Imaging of gynecological disease (4): clinical and ultrasound characteristics of struma ovarii.

OBJECTIVES: To describe the clinical history and ultrasound findings in women with struma ovarii. METHODS: Women with a histological diagnosis of struma ovarii who had undergone preoperative ultrasound examination were identified from the databases of five ultrasound centers. The tumors were characterized on the basis of ultrasound images, ultrasound reports and research protocols (when applicable) using the terms and definitions of the International Ovarian Tumor Analysis (IOTA) group. In addition, four authors reviewed all ultrasound images and described them using pattern recognition. RESULTS: Of 31 patients identified, 16 had pure struma ovarii (one malignant), whereas in 15 patients the struma ovarii were 'impure', constituting the major part of a dermoid cyst (all benign, bilateral in one case). Median age was 40 (range, 18-80) years and 22 (71%) patients were of fertile age. Thirteen patients (42%) were asymptomatic, nine (29%) presented with pain, six (19%) with bloating, two (6%) with irregular bleeding and one (3%) with thyreotoxicosis. Most pure struma ovarii (11/16 cases, 69%) contained solid components, but cystic components were always present. The color content at Doppler examination varied from none to abundant. Four patients had ascites. Using pattern recognition the most specific feature of pure struma ovarii was the 'struma pearl', i.e. a smooth roundish solid area, similar, but not identical, to the 'round white ball' seen in dermoid cysts. 'Struma pearls' were present in six cases of pure struma ovarii. Most (10/16, 63%) cases of impure struma ovarii manifested ultrasound features compatible with a dermoid cyst, but six manifested ultrasound features similar to those of pure struma ovarii, 'struma pearls' being seen in three of these. CONCLUSIONS: The sonographic features of struma ovarii vary. Struma ovarii may be suspected when a 'struma pearl' is seen. Whether 'struma pearls' are indeed a specific ultrasonographic feature of struma ovarii needs to be determined in a prospective study.

Lymphoma and other malignancies in primary Sjögren's syndrome: a cohort study on cancer incidence and lymphoma predictors.

OBJECTIVES: To assess the risk of lymphoproliferative disease or other malignancy (standardised incidence ratios (SIRs)), in patients with primary Sjögren's syndrome according to the American-European Consensus Criteria (AECC), compared with patients with sicca syndrome (non-AECC) and the background population. To identify predictors of malignancy and describe lymphoma types and survival probabilities. METHODS: A linked register study using information from the Malmö Primary SS Register, Swedish Cancer Register, and Cause-of-Death Register for calculation of SIRs was carried out. Detected lymphomas were reclassified according to the WHO classification. Cox regression analysis was used to study the predictive value of clinical, laboratory, and histological findings at the time of diagnosis. RESULTS: 507 patients with a median follow up of 8 years (range 1 month to 19 years) were included. SIRs (95% confidence interval (CI)) for malignancies in total and for non-Hodgkin's lymphomas (NHL) were 1.42 (0.98 to 2.00) and 15.57 (7.77 to 27.85), respectively, in those fulfilling the AECC (n = 286). In non-AECC sicca patients (n = 221) SIR for malignancy of any kind was 0.77 (0.41 to 1.32); no lymphoproliferative neoplasms were detected. Significant predictors of lymphoproliferative disease were purpura/skin vasculitis (hazard ratio (HR) = 4.64, 95% CI 1.13 to 16.45), low complement factor C3 (HR = 6.18, 95% CI 1.57 to 24.22), low C4 (HR = 9.49, 95% CI 1.94 to 46.54), CD4+ T lymphocytopenia (HR = 8.14, 95% CI 2.10 to 31.53), and a low CD4+/CD8+ T cell ratio < or = 0.8 (HR = 10.92, 95% CI 2.80 to 41.83). 7/12 (58%) NHLs were diffuse large B cell lymphomas. CONCLUSION: A 16-fold increased risk for development of NHL was found. CD4+ T lymphocytopenia is an additional strong risk factor for developing lymphoma.

Polymerized alpha-antitrypsin is present on lung vascular endothelium. New insights into the biological significance of alpha-antitrypsin polymerization.

AIMS: The damage to lung tissue in chronic obstructive pulmonary disease (COPD) may involve the progressive loss of pulmonary vascular endothelial cells. Endothelial binding of alpha1-antitrypsin (alpha1-AT) derived from plasma has been identified, and alpha1-AT deficiency is a known genetic risk factor associated with alpha1-AT polymerization and COPD development. Therefore, in the present study we aimed to investigate if alpha1-AT is present on the lung vascular endothelium, and if it is in a polymeric form. METHODS AND RESULTS: Postmortem paraffin-embedded tissue specimens from 15 COPD (chronic bronchitis and emphysema) cases with and without Z alpha1-AT (Glu342Lys) deficiency and from 10 cases without signs of COPD were studied. Immunohistochemistry was performed using the streptavidin-biotin method with a monoclonal ATZ11 antibody specific for polymeric alpha1-AT, and polyclonal antibodies against human alpha1-AT and neutrophil elastase. Vascular endothelium showed intense staining for alpha1-AT with the ATZ11 antibody in all cases; however, intensity of staining in patients with alpha1-AT deficiency was greater. No endothelial staining was observed with the anti-elastase antibody. CONCLUSIONS: This is the first demonstration that alpha1-AT bound to the vascular endothelium of lungs is in a polymeric form, which also suggests a possible previously unknown role for polymeric alpha1-AT in vivo.

Synthesis of gamma-carboxylated polypeptides by alpha-cells of the pancreatic islets.

gamma-Carboxylated proteins were detected in normal human pancreas by immunohistochemistry with a monoclonal antibody (M3B) specific for gamma-carboxyglutamyl residues. Staining appeared to be localized to the glucagon-secreting alpha-cells in the islets of Langerhans. Consistent with this, sections from a glucagonoma were stained much more intensely with the M3B antibody than those from an insulinoma. A murine alpha-cell line (alphaTC1 Clone 9) was cultured and gamma-carboxylated polypeptides, identified immunologically as prothrombin, protein S and (tentatively) Gas6, were isolated from the intracellular compartment by chromatography on an M3B-coupled resin. As in liver, prothrombin is synthesized by alpha-cells as a gamma-carboxylated zymogen that can be cleaved by ecarin to form an active serine protease that is inhibited by hirudin. The pancreas thus appears to be a novel site of synthesis for certain vitamin K-dependent proteins.

A functional prothrombin gene product is synthesized by human kidney cells.

gamma-carboxylated polypeptides were detected in the human kidney by immunohistochemistry with a monoclonal antibody (M3B) specific for gamma-carboxyglutamyl residues. An approximately 70-kDa gamma-carboxylated protein, subsequently identified as prothrombin, was isolated from the intracellular compartment of cultured human embryonic kidney (HEK293) cells by immunoaffinity chromatography on M3B-coupled resin. Immunohistochemical analyses demonstrated that prothrombin and another vitamin K-dependent protein, the growth arrest-specific protein 6, were detectable in human kidney. As in the liver, the kidney synthesizes prothrombin as a zymogen that can be cleaved by ecarin to an amidolytically active serine protease that is inhibited by hirudin. This demonstrates for the first time the de novo synthesis of a full-length, gamma-carboxylated, and functional prothrombin gene product by human kidney cells.

Ipsilateral local recurrence in relation to therapy and morphological characteristics in patients with ductal carcinoma in situ of the breast.

METHOD AND RESULTS: A standardized histopathological protocol has been designed, in which different histological characteristics of ductal carcinoma in situ (DCIS) are reported: nuclear grade (ng), growth pattern according to Andersen et al., necrosis, size of the lesion, resection margins and focality. Using this protocol a re-evaluation of a population-based consecutive series of 306 cases of DCIS has been done as well as a thorough clinical follow-up. After a median follow-up of 63 months, 13% have developed ipsilateral local recurrences, invasive and/or in situ. Ipsilateral local recurrence-free survival (IL-RFS) was significantly better for patients operated with mastectomy (ME) or breast conserving therapy (BCT) with radiotherapy (RT) than for patients operated with BCT without RT (5-year IL-RFS 96% vs 94% vs 79%, P<0.001). In the subgroup of BCT without RT there were significant differences in IL-RFS between histopathological subgroups: ng 1 + 2 (non-high grade) vs ng 3 (high grade; P=0.014), non-high-grade without comedo-type necrosis vs non-high-grade with comedo-type necrosis vs high-grade (the Van Nuys classification system; P=0.025). Growth pattern (not diffuse vs diffuse) and margins (free vs involved or not evaluated) showed a tendency (P=0.07 and 0.05, respectively) to be associated to IL-RFS. In contrast, no significant differences in IL-RFS were found in subgroups based on mode of detection, focality or size. Ninety-four per cent of the local recurrences after BCT appeared at the previous operation site. CONCLUSIONS: In the BCT without RT group, combinations of either non-high grade and not a diffuse growth pattern or non-high grade and free margins identified groups (constituting approximately 30% of the patients) were at low risk of developing ipsilateral recurrences (6-10%), compared to a 31-37% recurrence risk in the remaining groups during the observed follow-up time. The beneficial effect of post-operative RT for these low-risk groups can be questioned, and should be studied further.

Histologic grading in breast cancer--reproducibility between seven pathologic departments. South Sweden Breast Cancer Group.

Histologic grade, including tubular formations, nuclear grade, and mitotic activity, is a well-documented prognostic factor in breast cancer. In comparison with other prognostic parameters, the evaluation of histologic grade is cheap and can be performed, in principle, in all cases of breast cancer. One possible disadvantage is that the evaluation may vary between different pathological departments. The aim of the present work was therefore to study the reproducibility of the histologic grading system by distributing haematoxylin-erythrosin-stained slides from 93 invasive breast cancers to the seven pathology departments within the southern healthcare region of Sweden. The evaluation was performed blindly and without any knowledge of other clinical parameters. In 31% of the cases the same histologic grade was obtained for all departments. The overall mean kappa was 0.54, indicating a moderate reproducibility. Of the three factors included in histologic grade, the agreement was best for tubular formations and poorest for nuclear grade and mitotic activity. The overall moderate reproducibility should be considered when the clinical usefulness of histologic grading is compared with other prognostic instruments.

Detection of humoral antibodies to Renibacterium salmoninarum in rainbow trout Oncorhynchus mykiss and Atlantic salmon Salmo salar challenged by immersion and in naturally infected populations.

Humoral antibodies to heat-stable antigens of Renibacterium salmoninarum (Rs) were detected by enzyme-linked immunosorbent assay (ELISA) in rainbow trout Oncorhynchus mykiss and in Atlantic salmon Salmo salar challenged by immersion. A slow antibody response was found: 3% (1/30) was positive 4 wk after immersion and 72% (26/36) was positive after 8 wk. All 30 fish sampled after 4 wk were found to be infected, as determined by bacterial culture and/or the presence of soluble antigens in the kidney. At 6, 8 and 12 wk after immersion the proportion of positives indicated by ELISA was 58%. The Rs infection was detected by cultivation in 36% of sampled fish collected on the same occasion. Elevated antibody titres to Rs were detected in samples from both Atlantic salmon (59% in 1 farm) and from rainbow trout (20% in 1 of 5 sampled farms) in naturally exposed populations all of which classified positive for bacterial kidney disease (BKD). Elevated antibody titres were detected among sampled fish from populations of rainbow trout and salmon with clinical BKD. Samples collected from farm populations of rainbow trout, salmon and brown trout Salmo trutta, exposed to Rs but without clinical BKD, were negative in the ELISA, although Rs bacteria or soluble antigens were detected at the same sampling. The antibody ELISA method cannot be recommended for general fish health monitoring purposes, but may be a valuable tool for monitoring the disease progression during controlled experiments.

Oxyphil cell adenoma (oncocytoma) of the lacrimal sac. Review of the literature.

A case of oncocytoma of the lacrimal sac is presented. An 84-year-old woman with a mass in the lacrimal sac area and epiphora was operated with excision. Histological and electron microscopic examination revealed it to be an oncocytic adenoma. Oncocytic tumours of the lacrimal sac are very rare and to our knowledge this is the 14th case to be reported. Oncocytomas are composed of polyhedric cells with abundant oxyphil cytoplasm which is granular and contains large numbers of abnormal mitochondria. Non-neoplastic oncocytes may arise from the secretory epithelium of the sac in various chronic inflammatory states. They may also occur at an old age, as a result of the normal aging process.

Immunohistochemical analysis of oestrogen and progesterone receptors in endometriotic tissue and endometrium.

The objective of the study was to compare the localization and staining intensity of oestrogen and progesterone receptors in endometrium and endometriotic tissue. Using monoclonal antibodies towards oestrogen and progesterone receptors, analysis was performed in 63 endometriotic samples from 40 women and compared to endometrium obtained simultaneously from 25 of the women. Using a staining index, 'total immuno-staining score', calculated from the staining intensity multiplied by the fraction of positive cells, the receptor content was estimated semiquantitatively. The scores for both oestrogen and progesterone receptors were lower in endometriotic epithelial cells than in endometrial epithelial cells, but the differences reached statistical significance only for the progesterone receptor. No difference was found for stromal cells. There was a significant correlation between oestrogen receptor score in endometriotic tissue and in endometrium, but not for progesterone receptor score. In endometrium and vaginal and peritoneal endometriosis, the progesterone receptor score showed similar values, higher than those in ovarian endometriosis. The data from this large immunohistochemical study support previous results of quantitative steroid receptor analyses, indicating that the regulation of steroid effects, especially those of progesterone, differs between endometriotic and endometrial tissue.

CT of a parathyroid lipoadenoma. Case report.

A 54-year-old woman with primary hyperparathyroidism underwent parathyroid exploration following negative ultrasonography, CT and 99Tc-201Tl scintigraphy. A 2 x 1.5 x 1-cm large mass dorsal to the midportion of the left thyroid lobe was extirpated and a hyperfunctional lipoadenoma containing 70% or more of fatty tissue was verified microscopically. Retrospective evaluation of CT revealed a well demarcated lipomatous mass with a homogeneous density similar to that of subcutaneous fat corresponding to the surgical finding.

Joubert syndrome associated with Leber amaurosis and multicystic kidneys.

We describe a boy with manifestations of Joubert syndrome, Leber congenital amaurosis, and multicystic kidneys. In infants with unexplained neonatal tachypnea and late developmental delay, absence or hypoplasia of the cerebellar vermis should be sought. Joubert syndrome probably is an autosomal recessive disorder. In the subsequent pregnancy of the propositus' mother, we were able to make a prenatal diagnosis of Joubert syndrome, one of the first to be reported.

Radiotherapy for unresectable endocrine pancreatic carcinomas.

Surgery, when possible, is the treatment of choice for the uncommon endocrine tumours of pancreas. Unresectable cases are usually treated with cytostatic drugs or alpha-interferon. We describe a patient with unresectable, locally advanced endocrine pancreatic carcinoma (measuring 5 x 5 x 6 cm) that was totally cured by external radiation therapy only (40 Gy). This case together with four cases in the literature indicate that external radiation therapy should be considered in locally unresectable endocrine pancreatic carcinomas.

Bilateral and multifocal breast carcinoma. A clinical and autopsy study with special emphasis on carcinoma in situ.

Bilateral clinical breast carcinoma has been reported to appear in up to approximately 10% of patients with breast carcinoma. Increasing diagnostic activity has raised figures of bilaterality, mainly due to detection of lesions of the in situ type. Knowledge of the natural history of carcinoma in situ is incomplete and clinical implications are uncertain. In the present study bilateral lesions were analysed by extensive histological examination in the following groups of patients: (1) Forty-six women (median age 44 years) with clinical and mammographical unilateral invasive breast carcinoma, where the contralateral breast was removed at subcutaneous mastectomy (SCM) during the course of breast reconstruction, 24/46 (52%) had bilateral malignant lesions, four invasive carcinomas and 20 in situ carcinomas (two ductal carcinomas in situ /DCIS/, 15 lobular carcinomas in situ (LCIS), three both DCIS and LCIS). (2) Fifty-two women (median age 50 years) with a unilateral diagnosis of in situ carcinoma (32 DCIS, 16 LCIS, four both DCIS and LCIS), in whom both breasts were removed at SCM. 25/52 (48%) had bilateral malignant lesions, one invasive carcinoma, 24 in situ carcinomas (three DCIS, 18 LCIS, three both DCIS and LCIS). Twelve of 20 cases with LCIS (60%) were bilateral. Of 36 cases with DCIS, seven (19%) were bilateral. (3) The contralateral breast was removed at autopsy in 64 women previously unilaterally mastectomized (at median age 65) for invasive breast carcinoma. Fifteen of 64 (23%) had contralateral primary carcinoma at autopsy, four invasive carcinomas, 11 in situ carcinomas (six DCIS, five LCIS) and 8/64 (13%) had metastases in the breast. Multifocal malignant findings were also analysed in 47 SCM specimens after excisional biopsy for in situ carcinoma. In 35/47 (75%) further malignant lesions were present in spite of normal mammographic and clinical findings. Four were invasive and 31 had in situ lesions (16 DCIS, 10 LCIS, five both DCIS and LCIS): These findings may favour the hypothesis that some carcinomas in situ may remain silent or even regress. It is thus important to embark upon randomized trials to clarify the natural history of breast carcinoma in situ. Such a trial has been started in the southern region of Sweden.

Solid-cystic (papillary-cystic) tumours within and outside the pancreas in men: report of two patients.

Solid-cystic (papillary-cystic) tumours (SCT) of the pancreas are distinctive neoplasms with a predilection for young female patients. This is the first detailed report describing the occurrence of SCT in two young male patients. Except for the extapancreatic occurrence of one of the tumours (in the retroperitoneal region behind the head of the pancreas), all other clinicopathological features were identical to those characterizing the SCT in women. Immunostaining was (at least focally) positive for Lu 5 (broad spectrum keratin marker), vimentin and alpha-1-antitrypsin. The tumours were negative for neuroendocrine markers (except for neuron-specific enolase), pancreatic hormones and enzymes, pancreatic stone protein, carcinoembryonic antigen, CA 19-9 and nuclear oestrogen and progesterone receptors. This report does not support the suggested female sex hormone dependence of SCT.

Arterial rupture after microwave-induced hyperthermia and radiotherapy. With reference to two patients treated for recurrence in previously operated and irradiated areas.

Two patients who developed frank arterial bleeding after combined microwave-induced hyperthermia and radiotherapy are described. One patient received re-irradiation and hyperthermia for recurrent metastatic neck nodes of a mesopharyngeal carcinoma. Full course radiotherapy had been given 6 years previously and a right-sided radical neck node dissection had been performed 4 months earlier because of recurrent neck node metastases. Six weeks after the combined therapy for a second recurrence, which achieved complete remission, a fatal rupture of the carotid artery occurred. The other patient received re-irradiation and hyperthermia for a chest wall recurrence of a breast carcinoma, treated 5.5 years previously by sector resection and tangential beam radiotherapy, and treated again 2 years earlier with extensive surgery for a local recurrence. A frank arterial bleeding from the treated region was seen after 7 months, but could be arrested with surgery. This important complication in combined hyperthermia and radiotherapy does not seem to have been recognized before. Different explanations are discussed, such as the previous local treatment as well as high temperature and atherosclerosis per se.