Giant cell arteritis. Epidemiology, etiology and pathogenesis.

Giant cell arteritis (GCA) is a chronic inflammatory disorder targeting large and medium-sized arteries, which predominantly affects postmenopausal women. Its high incidence in populations with Scandinavian lineage, some familial accumulation, and the association with the HLA-DR4 haplotype indicate a genetic predisposition. Epidemiological observations, as well as the symptomatology, may indicate an infectious origin, but so far GCA has not been shown to be a truly infectious form of vasculitis. Immunological research indicates an antigen-driven disease with local T-cell and macrophage activation in the vessel wall. Morphologically, the inflammatory process appears to be initiated by a foreign-body giant-cell attack on calcified internal elastic membrane in arteries and on calcified atrophic parts of the aortic media. The ensuing diffuse chronic inflammation leads to vessel dilatation and extensive intimal thickening. The latter, which relates to the production of promoting factors by the inflammatory cells, causes arterial stenosis and ischemic complications. The possible role of female sex hormones in GCA requires further investigation. Mononuclear and giant cells in GCA display the cytoplasmic accumulation of estrogen receptor (ER) alpha. Cytoplasmic ER-alpha is also seen in media smooth-muscle cells in GCA and in non-GCA controls, but nucleotide sequence analysis of the ER-alpha gene revealed no differences between GCA patients and controls. In the future, comprehensive morphological, cell biological and immunological research will be required for a better understanding of the complex etiology and pathogenesis of GCA.

Atrophy of the aortic media in giant cell arteritis.

Aortic tissue from seven patients with giant cell arteritis (GCA) was investigated using light microscopy and immunocytochemistry. Four surgical cases and three autopsy cases were included. All the specimens displayed a severe reduction in the size and number of media smooth muscle cells immunopositive for alpha-smooth muscle actin (alpha-SMA). A subtotal loss of alpha-SMA-positive cells was seen in non-inflamed media tissue, continuing gradually towards multiple calcified acellular lesions totally devoid of alpha-SMA immunoreactivity. There was a slight to moderate granulomatous inflammatory reaction in the tissue surrounding part of the acellular lesions. Foreign body giant cell reaction and elastin degradation were found at the ends of the acellular calcified areas. The present findings indicate that the atrophy and the loss of alpha-SMA-positive cells in the aortic media in GCA is primary, and that the granulomatous reaction is secondary and directed against atrophic calcified media tissue.

Tumours in Iceland. 17. Malignant tumours of the oesophagus. Histological classification and epidemiological considerations.

We studied all primary malignancies of the oesophagus diagnosed in Iceland between 1955 and 1984 and reclassified tumours where histological material was available using the WHO classification system. Of a total of 329 tumours diagnosed in the time period, seven were excluded for various reasons. Of the remaining 322 tumours, 178 were in males and 144 in females. The age standardized incidence was 5.3/10(5) for males and 3.1/10(5) for females. The incidence of oesophageal tumours decreased for both sexes during the time period under investigation. Of 250 reclassified tumours (142 in males and 108 in females), squamous cell carcinomas comprised 81.6%. If the undifferentiated tumours are excluded, the squamous group accounted for 89.1% of the remaining tumours. Small cell carcinomas comprised 3.2% of all cases, which was higher than expected. Most of the tumours appear to be located in the middle part of the oesophagus. The vast majority of resected tumours extended through the wall of the oesophagus. A relatively higher proportion of tumours was confined to the submucosal or muscular layers in the latter half of the period. In conclusion, the epidemiological data in our study appear to resemble what is observed in the other Nordic countries for oesophageal tumours, except for slightly higher overall incidence in Iceland, especially for women.

A child with a t(11;19)(q14-21;p12) in a pulmonary mucoepidermoid carcinoma.

We report on a mucoepidermoid carcinoma (MEC) of the lung in a 6-year-old girl with a t(11;19)(q14-21;p12) as the sole karyotypic abnormality. An apparently identical t(11;19) has been reported previously in a MEC originating from the major and minor salivary glands. Our findings indicate that the t(11;19) is intimately associated with the mucoepidermoid phenotype and may be used as a diagnostic marker for this tumour type.

Ectopic metaplastic ossification after sternotomy.

Ectopic ossification is a rare complication after a major operation. We report a case of cutaneous infection and metaplastic ossification in an 80-year-old man who underwent coronary artery bypass grafting 4 years earlier. Computed tomographic scan demonstrated a partial pseudarthrosis of the corpus sterni. The infected part of the sternal scar was excised and sternal wires were removed. Eight months later, the wound has healed without complications and the cutaneous ossification is unaltered.

Vessel wall morphometry in giant cell arteritis.

OBJECTIVE: To investigate morphometrically the relationship between the degree of inflammatory reaction and arterial cross-sectional dimensions in giant cell arteritis (GCA). METHODS: The media and intima of cross-sectioned inflamed arteries from GCA patients were outlined. The media circumference and the media and intima cross-sectional areas were measured. The two segments in every biopsy displaying the least and most widespread media inflammation were compared, using a paired Student's t-test. Moreover, paired comparisons were made of the intima area in inflamed and noninflamed sectors in single cross-sections. RESULTS: The segment in each biopsy showing the most widespread media inflammation had the largest circumference and volume of media and intima; the intima cross-sectional area increased disproportionately. The intima was thickest in inflamed sectors in single cross-sections. CONCLUSION: The close spatial correlation between inflammatory media infiltration and the marked intimal expansion supports the contention that promoting factors produced by inflammatory cells play a pathogenetic role in GCA.

The pathogenesis of giant cell arteritis: morphological aspects.

The light-microscopic, electron-microscopic and immunocytochemical characteristics of giant cell arteritis (GCA) have been investigated in a number of studies on temporal arteries. Arterial atrophy and calcification of the internal elastic membrane appear to be prerequisites for the evolution of the inflammatory process. Foreign body giant cells form close to calcifications, apparently without connection with other inflammatory cells and probably by the fusion of modified vascular smooth muscle cells. The foreign body giant cells attack the calcifications. Lymphocytes accumulate around them and may be found in pockets in their cell surface. This focal reaction is found in atrophic, calcified arterial segments in a minority of inflamed temporal artery biopsies. More commonly seen is a diffuse mononuclear attack of the vessel wall in atrophic as well as non-atrophic segments which leads to severe arterial dilatation. Langhans giant cells form by the fusion of macrophages in the diffuse inflammatory infiltrate. The fact that the diffusely inflamed arteries are markedly widened compared to the focally inflamed vessels suggests that the inflammatory process starts as a focal foreign body giant cell reaction directed at calcifications which in turn initiates a more diffuse and widespread inflammation.

Morphological aspects of giant cells in giant cell arteritis: an electron-microscopic and immunocytochemical study.

OBJECTIVES: To compare the morphology of foreign body and Langhans giant cells in the two different inflammatory phases of giant cell arteritis (GCA). METHODS: Electron microscopy was performed on 6 positive temporal arterial biopsies. Light microscopy and immunocytochemistry for macrophage-associated antigen (KP1) and alpha-smooth muscle actin (alpha-SMA) were performed on 16 positive biopsies. RESULTS: A focal granulomatous reaction with foreign body giant cells was found only in association with the internal elastic membrane (IEM) in atrophic arterial segments, which often displayed calcification of the IEM. Diffuse invasion of lymphocytes and monocytes/macrophages affected non-atrophic as well as atrophic arterial segments. Within such segments Langhans giant cells were found in all layers of the wall. Electron microscopy of biopsies displaying the focal foreign body reaction revealed that large cells devoid of lysosomes but with cytoplasmic densities, tightly packed cytoplasmic filaments and numerous micropinocytotic vesicles formed clusters close to calcified parts of the internal elastic membrane. Furthermore, foreign body giant cells were surrounded by large cells devoid of lysosomes. Lysosomes tended to concentrate in central parts of the foreign body giant cells. In the diffusely inflamed arteries, the Langhans giant cells were surrounded by mononuclear cells rich in lysosomes. The lysosomes in the Langhans giant cells were more evenly distributed than in foreign body giant cells. Immunocytochemistry of biopsies displaying the focal granulomatous reaction revealed an uneven, often central immunoreactivity for the macrophage marker (KP1) in the foreign body giant cells, and immunostaining for alpha-smooth muscle antigen (alpha-SMA) showed their poor delineation from the surrounding vascular smooth muscle cells. The Langhans giant cells in the diffusely inflamed arteries displayed a strong even cytoplasmic immunoreactivity for KP1 and a distinct delineation from the smooth muscle cells in the alpha-SMA staining. CONCLUSION: Differences in terms of distribution, light microscopy, immunocytochemistry and electron microscopy between the two types of giant cells in GCA indicate a difference in their function as well as their histogenesis.

Estrogen receptors in giant cell arteritis. An immunocytochemical, western blot and RT-PCR study.

OBJECTIVE: Giant cell arteritis (GCA) is a chronic form of vasculitis which predominantly affects women over 50 years of age. The aim of this study was to analyse the presence of estrogen receptor alpha (ER) in the temporal arteries of patients with GCA. METHODS: Inflamed temporal artery biopsies from 43 GCA patients were stained with monoclonal antibodies to two different segments of the ER and compared with non-inflamed arteries from age- and sex-matched controls who had not received a clinical diagnosis of GCA. The protein that was extracted from 4 GCA-positive biopsies and 4 non-GCA controls was analysed using the Western blot method with a monoclonal antibody to ER. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis using primer pairs specific to ER-cDNA was performed on the total RNA from 4 GCA-positive biopsies and 4 non-GCA controls. RESULTS: The inflamed arteries expressed distinct cytoplasmic immunoreactivity to ER in activated mononuclear inflammatory cells and in giant cells. Biopsies from GCA patients and controls displayed cytoplasmic ER positivity in smooth muscle cells. Western blot analysis revealed two bands corresponding to approximately 64 and 54 kDa, respectively, in the inflamed arteries and controls. In the inflamed biopsies and non-GCA controls, RT-PCR analysis revealed a strong band corresponding to approximately 670 bp, as expected, and a weaker band corresponding to approximately 440 bp. CONCLUSION: In inflamed arteries from GCA patients, smooth muscle cells, activated mononuclear inflammatory cells and giant cells express cytoplasmic ER. Non-inflamed control arteries also express cytoplasmic ER in smooth muscle cells. The accumulation of cytoplasmic ER may suggest the involvement of estrogen not only in GCA but also in normal vascular aging. The results justify further investigations into the pathogenetic roles of estrogen metabolism in GCA.

Estrogen receptor alpha in giant cell arteritis: a molecular genetic study.

OBJECTIVE: Giant cell arteritis (GCA) predominantly affects postmenopausal women. Estrogen receptor alpha (ER alpha) accumulates in the cytoplasm of smooth muscle cells, activated mononuclear inflammatory cells and giant cells in the temporal arteries of GCA patients, as well as in smooth muscle cells in arteries from non-GCA controls. The aim of this study was to analyse whether this accumulation is related to structural aberrations in the ER alpha mRNA leading to a change in protein structure. METHODS: Total RNA was extracted from inflamed temporal artery tissue in two GCA patients and from non-inflamed arteries in two non-GCA controls. Products from the nested RT-PCR of the cDNA were cloned and plasmid inserts of 20 different clones from each case were investigated using nucleotide sequence analysis. RESULTS: A total of eight different types of transcripts lacking parts of the ER alpha mRNA were detected. Seven of these could be explained by alternative splicing. There were no significant differences between the GCA patients and the non-GCA controls in terms of the number of transcript variants. CONCLUSION: The accumulated cytoplasmic ER alpha in temporal arterial tissue from elderly persons appears mainly to be of wild type. The main structural changes in the ER alpha mRNA may be due to alternative splicing. Somatic mutations of the ER alpha gene appear to be rare and it is therefore unlikely that they are involved in the pathogenesis of GCA.

Calcification of the internal elastic membrane in temporal arteries: its relation to age and gender.

OBJECTIVE: To investigate the age and sex distribution of calcifications of the internal elastic membrane (IEM) in temporal arteries. METHODS: Calcifications of the IEM were assessed light-microscopically in temporal arteries from 40 women and 21 men, aged 51 or more, who were known not to have giant cell arteritis (GCA). Their relation to age and the difference between women and men were tested statistically. RESULTS: The IEM calcifications differed morphologically from the calcifications in Mönckeberg's mediosclerosis and atherosclerosis. They increased significantly with age and were 2.62 times more common in women than men. CONCLUSION: Previous morphological studies indicate that the inflammatory process in GCA is initiated by a foreign-body, giant-cell attack on calcifications of the IEM. The present study showed that IEM calcifications in non-GCA controls show an age and sex distribution similar to that of GCA morbidity. The results may indicate that the presence of IEM calcifications in the general population influences the age and sex distribution of GCA. Furthermore, the findings support the hypothesis that the calcifications, although not disease specific, may play a pathogenetic role in the latter.

Synchronous pulmonary metastases from renal cell carcinoma--a whole nation study on prevalence and potential resectability.

BACKGROUND: At the time of diagnosis, almost one third of patients with renal cell carcinoma (RCC) have metastasis. We studied the prevalence, survival, and potential resectability of synchronous pulmonary metastases (SPMs) in a well-defined cohort of RCC patients. MATERIAL AND METHODS: A retrospective whole nation study including RCC patients with SPM diagnosed 1970-2005 in Iceland. Imaging studies and histology were reviewed, the TNM system used for staging the primary tumors, and disease-specific survival estimated. Eligibility for SPM removal was evaluated using different criteria from the literature on surgical management of SPM, including solitary SPM and SPMs confined to one lung. RESULTS: Altogether, 154 patients (16.9%) had SPMs. In 55 of these patients (35.7%) the lungs were the only site, with detailed information available in 46 cases. Of these 46 patients with SPMs, 15 were unilateral, and of those 11 were solitary. All of these 11 patients were in good physical condition and were deemed eligible for surgical resection; however, only one of them was operated with metastasectomy. Disease-specific survival at five years for patients with solitary SPM was 27.2%, as compared to 12.7%, 7.1%, and 12.0% for patients with unilateral SPMs, all patients with SPMs, and patients with extrapulmonal metastases, respectively (p = 0.33). CONCLUSION: At the time of diagnosis, 16.9% of RCC patients had SPM. In one in three of these SPM patients metastases were confined to the lungs, while one in five had solitary pulmonary metastases. Although the benefit of pulmonary metastasectomy in RCC is still debated and criteria for resection are not well defined, it appears that many RCC patients with SPM are potentially eligible for pulmonary metastasectomy.

Renal cell carcinoma in young compared to older patients: comparison of clinicopathological risk factors and survival.

OBJECTIVE: Renal cell carcinoma (RCC) is primarily a disease of the elderly, most patients being diagnosed in their mid-60s. However, a significant number of patients are diagnosed at a younger age. The true effect of age at diagnosis on survival has been debated, tumor stage and grade being the strongest prognostic factors of survival. The aim of this nationwide study was to study the significance of young age at diagnosis as a prognostic factor in RCC. MATERIAL AND METHODS: This retrospective study included all living patients with histologically verified RCC in Iceland diagnosed between 1971 and 2000 (n = 629). Different clinicopathological factors of patients diagnosed aged < 50 years (n = 99) were compared to those of patients diagnosed aged > or = 50 years (n = 530). Disease-specific survival was compared and multivariate analysis was used to evaluate prognostic variables. RESULTS: Clinical presentation, TNM stage, grade, tumor size and histological subtypes were comparable between the two groups. Prognostic factors were the same in both groups, most of them having a stronger prognostic value in younger patients. Both 5- and 10-year disease-specific survival was significantly higher in the younger group (66.4% vs 54.5% at 5 years). CONCLUSIONS: The clinicopathological profiles are comparable in RCC patients aged < and > or = 50 years. The reason for the more favorable survival of younger patients is not known. Further studies are needed, including studies on possible differences in age-specific host-tumor response.

The epidemiology of biopsy-positive giant cell arteritis: special reference to changes in the age of the population.

OBJECTIVE: The incidence of giant cell arteritis (GCA) increases with age. The aim of the present study was to investigate whether the increasing incidence of biopsy-proven GCA in Göteborg, Sweden, could be explained in terms of a change in the age composition of the general population. METHODS: All cases of biopsy-verified GCA between 1976 and 1995 were recorded. The annual incidence was calculated for women and men aged 50 yr or older and its relationship with the age composition of the general population was tested statistically. RESULTS: There was a significant positive correlation between age and the risk of developing GCA. In the general population, there was a shift towards higher age; in 1976, the mean age of people 50 yr or older was 63.2 (men) and 65.0 (women), whereas in 1995 it was 65.0 (men) and 68.1 (women). After compensating for this, the incidence of biopsy-proven GCA still increased significantly. Moreover, for women aged 50 yr or older, the risk of developing the disease increased more among younger subjects than older ones. CONCLUSIONS: The increase in the incidence of biopsy-proven GCA between 1976 and 1995 could not be explained merely in terms of the increasing age of the general population. It is most probably related to an increase in the influence of other factors.

The epidemiology of biopsy-positive giant cell arteritis: special reference to cyclic fluctuations.

OBJECTIVE: The aim of this work was to study changes in the incidence of biopsy-proven giant cell arteritis (GCA) over a period of 20 yr in Göteborg, Sweden. METHODS: All cases of biopsy-verified GCA between 1976 and 1995 were included in the study. The annual incidence was calculated for the whole material, for women and men separately, and its fluctuations were tested statistically. In addition, the monthly variation during the last 9 yr could be statistically analysed for the whole material. RESULTS: In total, 665 patients were diagnosed with biopsy-verified GCA during the 20 yr period. The average annual incidence was 22.2/100000 inhabitants over 50 yr of age (women 29.8, men 12.5). The annual incidence increased significantly with time (P<0.001) for both men and women. Statistical analysis did not reveal any cyclic fluctuation in the annual incidence (P=0.26), while the monthly number of positive biopsies showed significant fluctuation with peaks in late winter and autumn (P=0.041). CONCLUSIONS: The annual incidence of biopsy-positive GCA increased during the years 1976 through 1995. The significant seasonal variation, as well as considerable variation in annual incidence, might be due to the influence of exogenous triggering factors, such as infections. Further support for an exogenous aetiology, in terms of a statistically significant cyclic fluctuation of the annual incidence, was not found, however.

Search for varicella zoster virus in giant cell arteritis.

Polymerase chain reaction and immunohistochemical analyses of formalin-fixed temporal arteries from 10 pathologically verified cases of giant cell arteritis did not reveal varicella zoster virus antigen or DNA.