasis. Greater than 90% of subjects in the high risk group received adjuvant systemic therapy even if they were lymph node negative pathologically. CONCLUSIONS: A clinically useable, three-variable model employing tumor and lymph node palpability, size, and lymphatic or vascular invasion can identify women with invasive breast carcinoma in whom axillary lymph node dissection is very unlikely to alter recommendations regarding adjuvant systemic therapy.     

A case of advance colon cancer responding to sequential methotrexate and 5-fluorouracil therapy

A 60-year-old female was diagnosed by X-ray examination and endoscopy as ascending colon cancer. Ultrasonography and computed tomography revealed two metastatic tumors in the liver. Abdominal surgery revealed peritoneal disseminations, massive lymph node metastasis and direct invasion of the transverse colon and ileum. From pathological examination the diagnosis was moderately differentiated adenocarcinoma. After right hemi-colectomy, sequential methotrexate and 5-fluorouracil therapy as well as oral administration of UFT, liver metastasis disappeared and no sign of ascites was found in this case. Complete response time was over 8 months. There have been no severe complications.     

Variations in nucleolar organizer regions during 9-10 dimethyl1-2 benzanthracene induced tongue carcinogenesis in rats

BACKGROUND: Many studies have reported the increased expression of epidermal growth factor receptor (EGFR) in various human malignancies and its association with the biologic behavior of the tumors. METHODS: We performed an immunohistochemical analysis of the EGFR in 217 cases of human esophageal squamous cell carcinoma, 161 lymph node metastases and 23 foci of squamous dysplasias. The findings were correlated with clinicopathologic features, including the clinical outcome. Southern blot analysis was performed in 42 cases for the detection of DNA amplification of the EGFR gene and subsequently was correlated with EGFR immunoreactivity. RESULTS: Epidermal growth factor receptor overexpression was detected in 71% of primary tumors and 88% of lymph node metastases, as compared to nonpathologic adjacent esophageal epithelium. Statistically significant correlations were observed between EGFR overexpression and sex, age, histologic type, and the presence of invasion. Tumor staining was classified into two patterns, homogeneous and heterogeneous, based on the distribution of EGFR-positive cells. The immunostaining patterns of primary tumors had a statistically significant correlation with histologic type, the presence of adventitial invasion, histologic stage and lymph node metastasis. There was a tendency toward a worse prognosis for those patients with EGFR overexpression in the primary tumor. Greater than 90% of the foci of squamous dysplasia demonstrated homogeneous EGFR overexpression. DNA amplification of the EGFR was observed in 21% of primary tumors, and all demonstrated immunohistochemical overexpression. CONCLUSIONS: Immunohistochemical overexpression of the EGFR, which was more frequent than EGFR DNA amplification, appears to play an important role in biologic behavior of human esophageal squamous cell carcinomas.     

Vascular invasion of O-1N, hamster squamous cell carcinoma with high potential of lymph node metastasis: ultrastructural comparison between lymphatics and blood vessels

The ultrastructural modes of lymphatic and blood vessel invasions were studied comparatively in hamsters with squamous cell carcinoma (O-1N) that had a high potential for lymph node metastasis. The endothelial injury, which was caused by mechanical stretching with the growth of O-1N, was the initial and characteristic feature common to both vascular invasions. Tumor cell nests penetrating the lymphatic lumen through disrupted endothelial cells still maintained their volume and continuity to the underlying tumor cell nests. In contrast, pronounced microthrombotic and neutrophilic reactions occurred at the site of blood vessel penetration. Within the lymphatic lumen, large clusters of O-1N cells were kept longer in spite of lymphocytic and macrophagic reactions. In blood vessels, clusters of tumor cells that had passed through dense fibrin layers were reduced in size and further disintegrated into smaller pieces by neutrophils. In conclusion, lymphatic invasion is a mechanical process, and smooth and direct invasion of large tumor cell nests into lymphatic vessels is responsible for causing more prompt and frequent lymph node metastasis in O-1N than a hematogenous type.     

Iodixanol in leg phlebography: a randomized, double-blind parallel group phase III trial comparing iodixanol to ioxaglate

In the past, interleukin-8 (IL-8) could be demonstrated within keratinocytes in normal epidermis and inflammatory skin diseases, like psoriasis and eczema. Using monoclonal antibodies, the distribution of IL-8 immunoreactivity was inversely related to the density of inflammatory infiltrate. Other in vitro observations indicated IL-8 to be a growth factor for keratinocytes. These results prompted an immunohistochemical examination of IL-8 immunoreactivity in malignant and semimalignant epithelial tumours of human skin. Whereas IL-8 could not be detected within the transformed cells of epithelial tumours or melanoma, some tumour cells within well differentiated squamous cell carcinoma and Bowen's disease showed IL-8 immunoreactivity. Thus, loss of IL-8 immunoreactivity can be a sign of malignant transformation. This indicates an important role in growth regulation as well as terminal differentiation of human keratinocytes.