Elastosis in lung carcinoma: Immunohistochemical, ultrastructural and clinical studies

Elastosis is the pathological finding of focal deposits of elastic fibers in abnormal amounts within tissue. It is well described in the case of infiltrating carcinoma of the breast, but elastosis in lung carcinoma has not been previously documented in detail. We investigated the characteristics of elastosis in lung carcinoma with light and electron microscopies, and immunohistochemistry for alpha-1-antitrypsin. A total of 184 surgically resected primary lung carcinomas were studied. Elastosis was detected in adenocarcinomas (85/106), squamous cell carcinomas (11/60) and adenosquamous carcinomas (5/7), but not in small-cell carcinomas (n = 4) or large-cell carcinomas (n = 5). The degree of elastosis in each case was divided into one of five grades, graded as 3+ to 1-. The score of elastosis was significantly higher in adenocarcinoma than that in squamous-cell carcinoma (P < 0.01). In the cases of adenocarcinoma, the mean score of elastosis in the well-differentiated type (WD n = 43) was higher than that in the moderately differentiated (MD) (n = 39; P = 0.012) and poorly differentiated (PD) types (n = 24; P < 0.01). The mean score of elastosis in MD adenocarcinoma was also higher than that in the PD type (P < 0.01). Light- and electron-microscopic analyses revealed that these elastic fibers in elastosis were composed of aggregates of thick mature and fine immature elastic fibers, and were positive for alpha-1-antitrypsin. It is suggested that both degraded elastic fibers and newly synthesized fibers are contained in the elastosis of lung carcinoma. Although no significant evidence was detected to suggest any correlation between elastosis and the degree of tumor invasion, the survival curves of adenocarcinomas with elastosis showed a significantly improved prognosis than of those without elastosis in the cases of stages IA and IB (n = 52; P = 0.026).     

Elastosis in lung carcinoma: immunohistochemical, ultrastructural and clinical studies

Elastosis is the pathological finding of focal deposits of elastic fibers in abnormal amounts within tissue. It is well described in the case of infiltrating carcinoma of the breast, but elastosis in lung carcinoma has not been previously documented in detail. We investigated the characteristics of elastosis in lung carcinoma with light and electron microscopies, and immunohistochemistry for alpha-1-antitrypsin. A total of 184 surgically resected primary lung carcinomas were studied. Elastosis was detected in adenocarcinomas (85/106), squamous cell carcinomas (11/60) and adenosquamous carcinomas (5/7), but not in small-cell carcinomas (n = 4) or large-cell carcinomas (n = 5). The degree of elastosis in each case was divided into one of five grades, graded as 3+ to 1-. The score of elastosis was significantly higher in adenocarcinoma than that in squamous-cell carcinoma (P<0.01). In the cases of adenocarcinoma, the mean score of elastosis in the well-differentiated type (WD n = 43) was higher than that in the moderately differentiated (MD) (n = 39; P = 0.012) and poorly differentiated (PD) types (n = 24; P<0.01). The mean score of elastosis in MD adenocarcinoma was also higher than that in the PD type (P<0.01). Light- and electron-microscopic analyses revealed that these elastic fibers in elastosis were composed of aggregates of thick mature and fine immature elastic fibers, and were positive for alpha-1-antitrypsin. It is suggested that both degraded elastic fibers and newly synthesized fibers are contained in the elastosis of lung carcinoma. Although no significant evidence was detected to suggest any correlation between elastosis and the degree of tumor invasion, the survival curves of adenocarcinomas with elastosis showed a significantly improved prognosis than of those without elastosis in the cases of stages IA and IB (n = 52; P = 0.026).     

Stromal Reaction to Neoplasia: Colonic Carcinomas

The stroma and stromal reaction in the normal colon and in 14 different colonic tumors were studied by electron microscopy. Elastosis is a significant part of the stromal reaction to colonic adenocarcinomas and rectal squamous cell carcinomas. Two carcinoid tumors elicited no significant elastosis. In some of the adenocarcinomas, small muscular arteries close to neoplastic tissue developed massive elastosis of the media. This may indicate that the elastosis is due to stimulation of nonneoplastic stromal cells by some unknown neoplastic factor or factors.     

Stromal Reaction to Neoplasia: Colonic Carcinomas

The stroma and stromal reaction in the normal colon and in 14 different colonic tumors were studied by electron microscopy. Elastosis is a significant part of the stromal reaction to colonic adenocarcinomas and rectal squamous cell carcinomas. Two carcinoid tumors elicited no significant elastosis. In some of the adenocarcinomas, small muscular arteries close to neoplastic tissue developed massive elastosis of the media. This may indicate that the elastosis is due to stimulation of nonneoplastic stromal cells by some unknown neoplastic factor or factors.     

Tenascin-C protein expression and mRNA splice variants in thyroid carcinoma

Tenascin-C (Tn-C) is a matricellular protein involved in the initial and intermediate stages of cell adhesion. The present study is the first undertaken to comparatively investigate Tn-C in neoplastic, non-neoplastic thyroid lesions and normal thyroid tissues. Forty-eight thyroid specimens were studied immunohistochemically using a monoclonal antibody against Tn-C. Immunohistochemistry was supplemented by RT-PCR analysis of the two Tn-C mRNA splice variants in 13 thyroid cancer cell lines. Normal and non-neoplastic tissues were devoid of Tn-C, as well as follicular neoplasms, Huerthle-cell and anaplastic carcinomas. Most papillary carcinomas showed a focally intensive extracellular staining, localized in the connective tissue stroma, whereas most medullary carcinomas showed a staining in the connective tissue but also in intracellular location mainly. RT-PCR analysis detected Tn-C mRNA in all thyroid cancer cell lines with prevalence of the large splice variant in all but the medullary line, characterized by a higher Tn-Csmall:Tn-Clarge ratio. In conclusion, Tn-C re-expression has been observed in papillary and medullary thyroid carcinomas with different staining patterns accompanied by the prevalence of different mRNA splice variants in cell cultures. It seems possible that Tn-C is rather synthesized by tumor cells than by activated stromal cells.     

Syndecan-1 expression in thyroid carcinoma: stromal expression followed by epithelial expression is significantly correlated with dedifferentiation

AIM: To investigate the expression of syndecan-1 in thyroid neoplasia. Syndecan-1 is a proteoglycan regulating cell adhesion. Previous studies have demonstrated that decreased expression of syndecan-1 is linked to malignant progression. METHODS AND RESULTS: Syndecan-1 expression in thyroid neoplasia was studied immunohistochemically. Syndecan-1 was expressed in stromal cells as well as neoplastic epithelial cells. Stromal syndecan-1 expression was observed more frequently in papillary carcinomas larger than 10 mm in size than in microcarcinomas and in widely invasive than in minimally invasive follicular carcinomas. Furthermore, poorly differentiated carcinomas showed this phenomenon more than well-differentiated carcinomas, but the expression in undifferentiated carcinomas was similar to that of poorly differentiated carcinomas. Epithelial syndecan-1 expression was more frequently observed in anaplastic (undifferentiated) carcinomas than in papillary and follicular carcinomas. No significant difference in epithelial expression was found between well and poorly differentiated carcinomas, but undifferentiated carcinomas expressed epithelial syndecan-1 more frequently than did poorly differentiated carcinomas. CONCLUSIONS: These results are in contrast to those previously reported for carcinomas at other sites. It is suggested that the role of syndecan-1 in thyroid carcinomas might be unique. Stromal syndecan-1 expression followed by its epithelial expression is significantly related to progression, including dedifferentiation of thyroid carcinoma.     

Mesenchymale Uterustumoren

Uterine stromal neoplasms are classified into endometrial stromal nodules and stromal sarcomas, as well as undifferentiated sarcomas. The two former groups demonstrate identical histological composition, consisting of small monomorphous cells with scant cytoplasm and round nuclei and typically contain numerous arteriolar-type vessels. Stromal tumors are distinct from stromal nodules by virtue of their myometrial and vascular invasion. Undifferentiated sarcomas consist of polymorphic cells and lack any cytological similarity to the stroma of normal proliferative endometrium. There is no smooth or striated muscle differentiation. Adenosarcomas are mixed neoplasms with a low grade stromal sarcoma component containing benign glands, which are surrounded by condensed neoplastic stroma. Typical uterine tumors resembling ovarian sex cord tumors (UTROSCT Type2) show predominant sex cord differentiation in a well circumscribed nodule. Focal sex cord differentiation may occur in stromal nodules and stromal sarcomas (UTROSCT Type2).     

Cystic Medullary Thyroid Carcinoma: Report of a Case with Morphological and Clinical Correlations

Cystic lesions of the thyroid are common findings. Although many thyroid cysts are of benign, some cases of hemorrhagic degenerative changes occur in neoplastic nodules, mostly follicular neoplasms and papillary carcinomas. The occurrence of hemorrhagic changes in medullary carcinomas has never been documented with aspirative cytological and histological pictures to the best of our knowledge. A case of medullary thyroid carcinoma with a large central hemorrhagic cyst is described, and the literature regarding the pathogenesis of this regression and the occurrence of cystic neoplasms in the thyroid is reviewed.     

Immunohistochemical detection of X-linked inhibitor of apoptosis (XIAP) in neoplastic and other thyroid disorders

The X-linked inhibitor of apoptosis (XIAP) is the most potent of the inhibitors of apoptosis, a group of related caspase inhibitors. X-linked inhibitor of apoptosis expression correlates with radio- and chemoresistance and clinical aggressiveness in certain tumors. XIAP expression was examined in 106 specimens from neoplastic and other thyroid disorders, which underwent citrate-based antigen retrieval and staining with monoclonal anti-XIAP. Normal thyroid was XIAP-negative. Of 35 papillary thyroid carcinomas (PTCs), 29 (83%) stained variably in intensity and/or extent. An insular carcinoma was strongly positive and 1 of 4 anaplastic carcinomas moderately positive. Follicular, medullary, and 3 of 4 anaplastic carcinomas, oncocytic neoplasms, and a hyalinizing trabecular tumor were nonstaining. Hashimoto's thyroiditis and adenomatous goiters were either nonstaining or occasionally stained in oncocytic foci. Because XIAP was highly specific for PTC among the thyroid neoplasms, it may be a useful marker for differential diagnosis when used alone or in combination with other markers. XIAP may also be useful in differentiating insular carcinoma from follicular neoplasm in certain difficult cases. In addition, the selective expression of XIAP in PTC and some high-grade thyroid malignancies also provides clues to the role of the apoptotic pathway in the tumorigenesis of these neoplasms.     

Elastosis in benign and malignant breast disease

Elastosis, the presence of clumps of elastic fibers, is known to occur frequently in association with breast carcinoma. To test the hypothesis that the degree of elastosis increases progressively in fibrocystic disease with the severity of epitheliosis (epithelial hyperplasia, papillomatosis; widely believed to be the only premalignant component of fibrocystic disease) and increases further with intraductal and infiltrating duct carcinoma, breast tissue stained for elastic fibers from 84 women in the fifth decade of life was studied. Fourteen cases were evaluated in each of six disease categories: fibrocystic disease without epitheliosis; fibrocystic disease with epitheliosis, graded subjectively as mild, moderate, or severe (based on the degree of epithelial hyperplasia); intraductal carcinoma; and infiltrating duct carcinoma of the breast. Periductal elastosis and stromal elastosis were graded on a scale of 0 to 4 (absent to massive). The grades of both periductal elastosis and stromal elastosis were compared with those for the six disease categories ranked by increasingly advanced disease. The results indicate that the grades of periductal elastosis (Spearman rank correlation coefficient [R] = 0.54; P less than 0.001) and stromal elastosis (R = 0.75; P less than 0.001) increase progressively with the severity of breast disease.     

ret/PTC and BRAF act as distinct molecular, time-dependant triggers in a sporadic Irish cohort of papillary thyroid carcinoma

The purpose of this study was to assess BRAF mutation rates in various thyroid tissues and to investigate if concomitant mutations with ret/PTC activation occurred in inflammatory and neoplastic lesions. To this end, we developed a novel Taqman based screening assay for the common T1799A BRAF mutation. Heterozygous T1799A mutations were detected in 13 of 34 (44%) papillary thyroid carcinomas (PTCs) tested. No such mutations were detected in the other tissue types tested. Concomitant presence of both oncogenes was reported in 5 of the 34 PTCs. A significant temporal trend was observed, with ret/PTC chimera detected for the most part before 1997 and BRAF mutations being more prevalent after 1997. The results suggest that some environmental/etiological agent(s) may have influenced the pathobiology of thyroid tumor development, among the population examined, over time.     

Immunohistochemical and immunoelectron microscopical localization of procollagen III peptide in papillary carcinoma of thyroid

The immunohistochemical localization of procollagen III peptide, a precursor of type III collagen, was examined in 38 papillary carcinomas and 25 follicular neoplasms using an immu-noperoxidase technique. Although localization of procollagen ill peptide was not demonstrated in normal follicular cells, distinct cytoplasmic immunostaining of neoplastic cells was frequently found in the tissues examined, as were stromal fibroblasts. Such cytoplasmic immunostaining was observed in 92.1 % of 38 papillary carcinomas and in 36.0% of 25 follicular neoplasms. Cytoplasmic immunoreactivity in papillary carcinomas was more intense at the peripheral zone of the tumor and correlated with the degree of invasiveness. The controls, in which the primary antibody was preabsorbed with procollagen ill peptide or replaced with normal rabbit serum, showed only faint background staining in all specimens. Immunoelectron microscopical examination revealed that electron-dense deposits, indicating procollagen III peptide, were located in the perinuclear space, Golgi apparatus, and rough endoplasmic reticulum of papillary carcinoma cells. These results suggest that neoplastic cells, especially papillary carcinoma cells, could play an important role in type III collagen production, possibly in connection with the creation of an environment that is conducive to their progression.     

ULTRASTRUCTURAL CYTOCHEMICAL DEMONSTRATION OF ELASTIN IN THE MATRIX OF SALIVARY GLAND TUMORS

Following light microscopic survey of the incidence of elastic tissue in 80 salivary gland tumors, tissue samples from 14 pleomorphic adenomas, three myoepitheliomas, and eight adenoid cystic carcinomas were processed for cytochemical demonstration of elastin with the tannic add stain for ultrathin sections. For comparative study, some other tumor types devoid of elastic tissue at the light microscopic level and non-neoplastic submandibular glands were also investigated. Elastic deposits of varying amounts were clearly revealed on the basal-lamina-like material and/or masses of microfibrils in the matrix close to the neoplastic myoepithelium and, to a lesser degree, immediately beneath the non-neoplastic myoepithelium. None of the other tumor types without myoepithelial differentiation contained elastic deposits closely associated with the neoplastic cells. Intimate topographical relationship of such an immature elastic fiber or developing elastic tissue to the neoplastic myoepithelial cells strongly indicated the primary origin of elastic components from these cells. It is postulated that the potential of salivary tumor cells to produce elastin is regarded as an indicator of their myoepithelial nature or differentiation.     

Ultrastructural cytochemical demonstration of elastin in the matrix of salivary gland tumors

Following light microscopic survey of the incidence of elastic tissue in 80 salivary gland tumors, tissue samples from 14 pleomorphic adenomas, three myoepitheliomas, and eight adenoid cystic carcinomas were processed for cytochemical demonstration of elastin with the tannic acid stain for ultra-thin sections. For comparative study, some other tumor types devoid of elastic tissue at the light microscopic level and non-neoplastic submandibular glands were also investigated. Elastic deposits of varying amounts were clearly revealed on the basal-lamina-like material and/or masses of microfibrils in the matrix close to the neoplastic myoepithelium and, to a lesser degree, immediately beneath the non-neoplastic myoepithelium. None of the other tumor types without myoepithelial differentiation contained elastic deposits closely associated with the neoplastic cells. Intimate topographical relationship of such as immature elastic fiber or developing elastic tissue to the neoplastic myoepithelial cells strongly indicated the primary origin of elastic components from these cells. It is postulated that the potential of salivary tumor cells to produce elastin is regarded as an indicator of their myoepithelial nature or differentiation.     

Role of arterial occlusion in pulmonary scar cancers

The pathogenesis of scars in lung carcinomas was studied in 57 consecutively resected small (less than or equal to 3 cm) peripheral lung cancers. Central, pigmented scars rich in elastic fibers were most frequently found in adenocarcinomas with predominantly non-destructive, intraalveolar growth pattern. In these cancers with elastin-rich scars, active neoplastic occlusion of one or more arteries was almost always found (96%). Infarction of tumor tissue and its supporting pulmonary stroma was frequently seen separating the central scar from the viable peripheral tumor zone. The elastic fibers of alveolar walls survived and condensed into a compact central scar. Based on these observations, it is suggested that scarring in peripheral lung cancers is often caused by mechanisms unique to the lung. Lung cancers often invade and occlude branches of pulmonary arteries, causing ischaemic necrosis (infarction) of the neoplasm and its stroma. In these neoplasms, often growing mainly in air spaces and preserving the pulmonary framework as their stroma, the elastic fibers of the aLveoli remain preserved despite necrosis, so that the alveolar elastic collapses to form the characteristic elastin-rich scar following absorption of necrotic debris.     

Elastosis in neoplastic and non-neoplastic tissues from patients with mammary carcinoma

We studied a series of 585 patients with non-invasive or invasive ductal carcinoma in an attempt to assess the significance of elastosis. Elastosis in the neoplasm was recognized in 60% of the 549 patients with invasive ductal carcinoma. The grade of elastosis was correlated with both the histologic grade of differentiation and the 5-year survival rate. The incidence of elastosis, however, was 17% in the 36 patients with non-invasive ductal carcinoma and 38% in the 21 with invasive ductal carcinoma with a predominant intraductal component. The increased elastic tissue may therefore be influenced by the stromal infiltration of cancer cells. Mastectomy specimens from another series of 100 patients with mammary carcinoma were examined with regard to the volume of elastic tissue. Increased periductal elastic fibers were also identified in the non-neoplastic tissue, but the volume density was far less than in the neoplasm. A significant correlation was found between the increased amount of periductal elastic fibers in the non-neoplastic tissue, periductal elastosis of the neoplasm and an increase in parity. We propose that cancer cells in mammary carcinoma exert an inductive effect on mesenchymal cells for the synthesis of elastic material, under the basic condition of an increased amount of elastic fibers with an increase in parity.     

FAP-alpha and uPA show different expression patterns in premalignant and malignant esophageal lesions

Fibroblast activation protein-alpha (FAP-alpha) and urokinase-type plasminogen activator (uPA) are serine proteases involved in cancer invasion and metastasis. The authors examined FAP-alpha and uPA expression in premalignant and malignant stages of esophageal adenocarcinoma by immunohistochemistry. Additionally, Western blotting was performed on fresh-frozen tissue samples. FAP-alpha and uPA were detected in metaplastic, dysplastic, and carcinoma cells, as well as in adjacent stroma. Stromal FAP-alpha expression was associated with depth of tumor invasion, while stromal uPA expression correlated with lymph node metastases in adenocarcinomas. Stromal uPA expression in cells with premalignant changes correlated with histological grading. Immunoblotting showed higher protease expression in carcinoma tissues than in normal esophageal epithelium. These results suggest that FAP-alpha and uPA expression in metaplastic, dysplastic, and esophageal cancer tissue is associated with neoplastic progression of esophageal lesions.