Periductal Infiltration Research Articles

Current concepts of autoimmune exocrinopathy: immunologic mechanisms in the salivary pathology of Sjögren's syndrome.

Sjögren's syndrome is a systemic autoimmune disorder characterized by symptoms of oral and ocular dryness and a chronic, progressive loss of salivary and lacrimal function. The exocrine involvement is the result of a focal, peri-ductal mononuclear cell infiltrate and the subsequent loss of secretory epithelial cells. The mechanisms of this autoimmune exocrinopathy are not understood fully. Many recent investigations have described alterations in a number of immune mediators within the salivary glands. These studies provide new insights into the immune regulation of normal salivary gland functions and the mechanisms of gland damage in Sjögren's syndrome.

91 P - Periductal mastitis and mammary duct ectasia - two stages of the same disease?

This paper deals with a disease known under several names: obliterative mastitis, plasma cell mastitis, periductal mastitis, comedomastitis, mammary duct ectasia, which seem to define different stages of the same illness. Out of 67 cases of benign breast diseases recorded in our hospital during a 3-year interval, 15 cases were diagnosed as periductal mastitis or mammary duct ectasia. The dominant pathological findings in younger patients (17–40 years) were periductal infiltration with plasma cells, lymphocytes or polymorphic cells, while in older patients (over 52) duct ectasia and nipple retraction were prevalent, being frequently associated with periductal infiltration. Microbiological examination of the intraoperative samples showed different germs in most cases. Thus antibiotic prophylaxis was justifted in our cases. Our study supports the idea that this disease begins with a silent ductal infection with periductal infiltration, and ends with chronic inflammation and fibrosis with consequent duct ectasia. Therefore, periductal mastitis, non-puerperal mastitis and duct ectasia arc stages of the same pathological process. Due to the clinical similarity with breast cancer, treatment by sectorectomy becomes mandatory. This paper deals with a disease known under several names: obliterative mastitis, plasma cell mastitis, periductal mastitis, comedomastitis, mammary duct ectasia, which seem to define different stages of the same illness. Out of 67 cases of benign breast diseases recorded in our hospital during a 3-year interval, 15 cases were diagnosed as periductal mastitis or mammary duct ectasia. The dominant pathological findings in younger patients (17–40 years) were periductal infiltration with plasma cells, lymphocytes or polymorphic cells, while in older patients (over 52) duct ectasia and nipple retraction were prevalent, being frequently associated with periductal infiltration. Microbiological examination of the intraoperative samples showed different germs in most cases. Thus antibiotic prophylaxis was justifted in our cases. Our study supports the idea that this disease begins with a silent ductal infection with periductal infiltration, and ends with chronic inflammation and fibrosis with consequent duct ectasia. Therefore, periductal mastitis, non-puerperal mastitis and duct ectasia arc stages of the same pathological process. Due to the clinical similarity with breast cancer, treatment by sectorectomy becomes mandatory.

Effects of Calorie Restriction on Transforming Growth Factor β1 and Proinflammatory Cytokines in Murine Sjogren's Syndrome

The present study was carried out to determine whether restricting dietary calories prevents salivary gland abnormalities and modulates expression of transforming growth factor β and proinflammatory cytokines, IL-6, and TNFα in major salivary glands (SG) of autoimmune lupus-prone (NZB × NZW)F 1 (B/W) female mice. These mice develop focal lymphocytic interstitial and periductal round cell infiltrates in salivary glands similar to those of humans with Sjogren's syndrome. Weanling B/W mice were fed a nutritionally adequate semipurified diet either ad libitum (AL) or a calorie-restricted (CR; 40% less calories than AL) diet. The mice were sacrificed at 3.5 months (young) and 8.5 months (old) of age. Histopathologic and histomorphometric analyses as well as growth factor and cytokine protein and mRNA expression were carried out in the SG. Histomorphometric analysis of SG from young mice showed no differences between AL and CR mice, but old AL (vs old CR) had a 7.3-fold higher focus score and a 34-fold increase in percentage area inflammation. mRNA analysis revealed significantly higher levels of TGFβ1 in SG of old CR (6.8-fold) mice. In contrast, CR reduced mRNA expression of proinflammatory cytokines (IL-6, 2.9-fold for young and 4.8-fold for old; TNFα, old 3.9-fold). By immunoblotting, significantly higher levels of TGFβ1 protein was detected in old CR mice (vs old AL; 13.2-fold). IL-6 and TNFα proteins were undetectable in both young and old CR groups, whereas an increase in IL-6 (4.7-fold) and TNFα (9.3-fold) was observed in old AL mice. These results indicate that amelioration of the histological severity of disease in SG of B/W mice is paralleled and possibly mediated by increased expression of immunosuppressive TGFβ1 and decreased expression of proinflammatory cytokines.

Ductal carcinoma in situ treated with lumpectomy and irradiation: Histopathological analysis of 49 specimens with emphasis on risk factors and long term results

Forty-nine women with ductal carcinoma in situ (DCIS) treated with lumpectomy and irradiation were studied retrospectively. The median age was 50 years (range, 29 to 73 years) and the median follow-up time from initiation of therapy was 86 months (range, 17 to 230 months). Twelve patients presented with palpable masses (0.4 to 4 cm), three with breast thickening, and three with nipple discharge. In 31 patients the tumors were detected by mammography. Intraoperatively, excision of lesions was confirmed by specimen xray (38 specimens) or gross inspection (five specimens) and was recorded to be complete. No record was available in the other six patients. Margins of excision free of DCIS were microscopically confirmed in 25 specimens. The size of impalpable DCIS lesions recorded in 25 patients ranged from 0.4 to 5.0 cm (mean, 1.5 cm). Using Lagios' classification system, there were 18 classic comedocarcinomas, high nuclear grade (NG) with necrosis; seven cribriform/ papillary, high NG with necrosis; 17 cribriform/micropapillary, intermediate NG with or without necrosis; and seven cribriform/micropapillary, low NG without necrosis. In two patients residual malignant calcifications were present on the postoperative mammogram. Disease recurred in the treated breast at the site of incision in five patients at 18 months and 8, 11, and 12 (two patients) years from initial therapy. The rate of local disease recurrence was 2% at 5 years and 6% at 10 years; three recurrences showed invasive ductal carcinoma and two were DCIS. To evaluate risk factors the following characteristics were considered: necrosis, NG, histological type, periductal fibrosis, periductal lymphoid infiltrate, margin status, age, and method of tumor detection. The end points chosen were recurrence and death from any cause (because only one patient died of disease). Although the recurrences were attributed to residual disease in two patients, of the clinical and pathological parameters evaluated, only periductal fibrosis showed a significant relationship with outcome, with a P value ≤ .05 by the Wilcoxon test. On the other hand, using the proportional hazards model, necrosis was a significant predictor for recurrence ( P = .02), as was the pair fibrosis and tumor detection when taken together ( P = .05). Fibrosis significantly associated with high NG, Lagios' histological subtypes I and II, periductal lymphoid infiltrate, and necrosis ( P ≤ .0006). Our study indicates that (1) complete excision, based on specimen radiological/mammographic correlation, microscopic evaluation of resection margins, and postexcision mammogram, is an important determinant of local control; (2) determination of high risk factors (ie, periductal fibrosis, necrosis, and tumor detection) is important in predicting local failure; and (3) delayed tumor recurrence may be seen in high risk DCIS after radiation therapy (XRT).

Significance of tubuloreticular structures in infants with neonatal lupus erythematosus and their mothers with Sjögren's syndrome.

Four infants with neonatal lupus erythematosus who had annular erythema on the trunk and face reacted positively to tests for anti-Ro(SS-A)/La(SS-B) antibodies. Electron microscopic examination of vascular endothelial cells in the annular erythema revealed the presence of tubuloreticular structures. Once anti-Ro(SS-A)/La(SS-B) antibodies had turned negative, these tubuloreticular structures were no longer evident in the vascular endothelial cells in the same area where annular erythema had been present. Mothers of these 4 infants reacted positively to anti-Ro(SS-A)/La(SS-B) antibodies, but had no sicca syndrome. A biopsy taken from the minor salivary gland of the lip of each mother revealed marked periductal mononuclear cell infiltration. Primary subclinical Sjögren's syndrome was confirmed. Tubuloreticular structures were also observed in the vascular endothelial cells in the region of the minor salivary gland. These findings suggest that the presence of tubuloreticular structures may be related to anti-Ro(SS-A)/La (SS-B) antibodies.

Immunohistochemical distribution of c‐erbB‐2 in in situ breast carcinoma—a detailed morphological analysis

An immunohistochemical study of c-erbB-2 expression was carried out on in situ (non-invasive) breast carcinoma, using antibody 21N, raised to the intracytoplasmic domain of the c-erbB-2 oncogene product. Strong membrane staining was observed in 44 out of 74 (59 per cent) cases of ductal carcinoma in situ (DCIS), but none of 48 lobular carcinoma in situ (LCIS) lesions. A detailed comparative morphological evaluation using several different parameters, including histological subtypes, was performed within the DCIS group. The results showed that there was a significant correlation between c-erbB-2 expression and the presence of large cell size, periductal lymphoid cell infiltration, marked nuclear pleomorphism, multinucleation, and a high mitotic rate. Of these, cell size appears to be the most important predictor of c-erbB-2 status, followed by the presence of periductal lymphoid cell infiltration. These results indicate, firstly, that LCIS and DCIS are biologically (as well as histologically) different and, secondly, that a subgroup of DCIS, which is associated with c-erbB-2 over-expression, exists and appears to have distinct histological features. The subgroup of DCIS cases which over-express c-erbB-2 may be a biologically definable category with prognostic importance. These results may therefore have relevance to breast screening programmes, but a larger study incorporating clinical data would be necessary to correlate these findings with clinical outcome.

Neonatal Lupus Syndrome and Microtubular Structure

A female infant, at 6 weeks old, with the clinical manifestation of annular erythemas on the trunk and face, was positive for anti-SS-A and anti-SS-B antibodies. The annular erythema disappeared spontaneously at the age of 7 months when anti-SS-A and anti-SS-B antibodies were negative. Electron microscopic observation of the vascular endothelial cells on the annular erythema revealed microtubular structures. Later microtubular structures were found absent from the vascular endothelial cells of the area where the annular erythema had disappeared. The patient's mother is suffering from Sjögren's syndrome; she has no clinical symptoms but anti-SS-A and anti-SS-B antibodies are positive and a biopsy of small salivary glands of the lip demonstrated a marked periductal mononuclear cell infiltration. Microtubular structures were observed in her vascular endothelial cells in the small salivary gland region. These findings suggest that disappearance of microtubular structure may have some relationship with anti-SS-A and anti-SS-B antibodies.

Lacrimal gland, cornea, and tear film in the NZB/NZW F1 hybrid mouse.

The NZB/NZW F1 hybrid mouse has been reported to contract a disease similar to Sjögren's syndrome in man. We studied lacrimal gland morphology, corneal morphology, and tear osmolarity in this mouse as a function of age. Lacrimal glands of hybrid mice contained abnormal periductal infiltrates of lymphocytes and plasma cells. Maximum infiltration of the lacrimal gland occurred in the 29-week-old female hybrid mouse and was estimated to involve 12% of the gland, but was insufficient to alter tear osmolarity relative to DBA and Balb/c control mice. Nevertheless, both NZB/NZW F1 hybrid mice and DBA and Balb/c control mice had tear osmolarity and corneal surface morphology similar to that reported for keratoconjunctivitis sicca in man. Although the NZB/NZW F1 hybrid mouse may provide a valuable model for the study of lacrimal gland infiltration, since its tear osmolarity and ocular surface remain normal for a mouse, its usefulness as a model for ocular surface disease in human keratoconjunctivitis sicca may be more limited than previously thought.

Immunocompetent cells in labial salivary glands in secondary Sjögren's syndrome associated with SLE.

T and B lymphocyte (sub)populations were identified by monoclonal hybridoma antibodies (the avidin-biotin-peroxidase complex method), in the periductal lymphocyte-rich infiltrates in the labial salivary glands of 8 patients with secondary Sjögren's syndrome (2 degrees SS) associated with systemic lupus erythematosus (SLE). 59 +/- 7% and 17 +/- 3% of inflammatory round cells in situ were T3-positive and surface(SIg)- or cytoplasmic(CIg) immunoglobulin-positive, respectively. This suggests a local T lymphocyte dominance in salivary glands in 2 degrees SS associated with SLE. The local ratio of cells expressing T inducer/helper: T suppressor/cytotoxic phenotype was 3.5 +/- 0.8 (range 0.9-7.6) indicating large variations between individual patients. 46 +/- 9% of all inflammatory cells in situ were endogenous peroxidase-negative, Ia-positive cells, suggesting an active role for the locally accumulated T lymphocytes.

Sjögren's syndrome in systemic lupus erythematosus and rheumatoid arthritis: immune effector cells in salivary glands.

A simultaneously capturing azo dye method for acid alpha-naphthyl acetate esterase was used to characterize the cellular infiltrate in labial salivary glands in 25 patients with Sjögren's syndrome (SS). There was no significant difference in the T-pattern lymphocyte percentage in situ between the untreated group with SS and the group treated with 10 +/- 2 mg prednisone/day. There was a significant correlation (P less than 0.05) between the T-pattern lymphocyte percentage in situ and the focus-score value. In secondary (2 degrees) SS in cases of systemic lupus erythematosus (SLE) and rheumatoid arthritis, respectively, 55% +/- 4% (range 41-69) and 43% +/- 7% (range 15-80) of all inflammatory cells in the periductal lymphocyte-rich infiltrates were T-pattern lymphocytes. In other SS patients the corresponding value was 28% +/- 7% (range 4-50). The T-pattern lymphocyte percentage in situ was dependent on the disorder associated with SS (P = 0.07). The present results indicate the dominance of T-lymphocytes in situ in 2 degrees SS with SLE and suggest that there are differences in cell-mediated immunity in different clinical subgroups of SS.

In situ characterization of the cellular infiltrate in labial and palatine glands in Sjögren's syndrome.

The inflammatory cells in the minor salivary glands in situ in 11 patients with Sjögren's syndrome were characterized by using intracellular markers for T lymphocytes, plasma cells, mononuclear phagocytes and granulocytes. The methods used to demonstrate the markers were optimized histochemical and immunoperoxidase techniques which did not disturb the simultaneous morphological study of the marker-positive cells. Acid alpha-naphthyl acetate esterase (ANAE)-positive T lymphocytes accounted for 33 +/- 22%, mononuclear phagocytes for 8 +/- 4% and ANEA-negative (B) lymphocytes for 59 +/- 23% of all cells in the periductal lymphocyte-rich infiltrates, indicating great variations between individual patients. However, variations between labial and palatine glands in individual patients were usually less than 10%, indicating that the disease was at the same stage. Plasma cells were located peripherally to the lymphocytic foci and situated between the glandular acini. Equal proportions of plasma cells containing kappa-light chains (34 +/- 8%) and lambda-light chains (31 +/- 10%) were seen in individual patients, indicating polyclonal B lymphocyte activation. The results indicate differences in the local pathogenetic mechanisms or stage of disease in individual patients with Sjögren's syndrome.

The pathogenesis of miliaria rubra. Role of the resident microflora.

Anhidrosis was induced in volunteers by covering the skin with an impermeable plastic film. The degree of sweat suppression and miliaria after a thermal stimulus was directly proportional to the increase in the density of resident aerobic bacteria, notably cocci. No anhidrosis resulted when antibacterial substances were used to prevent the expansion of the microflora. Histological study showed a PAS-positive diastase resistant amorphous mass deep within the acrosyringium after 2 days of occlusion, accompanied by a periductal dermal infiltration of leukocytes. After another 2 days the duct became clogged by an amalgam of degenerating leukocytes. This impaction sloughed after about 3 weeks as a result of epidermal renewal. Colonies of bacteria were never found within the ducts. It is postulated that cocci secrete a toxin which injures luminal cells and precipitates a cast within the lumen. Infiltration by leukocytes creates an impaction which completely obstructs the passage of sweat for several weeks.

Preneoplastic changes in rabbit pancreatic duct cells produced by dimethylhydrazine.

Permeation catheters containing 40% dimethylhydrazine (DMH) were implanted into the main pancreatic duct of New Zealand white rabbits. The catheters were constructed of silicone polycarbonate with a 4- to 10-day carcinogen release rate. Rabbits implanted with catheters containing DMH showed pancreatic ductal cell hyperplasia, metaplasia and dysplasia with periductal cell infiltration, adenosis and adenoma formation. These changes began approximately 9 to 12 weeks after implantation and persisted for 75 to 80 weeks. Specificity of the delivery system appeared to be excellent in that pathologic effects were observed only in the pancreatic and peripancreatic tissues. Moreover, these effects were probably directly related to the implanted carcinogen since similar maintained effects were not observed in control animals.

Inflammatory damage to ducts in mammary dysplasia: a cause of duct obliteration.

Study of 600 cases of benign mammary dysplasia showed periductal foam-cell infiltration in 62 cases. Fibrotic obliteration of ducts was found in 24-2 per cent. of the lesions with foam-cell infiltrates. By contrast, lesions of benign mammary dysplasia lacking periductal foam-cell infiltration showed a significantly lower proportion of ductal obliteration (3-3 per cent). The differences between the proportions of lesions containing obliterated ducts was most marked in younger subjects before the age of 50 yr; thereafter the differences became very much less. On the basis of the morphological observations it is suggested that periductal mastitis with significant foam-cell infiltration may damage the ducts. Some ducts appear to become occluded by collagenous plugs, whereas others show evidence of epithelial regeneration, recanalisation and healing. These findings suggest that periductal mastitis with prominent foam-cell infiltration may be the cause of one type of fibrotic duct obliteration.

Periductal foam cells in benign mammary dysplasia.

The morphology and associations of periductal foam cells were studied in an unselected consecutive series of 576 lesions of benign mammary dysplasia. Periductal foam cells were found to all ages in 10-1 per cent. of the lesions. Their copious foamy cytoplasm, associations with giant cells and infiltrates of periductal small round cells, ochrocytes and colostrum cells suggest that they are macrophages. Mammary epithelium was often damaged at the site of periductal foam-cell infiltration.

Effects of cadmium upon the excurrent duct system of the rat testis.

AbstractThis report describes lesions observed in excurrent ducts of the testis in 152 of 518 rats, in the course of studies concerned with cadmium‐induced testis injury and the actions of selenium and zinc, separately and combined, in protecting against such damage. All elements were injected subcutaneously, as soluble salts. Necropsy was usually five days (77% of rats) after cadmium injection, but lesions were observed within six hours.Ductuli efferentes showed variable degrees of sperm blockage, epithelial hyperplasia and metaplasia, periductal round cell infiltration, fibrosis and contraction. In 56 of 93 rats showing only ductuli lesions, testes were either normal or exhibited dilation of the rete testis and of variable numbers of seminiferous tubules, with or without “pressure degeneration” of the germinal epithelium. In the other 37 rats, the testes showed cadmium‐induced injury.Lesions involving both ductuli efferentes and proximal segments of the caput epididymis (13 rats), or the latter alone (46 rats), tended to be associated with more severe testis damage. Epididymal lesions were characterized by focal proliferation and desquamation of duct epithelia, and formation of spermatoceles.The lesions observed were attributed primarily to ischemia, secondary to effects of cadmium upon the capillary bed of the tissues involved. However, their possible enhancement or modification by direct chemical action of cadmium, selenium or zinc upon the duct system or perivascular tissues could not be excluded.

Photosensitivity diseases in New Zealand

Summary Facial eczema damage in the rabbit is essentially the same as that in the sheep and guinea pig, but the lesion in the rabbit is much more acute and develops more rapidly. The essential feature is an acute cholangitis characterised by periductal oedema, fibrosis, and cellular infiltration. The extra-hepatic biliary system is markedly affected. The degree of oedema and fibrosis is proportional to the size of the duct. The smallest duct branches often show no change. Occlusion of medium-sized ducts and proliferation of bile ductules proximal to the site of occlusion is also seen. Branches of the portal vein and hepatic artery become involved in the inflammatory process and damage to the wall of these vessels sometimes occurs.