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. ACTA PATHOL JPN 38: 1537-1546, 1988.     

AN ULTRASTRUCTURAL STUDY ON PERIDUCTAL ELASTOSIS IN HUMAN BREAST TUMORS

An ultrastructural study on elastosis of human breast tumors was made with special attention to the periductal elastosis and the cell responsible for elastic fiber formation. The elastosis was found prominently in scirrhous type of duct carcinoma. In the area of mild periductal elastosis, the elastic fibers with many microfibrils and a tiny central elastin were seen around the periductal fibroblasts which were characterized by attenuated cytoplasms with aggregates of microfilaments and slightly developed rough endoplasmic reticulum. With the thickening of the periductal wall, such an area was replaced by abundant mature elastic fibers with peripheral microfibrils and a few intervening ordinary fibroblasts. Therefore, it was suggested that the periductal fibroblasts which transformed into ordinary fibroblasts during the development of elastosis were primarily concerned with the elastic fiber formation. In the interlobular tissue in which both fibroblasts and myofibroblasts were present, the elastic fibers were larger than those of the periductal area and had less microfibrils in their periphery. The relationship between microfibrils and elastin during the early elastosis, maturation process of the elastic fibers, and cell modulation of the fibroblasts in the breast elastosis were discussed.     

Elastosis in the normal aging breast. A histopathologic study of 140 cases.

The incidence and pattern of elastosis of the breast was studied in tissue specimens taken at autopsy from 140 women with clinically normal breasts, ranging in age from 19 through 101 years. Elastosis, presence of excess elastic fibers, while less common in younger women, may be found in nearly half of all women over age 50 years with no breast disease. Elastosis occurs in three sites: diffusely in the stroma, around vessels, and around ducts. In the first two sites, it bears little relationship to age, while periductal elastic tissue appears to accumulate with age, probably reflecting parity, until about age 50 years. Thereafter, it is found at a more or less constant incidence and degree. While it may be associated with breast cancer, periductal elastosis by itself is not a cause for concern. Marked perivascular elastosis is, however, uncommon at any age, and its presence should suggest a special search for carcinoma, if not already evident.     

Minute pancreatic adenocarcinoma presenting with stenosis of the main pancreatic duct

We describe a case of minute pancreatic ductal adenocarcinoma featuring stenosis of the main pancreatic duct (MPD) and associated with histological findings of periductal elastosis and fibroblast proliferation. A 53-year-old Japanese man with preoperative radiological evidence of MPD stricture and dilation of the distal MPD, and suspected of having pancreatic cancer, underwent successful resection. Neither radiological nor macroscopic examination directly disclosed any tumorous lesions, and a small focus of carcinoma (8 x 8 mm) was only revealed on microscopic examination. The tumor was a poorly differentiated, invasive ductal adenocarcinoma that had invaded the intrapancreatic nerves and veins. Interestingly, the MPD located at the edges of the tumor had not been destroyed by the carcinoma, but its wall had been thickened by elastic tissue and fibroblast proliferation, resulting in stenosis. The peripheral pancreas exhibited secondary obstructive pancreatitis. To date, the detection of small pancreatic tumor masses using imaging procedures remains difficult, and most patients are diagnosed on the basis of pancreatic ductal changes. However, the published work on small pancreatic cancers contains little information about the histological features of the affected MPD. The present findings suggest that MPD strictures are not always provoked by destruction or filling with cancer cells, and that they can be caused by periductal elastosis and fibroblast proliferation in a minute carcinoma. Such changes in the MPD may therefore be of clinical importance in the detection of early stage cancers.     

Vascular and ductal elastotic changes in pancreatic cancer

This study aims to identify and define the type and frequency of elastotic alterations of vessels and ducts in pancreatic ductal carcinoma (PDAC) and evaluate its diagnostic significance. Representative tissue from 36 Whipple specimens, stained with Verhoeff's Van‐Gieson, was studied focusing on the density and distribution of elastic fibers in walls of vessels and ducts, in perivascular and periductal tissue and in tumor stroma. Vessels and ducts within the carcinoma, at tumor periphery and in non‐tumoral pancreas were grouped and examined separately. Vimentin and α‐SMA immunostains were used for the depiction of fibroblasts and myofibroblasts. Histochemistry revealed mild to severe elastotic changes of vessels and ducts in all examined cases. Vascular and ductal elastosis was more prominent within the tumor and diminished at tumor periphery. In tumor stroma and non‐tumoral pancreatic tissue mild or no elastosis was identified. α‐SMA+ cells were observed in large numbers in tumor stroma and as a ring around carcinomatous structures. There were scant α‐SMA+ cells around elastotic and non‐elastotic vessels. Conclusively, vascular and ductal elastosis is a tumor‐associated phenomenon in PDAC. Its presence is indicative of benignity acquiring a possible diagnostic role.     

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.     

Abnormal Elastic Fibers in Elastosis of Breast Carcinoma UItrastructuraI and ImmunohistochemicaI Studies

Elastosis in benign and malignant breast lesions was studied by light microscopic immunohistochemistry for elastin and by electron microscopy. Upon immunohistochemical examination for elastin, elastosis, particularly in scirrhous-type ductal carcinoma, showed two characteristic staining patterns: fibrously and intensely stained elastic fibers and evenly stained elastic masses. Elastic fibers showing increased fibrous staining occurred mainly in the stromal areas, and were considered to be newly formed because they consisted of tannic acid-positive amorphous components and abundant microfibrils. Evenly stained elastic masses were observed mainly in the periductal areas and showed less intense stainability. These masses consisted of numerous fine amorphous components with plentiful microfibrils. In some regions within these masses, there were condensed accumulations of irregularly arranged small amorphous components associated with only a few microfibrils. These amorphous components had an ill-defined outline and were occasionally associated with spiralling collagen fibrils and cell debris. On the basis of these findings, the periductal evenly stained elastic masses were thought to be formed by excessive production of elastic fibers and degradation of pre-existing and newly formed elastic fibers. Acta Pathol Jpn 39: 245–253, 1989.     

Histopathological study on branches of the pancreatic duct in obstructive pancreatic disorders

Branches of the pancreatic duct in obstructive pancreatic disorders were studied histopathologically. Obstructive pancreatic disorders were observed in 25 out of 32 patients with pancreatic carcinoma. The main pancreatic duct was dilated in all 25 cases. Luminal conditions in the branches of the pancreatic duct were divided as follows: dilated, obstructed and unchanged. The dilated duct was found in all 25 cases and showed mainly cystic dilatation with flat epithelia. The obstructed duct was found in 10 cases and revealed granulation tissue in the lumen, disappearance of epithelia and increase in the number of elastic fibers in the periductal space. The pancreatic tissue distal to the tumor frequently showed isolated islets of Langerhans with elastosis. Morphogenesis of elastosis was interpreted as follows: during the process of shortening or disappearance of the duct, elastic fibers increased in number and remained in the fibrous tissue. Hence, the elastosis was considered to be a remnant in which the pancreatic duct had once existed. Therefore, the branches of the pancreatic duct in obstructive pancreatic disorder were classified into four types as follows: dilated, obstructed, remnant and unchanged.     

Prognostic significance of mitotic figures in metastatic mammary ductal carcinoma to the lymph nodes

We previously reported that the number of mitotic figures in metastatic mammary carcinoma to the lymph nodes accurately predicted the outcome of patients with invasive ductal carcinoma with nodal metastasis. To confirm these previous findings, the present study investigated the number of mitotic figures and other histologic characteristics in metastatic mammary carcinoma to the lymph nodes and their associations with patient outcome according to nodal status and the histologic grade of primary invasive ductal carcinomas in a different series of 1039 patients with invasive ductal carcinoma. Multivariate analyses examining well-known clinicopathologic factors, the number of mitotic figures in the primary invasive ductal carcinomas, the grading system for lymph vessel tumor emboli, the p53 Allred score risk classes of tumor-stromal fibroblasts forming and not forming a fibrotic focus, and 9 histologic features of metastatic mammary carcinoma to the lymph nodes were performed. The presence of 6 or more mitotic figures in metastatic mammary carcinoma to the lymph nodes significantly increased the hazard ratios for tumor recurrence and tumor-related death among patients with invasive ductal carcinoma as a whole, those with nodal metastasis, and those with a histologic grade of 2 or 3. The presence of 6 or more mitotic figures in metastatic mammary carcinoma to the lymph nodes also significantly increased the hazard ratio for tumor recurrence among patients with histologic grade 1 invasive ductal carcinoma. In conclusion, this study clearly confirmed the excellent outcome predictive power of the number of mitotic figures in metastatic mammary carcinoma to the lymph nodes.     

Relation of elastosis to biochemical and immunohistochemical steroid receptor findings,Ki-67 and epidermal growth factor receptor (EGFR) immunostaining in invasive ductal breast cancer

We studied 1073 cases of invasive ductal breast cancer, NOS for their elastic content (DEL, ductal + periductal elastosis; TEL, tumour elastosis) and compared the findings with the results of biochemical and immunohistochemical steroid hormone receptor examination. Tumours of patients up to 50 years of age and older were examined separately. In a number of tumours elastosis was also examined in relation to Ki-67 and epidermal growth factor receptor (EGFR) immunostaining. Sensitivity and specificity of DEL and TEL for predicting the receptor, Ki-67 and EGFR findings were estimated. Sensitivity of DEL and TEL for oestrogen and progesterone receptors is dependent on the degree of tumour differentiation and the degree of elastosis, increasing from DEL 1° and TEL 1° to DEL 3° and TEL 3°. It was more evident in grade 1 (G1) and G2 than in G3 carcinomas. Elastosis is a useful predictor of positive receptor findings particularly in G1 and G2 tumours with moderate and high-grade elastosis. It is a similarly useful predictor of negative receptor values in G3 carcinomas. The predictive value of DEL and TEL for the results of Ki-67 and EGFR immunostaining gradually decreases with increasing elastosis, consistent with the assumption that Ki-67 and EGFR identify the degree of tumour proliferation and invasion, while elastosis correlates with the degree of differentiation of breast cancer. Elastosis is a poor predictor of Ki-67 and EGFR findings in any individual breast cancer. Moderate and high-grade elastosis points to positive steroid hormone receptor assays in G1 and G2 carcinomas. In contrast, the lack of elastosis in G3 carcinomas may indicate a negative receptor assay. Both findings have a high degree of reliability.     

Elastosis in breast carcinoma: I. Immunohistochemical characterization of elastic fibres

Elastosis associated with invasive ductal and lobular carcinomas of the breast was examined by tinctorial and immunohistochemical staining methods, enzyme digestion, and electron microscopy. The elastotic material exhibited the tinctorial staining properties of elastic fibres, and the ultrastructural appearances were those of elastic fibres although there was a higher proportion of microfibrils than in normal mature elastic fibres. The elastosis was immunostained by antisera to human fetal elastin, lysozyme and amyloid P component, as in other sites where elastic fibres are found. These findings indicate that immunohistochemically intact elastic fibres are present in the elastosis of breast cancer. They also demonstrate that lysozyme and amyloid P component are co-distributed with elastic fibres in elastosis of breast carcinoma, as distinct components with different susceptibilities to enzyme digestion. The cellular origin of elastosis in breast carcinoma remains uncertain.     

Mammary carcinoma with osteoclast-like giant cells--report of two cases

Authors describe two cases of a rare type of mammary carcinoma occurring in 47-year and 49-year-old women, characterised by osteoclast-like giant cells, hypervascular stroma, and signs of older and recent haemorrhages on the background of the conventional type of breast carcinoma. In both cases there was diagnosed moderately differentiated ductal invasive carcinoma with osteoclast-like giant cells, which were present in tumorous stroma as well as scattered between tumorous cells. Immunohistochemical analysis (vimentin and CD68 positivity and negativity of cytokeratins, EMA and S-100 protein) confirmed a histiocytic origin of these giant cells as well as their reactive non-neoplastic nature. Clinical and morphological features of this unusual type of breast carcinoma indicate that it should be regarded as an unique clinical- histomorphological entity with probably better prognosis when compared to ductal invasive carcinoma not otherwise specified and it should not be included among metaplastic breast carcinomas.     

Prognostic significance of tumor grading and staging in mammary carcinomas with neuroendocrine differentiation

Invasive mammary carcinoma with neuroendocrine differentiation has been controversial in terms of its definition and clinical outcome. In 2003, the World Health Organization histologic classification of tumors designated this entity as neuroendocrine carcinoma of the breast and defined mammary neuroendocrine carcinoma as expression of neuroendocrine markers in more than 50% of tumor cells. It is an uncommon neoplasm. Our recent study showed that it is a unique clinicopathologic entity and has a poor clinical outcome compared with invasive mammary carcinoma with similar pathologic stage. Other investigators have also demonstrated a different molecular profile in this type of tumor from that of invasive ductal carcinoma. It is unknown whether the current prognostic markers for invasive mammary carcinoma are also applicable for neuroendocrine carcinoma of the breast. In the current study, we reviewed the clinicopathologic features and outcome data in 74 cases of mammary neuroendocrine carcinoma from the surgical pathology files at The University of Texas, MD Anderson Cancer Center, to identify relevant prognostic markers for this tumor type. As shown previously by univariate analysis, large tumor size, high nuclear grade, and presence of regional lymph node metastasis are adverse prognostic factors for overall survival and distant recurrence-free survival. In the current study, multivariate analysis revealed that overall survival was predicted by tumor size, lymph node status, and proliferation rate as judged by Ki-67 immunohistochemistry. Only nodal status proved to be a significant independent prognostic factor for distant recurrence-free survival. Neither mitosis score nor histologic grade predicted survival in mammary neuroendocrine carcinoma. Our data suggest that routine evaluation of Ki-67 proliferation index in these unusual tumors may provide more valuable information than mitotic count alone.     

Elastosis in breast carcinoma: II. Association of protease inhibitors with immature elastic fibres

The elastosis of 11 invasive ductal and infiltrative lobular carcinomas of the breast was specifically immunostained for the plasma protease inhibitors alpha-1 antitrypsin, alpha-1 antichymotrypsin, alpha-2 macroglobulin, inter alpha trypsin inhibitor and C1 esterase inhibitor. None of these components was detected in the elastic fibres of normal ducts or blood vessels in the breast. The elastosis in breast carcinomas was also stained by Concanavalin A and Triticum vulgaris lectins. Such lectin staining probably represents binding to the microfibrillar component of elastic fibres, which is increased in immature elastic fibres, thus suggesting that the elastotic fibres of breast carcinoma are recently synthesised. It is suggested that the presence of protease inhibitors may influence the metabolism of elastic fibres, facilitating elastic fibre proliferation by the inhibition of elastinolytic enzymes.     

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 the male breast

Elastosis, a common finding in infiltrating ductal and lobular carcinomas of the female breast, has also been described in a variety of other benign and malignant lesions. However, elastosis has not been previously documented in male breast lesions. Ten cases of gynaecomastia and five neoplastic lesions of the male breast were evaluated for elastosis. In gynaecomastia, elastosis is a feature of the ducts surrounded by collagenized fibrous tissue but not of ducts with loose connective tissue stroma. This association is also evident to some extent in neoplastic lesions. These findings suggest that elastosis is an expression of periductal fibrosis irrespective of the nature of the lesion.     

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).     

Morphological characterization of the breast in Proteus syndrome complicated by ductal carcinoma in situ

Proteus syndrome (PS) is a severe, variable, and rare disorder with asymmetric and disproportionate overgrowth of body parts, cerebriform connective tissue nevi, epidermal nevi, dysregulated adipose tissue, and vascular malformations. It is associated with benign and occasionally malignant tumors. We report the first case of ductal carcinoma in situ (DCIS) in a 28-yr-old woman with PS who underwent a mastectomy for asymmetric overgrowth. The cut surface of the tissue showed a discrete, white, lobulated, solid mass with multiple cysts with occasional small polypoid nodules. Microscopically, the tissue was characterized by neoplastic and non-neoplastic changes. The former consisted of multiple intraductal papillomas and low-grade intraductal papillary, solid, and cribriform carcinoma. The non-neoplastic changes were characterized by cysts of various sizes, lined by cuboidal or apocrine cells, focally with epithelial papillary proliferation; the lumens contained eosinophilic, mucicarmine-positive, and PAS-positive material. Variable ductal proliferation and periductal, peri- and intra-lobular fibrosis with loose fibrous connective tissue was present. The carcinoma was positive for ER, PR, CK7, and MIB-1 (40%), and negative for p53 and CK20 staining. We conclude that DCIS may be one of the tumors associated with PS and that the proliferative phenotype serves as an initiator for carcinogenesis. This case highlights the difficulty of recognizing small foci of carcinoma in an asymmetrical overgrowth of the breast in a young woman with PS.     

Ductal carcinoma of the breast. An analysis of proportions of intraductal and invasive components

One hundred and ninety patients with mammary ductal carcinoma were studied to evaluate the correlation of proportions of intraductal and invasive tumor growth to histologic and immunohistochemical features. Initially, attempts were made to divide the cases into 6 groups according to the proportion of extraductal invasive areas within the whole tumor. It has been found that ductal carcinoma could be divided, on this criterion, into 2 groups. One comprised tumors in which invasive areas made up less than 20% of the tumor, the other included those with invasive areas exceeding 20%. In the former, intraductal and invasive components exhibited a lower grade of nuclear and tumor component and a higher incidence of cells with CEA immune positivity. The latter manifested higher grades in both intraductal and invasive components and a lower incidence of CEA positive cells. Many of the latter tumors had a solid or comedo-like growing pattern of the intraductal component. There was a significant difference in the prognosis between the two categories. We conclude that like intraductal carcinomas, invasive ductal carcinomas with a predominant intraductal component should be considered a lower grade malignancy.     

Stromal changes in early invasive breast carcinoma. An immunohistochemical, histoenzymological and ultrastructural study

The purpose of this work was to detect in periductal connective tissue of breast carcinoma in situ changes induced by intraductal tumor cells before any dehiscence in basement membrane. Histological, electron microscopic, immunohistochemical and histoenzymological methods were used in 3 carcinomas in situ, 4 microinvasive carcinomas and 13 control invasive carcinomas. We could demonstrate a high functional activity of fibroblasts with secretion of mucopolysaccharides and type III collagen around intraductal carcinomas. These changes occurred simultaneously to those of the basement membrane which was either thinning or thickening. Any dehiscence in basement membrane secondarily induced in this periductal stroma the usual changes seen in invasive stroma, peculiarly numerous vascular pedicles, myofibroblasts, elastic material. These periductal stromal changes are interpreted according to recent concepts about the possible influence of tumor cells upon their environment: stimulation of mitotic and metabolic activity of fibroblasts: stimulation of angiogenesis by means of an angiogenic factor.