Bronchiolitis obliterans organizing pneumonia following nitric acid fume exposure.

We describe a patient with clinical, radiological and pathological features of bronchiolitis obliterans organizing pneumonia. Investigation showed that this was likely to have been a delayed consequence of inhalation of nitric acid fumes (containing nitrogen dioxide) after a fire. This case shows that thorough investigation of the aetiology is important not only in clinical management but also in ensuring patients benefit from appropriate work injury compensation.

The patella as an unusual site of renal cell carcinoma metastasis.

We report a rare case of renal cell carcinoma with metastasis to the patella in a 49-year-old man, who presented with seven months of left knee pain after a fall. Only two similar cases have been reported. Patellar metastasis is rare because it has a relatively poor blood supply and microemboli would have been sieved out by the pulmonary circulation. Patellectomy is the usual treatment for such cases. We suspect that the preferential metastasis in our patient is a result of tropism. Our treatment for this patient is unique. We opted for a patella-preserving operation involving the use of cryotherapy, as this treatment modality preserved the quality of life. An opportunistic biopsy one year later confirmed the absence of active disease within the patella. This case uniquely provides human in vivo histological confirmation that an intralesional procedure with local and systemic adjuvant therapy effectively controls local disease.

Myelolipoma within a non-functional adrenal cortical adenoma.

Myelolipoma within an adrenal cortical adenoma is a very rare cause of adrenal incidentaloma, and only nine cases have been reported in the English and Japanese literature. We report a 66-year-old Chinese man, with a history of hypertension and hyperlipidaemia, who presented with lower limb oedema and had a computed tomography (CT ) of the abdomen done to exclude intra-abdominal mass. His lower limb symptoms resolved after switching his antihypertensive medication. CT of the abdomen showed a large heterogeneously-enhancing mass in the left suprarenal region, measuring 72 mm by 55 mm. Clinical history, physical examination and laboratory results did not show any evidence to suggest metabolic disorder such as Cushing's syndrome, hyperaldosteronism or catecholamine hypersecretion. The patient underwent a left adrenalectomy, and a histopathological study confirmed the mass to be a non-functional adrenal cortical adenoma containing myelolipoma. The patient was well postoperatively and was discharged uneventfully. To the best of our knowledge, this is the first non-functional adrenal cortical adenoma reported; in the nine cases of myelolipoma within an adrenal cortical adenoma reported previously, all the patients had Cushing's syndrome. The literature on synchronous myelolipoma with adrenal adenoma, and myelolipoma within functional adrenal adenoma, is reviewed.

Diabetic fibrous mastopathy.

Diabetic fibrous mastopathy is reported in a 37-year-old premenopausal woman. A known case of insulin-dependent diabetes mellitus, she presented with bilateral hard breast lumps, which were suggestive of malignancy on both ultrasonography and mammography. Fine-needle aspiration cytology and core biopsy showed fibrosis. An incisional biopsy further excluded malignancy and was conclusive for diabetic fibrous mastopathy.

Epigenetic identification of ADAMTS18 as a novel 16q23.1 tumor suppressor frequently silenced in esophageal, nasopharyngeal and multiple other carcinomas.

Tumor suppressor genes (TSGs) often locate at chromosomal regions with frequent deletions in tumors. Loss of 16q23 occurs frequently in multiple tumors, indicating the presence of critical TSGs at this locus, such as the well-studied WWOX. Herein, we found that ADAMTS18, located next to WWOX, was significantly downregulated in multiple carcinoma cell lines. No deletion of ADAMTS18 was detected with multiplex differential DNA-PCR or high-resolution 1-Mb array-based comparative genomic hybridization (CGH) analysis. Instead, methylation of the ADAMTS18 promoter CpG Island was frequently detected with methylation-specific PCR and bisulfite genome sequencing in multiple carcinoma cell lines and primary carcinomas, but not in any nontumor cell line and normal epithelial tissue. Both pharmacological and genetic demethylation dramatically induced the ADAMTS18 expression, indicating that CpG methylation directly contributes to the tumor-specific silencing of ADAMTS18. Ectopic ADAMTS18 expression led to significant inhibition of both anchorage-dependent and -independent growth of carcinoma cells lacking the expression. Thus, through functional epigenetics, we identified ADAMTS18 as a novel functional tumor suppressor, being frequently inactivated epigenetically in multiple carcinomas.

Identification of novel BRCA large genomic rearrangements in Singapore Asian breast and ovarian patients with cancer.

Large genomic rearrangements have been reported to account for about 10-15% of BRCA1 gene mutations. Approximately, 90 BRCA rearrangements have been described to date, all of which but one have been reported in Caucasian populations of predominantly Western European descent. Knowledge of BRCA genomic rearrangements in Asian populations is still largely unknown. In this study, we have investigated for the presence of BRCA rearrangements among Asian patients with early onset or familial history of breast or ovarian cancer. Using multiplex ligation-dependent probe amplification (MLPA), we have analyzed 100 Singapore patients who previously tested negative for deleterious BRCA mutations by the conventional polymerase chain reaction-based mutation detection methods. Three novel BRCA rearrangements were detected, two of which were characterized. The patients with the rearrangements, a BRCA1 exon 13 duplication, a BRCA1 exon 13-15 deletion and a BRCA2 exon 4-11 duplication, comprise 3% of those previously tested negative for BRCA mutations. Of the BRCA1 and BRCA2 pathogenic mutations identified in our studies on Asian high-risk breast and ovarian patients with cancer to date, these rearrangements constitute 2/19 and 1/2 of the BRCA1 and BRCA2 pathogenic mutations, respectively. Given the increasing number of rearrangements reported in recent years and their contribution to the BRCA mutation spectrum, the presence of BRCA large exon rearrangements in Asian populations should be investigated where clinical, diagnostic service is recommended.

Metaplastic carcinoma of the breast: a clinicopathological review.

BACKGROUND: Mammary metaplastic carcinoma encompasses epithelial-only carcinoma (high-grade adenosquamous carcinoma or pure squamous cell carcinoma), biphasic epithelial and sarcomatoid carcinoma and monophasic spindle cell carcinoma. AIM: To evaluate the clinicopathological features of a large series of 34 metaplastic carcinomas. METHODS: 10 epithelial-only, 14 biphasic and 10 monophasic metaplastic carcinomas were assessed for nuclear grade, hormone receptor status, HER2/neu (cerbB2) oncogene expression, Ki-67 and p53, lymph node status and recurrence on follow-up. RESULTS: Intermediate to high nuclear grade were assessed in most (33/34) tumours. Oestrogen and progesterone receptors were negative in 8 of 10 epithelial-only, all 14 biphasic, and 9 of 10 monophasic tumours, cerbB2 was negative in 7 of 10 epithelial-only, all 14 biphasic and 8 of 10 monophasic tumours. Ki-67 was found to be positive in 6 of 10 epithelial-only, 6 of 14 biphasic, and 7 of 10 monophasic tumours, whereas p53 was positive in 6 of 10 epithelial-only, 7 of 14 biphasic, and 8 of 10 monophasic tumours. Lymph node metastases were seen in 7 of 7 epithelial-only, 7 of 11 biphasic, and 3 of 7 monophasic tumours. Recurrences were seen in 4 of 7 epithelial-only, 8 of 9 biphasic, and 4 of 9 monophasic tumours. CONCLUSIONS: All three subtypes of metaplastic carcinoma are known to behave aggressively, and should be differentiated from the low-grade fibromatosis-like metaplastic carcinoma, which does not metastasize. Oncological treatment options may be limited by the frequently negative status of hormonal receptor and cerbB2.

Morphological and immunophenotypic analysis of breast carcinomas with basal and myoepithelial differentiation.

The aim of this study was to assess the morphological characteristics and immunohistochemical profile of breast carcinomas with basal and myoepithelial phenotypes to obtain a better understanding of their biological behaviour and nature. One thousand nine hundred and forty-four invasive breast carcinomas were examined, using tissue microarray (TMA) technology and immunohistochemistry, to identify those tumours that showed basal and myoepithelial phenotypes, and their immunophenotype profile was characterized using a variety of markers. In addition, haematoxylin and eosin-stained sections of these tumours were studied for several morphological parameters. The findings were correlated with patient and tumour characteristics and outcome data. Tumours were classified into two groups: (1) tumours with basal phenotype [expressing one or both basal markers (CK5/6 and/or CK14)] and (2) tumours with myoepithelial phenotype (expressing SMA and/or p63). Group 1 was further subdivided into two subgroups: (A) dominant basal pattern (more than 50% of cells positive) and (B) basal characteristics (10-50% of cells positive). Group 1 tumours constituted 18.6% (8.6% and 10% for groups 1A and 1B, respectively) and group 2 constituted 13.7% of the cases. In both groups, the most common histological types were ductal/no specific type, tubular mixed and medullary-like carcinomas; the majority of these tumours were grade 3. There were positive associations with adenoid cystic growth pattern, loss of tubule formation, marked cellular pleomorphism, poorer Nottingham prognostic index, and development of distant metastasis. In addition, associations were found with loss of expression of steroid hormone receptors and FHIT proteins and positive expression of p53 and EGFR. The most common characteristics in group 1 were larger size, high-grade comedo-type necrosis, development of tumour recurrence, and absence of lymph node disease. Group 2 tumours were more common in younger patients and were associated with central acellular zones, basaloid change, and positive E-cadherin protein expression. Group 1 characteristics were associated with both reduced overall survival (OS) [log rank (LR) = 22.5, p < 0.001] and reduced disease-free interval (DFI) (LR = 30.1, p < 0.001), while group 2 characteristics showed an association with OS (LR = 5, p = 0.02) but not with DFI. Multivariate analysis showed that basal, but not myoepithelial, phenotype has an independent value in predicting outcome. Breast cancers with basal and myoepithelial phenotypes are distinct groups of tumours that share some common morphological features and an association with poor prognosis. The basal rather than the myoepithelial phenotype has the strongest relationship with patient outcome.

Breast pathology practice: most common problems in a consultation service.

Considerable progress has been made in understanding breast lesions utilizing molecular methods, but conventional morphology, simple immunohistochemical stains and common sense still prevail in diagnosing the vast majority of breast disease. The focus of this review is to identify the most common breast lesions sent to our consultation practice, and to reiterate salient diagnostic features, differential diagnoses and common pitfalls in identifying these lesions. Separation of epithelial proliferative lesions and differentiation between usual epithelial hyperplasia (UEH) and atypical ductal hyperplasia (ADH) are the most common problems encountered in our Consultation practice. Differentiation between UEH and ADH is based on the assumption that ADH is a clonal process, recognized by a uniform phenotype and more recently described immunohistochemical markers such as differential cytokeratin and also hormone receptor expression. Difficulty in subtyping invasive carcinomas and exclusion of in situ and/or invasive carcinoma in a sclerosing lesion is also commonly noted. Finally, problems in distinguishing various papillary and fibroepithelial lesions are also encountered. The use of common immunohistochemical stains such as various cytokeratin and myoepithelial markers, E-cadherin and hormone receptors is helpful in solving most of these diagnostic dilemmas.

Cyclooxygenase-2 expression in Warthin's tumour.

OBJECTIVES: To determine whether cyclooxygenase-2 (COX-2) is overexpressed in Warthin's tumours, and to characterize its pattern of expression. METHODS: Twenty-one paraffin-embedded Warthin's tumour specimens were analysed by immunohistochemical staining for expression of human COX-2. Semi-quantitative analysis of the staining was performed. RESULTS: In all of the specimens, we found that there was overexpression of COX-2 within the epithelial component of the tumours, with no expression in the lymphoid components. There was also overexpression of COX-2 in the salivary duct system of normal parotid tissue. CONCLUSIONS: Our results suggest that COX-2 is up-regulated in the epithelial component of Warthin's tumours. Our findings support the hypothesis that Warthin's tumours originate from heterotopic ductal epithelial cells of the parotid gland. The role of COX-2 expression in the pathogenesis of Warthin's tumours remains to be determined.

Macronodular hepatic tuberculosis associated with portal vein thrombosis and portal hypertension.

Tuberculosis (TB) of the liver is usually associated with miliary spread. Macronodular TB of the liver is rare. A case of macronodular TB of the liver in a 31-year-old woman causing portal vein thrombosis and portal hypertension is presented. Ultrasound and CT appearances are described. There was coexistent ileo-caecal TB with extensive mesenteric and retroperitoneal lymphadenopathy. Macronodular TB should be considered in the differential diagnosis when a patient presents with multiple calcified masses in the liver with portal vein thrombosis and portal hypertension.

Stromal nitric oxide synthase (NOS) expression correlates with the grade of mammary phyllodes tumour.

BACKGROUND: Nitric oxide synthase (NOS), particularly endothelial and inducible forms (e/i-NOS), are expressed in various cancers, including breast cancer. In mammary fibroepithelial lesions, NOS expression in stromal cells has been reported to be lower in fibroadenomas than in phyllodes tumours. AIMS: To investigate NOS expression in phyllodes tumours of varying degrees of malignancy. METHODS: One hundred and sixty seven mammary phyllodes tumours (97 benign, 47 borderline malignant, and 23 frankly malignant) were evaluated for e-NOS and i-NOS expression by immunohistochemistry. Correlations with previously reported expression of stromal vascular growth factor (VEGF) and microvessel density were also performed. RESULTS: Stromal expression of e-NOS was absent, weak, moderate, and strong in 43%, 31%, 13%, and 13% of benign tumours; 17%, 26%, 13%, and 44% of borderline malignant tumours; and 17%, 35%, 13%, and 35% of frankly malignant tumours, respectively. Stromal expression of i-NOS was 77%, 18%, 4%, and 1% in benign tumours; 42%, 28%, 19%, and 11% in borderline malignant tumours; and 43%, 13%, 26%, and 18% in frankly malignant tumours, respectively. Stromal expression of both i-NOS and e-NOS was significantly different between the benign and malignant (borderline and frank) groups of phyllodes tumours (p < 0.0001). Furthermore, the expression of i-NOS correlated with stromal VEGF expression and microvessel density. The expression of NOS in the epithelial cells was strong, and showed no differences between the different groups of tumours. CONCLUSIONS: Higher stromal expression of NOS in phyllodes tumours is associated with malignancy, suggesting a possible role in malignant progression, particularly metastasising potential.

Cyclooxygenase 2 expression in nasopharyngeal carcinoma: immunohistochemical findings and potential implications.

BACKGROUND: Cyclooxygenase 2 (COX-2), an inducible prostaglandin synthase, participates in inflammatory and neoplastic processes. It is expressed by various tumours and contributes to carcinogenesis. Notably, COX-2 inhibitors appear to have tumour suppressor effects and are being evaluated in clinical trials. AIMS: To investigate COX-2 expression in nasopharyngeal carcinoma (NPC), a common tumour in parts of Asia, and to discuss potential implications. METHODS: Eighty five cases of NPC were reviewed. COX-2 immunohistochemistry and semiquantitative assessment of expression in nasopharyngeal biopsies were performed. Because COX-2 is proangiogenic, tumour microvessel density was also assessed with the use of CD31 immunohistochemistry. RESULTS: Histologically, 78 NPCs were undifferentiated, six were non-keratinising, and one was keratinising. Thirty nine NPCs had adjacent dysplastic epithelium. COX-2 expression was noted in 60 NPCs, 14 of 39 samples of dysplastic epithelium, and only one of 25 samples of normal epithelium (p < 0.01). Microvessel density was not significantly different between COX-2 positive and COX-2 negative tumours (p = 0.774). Tumour COX-2 positivity was not associated with higher tumour stage (p = 0.423). CONCLUSION: COX-2 expression is more frequently seen as nasopharyngeal epithelium progresses from normal to dysplastic to carcinoma. This suggests that COX-2 contributes to the multistep process of NPC carcinogenesis. COX-2 represents a therapeutic target for COX-2 inhibitors, and there is thus a basis for the further investigation of this adjuvant treatment modality for NPC. COX-2 inhibitors are known to potentiate the antitumour effects of radiotherapy, which is the primary treatment for NPC.

Stromal CD10 expression in mammary fibroadenomas and phyllodes tumours.

BACKGROUND/AIMS: CD10 (CALLA) has recently been reported to be expressed in spindle cell neoplasia, and has been used to differentiate endometrial stromal sarcoma from leiomyoma and leiomyosarcoma. In the breast, myoepithelial cells express CD10, but there are few studies of the expression of CD10 in mammary fibroepithelial lesions. METHODS: Stromal CD10 expression was studied in 181 mammary phyllodes tumours (102 benign, 51 borderline malignant, and 28 frankly malignant) and 33 fibroadenomas using immunohistochemistry, to evaluate whether differences in expression correlated with the degree of malignancy. RESULTS: There was a progressive increase in the patients' age and tumour size, from fibroadenoma to phyllodes tumours with an increasing degree of malignancy (p < 0.001). Stromal CD10 expression was positive in one of 33 fibroadenomas, six of 102 benign phyllodes tumours, 16 of 51 borderline malignant phyllodes tumours, and 14 of 28 frankly malignant phyllodes tumours. The difference was significant (p < 0.001) and an increasing trend was established. Strong staining was seen in subepithelial areas with higher stromal cellularity and activity. Stromal CD10 expression had a high specificity (95%) for differentiating between benign lesions (fibroadenomas and benign phyllodes tumours) and malignant (borderline and frankly malignant) phyllodes tumours. CONCLUSIONS: CD10 may be a useful adjunct in assessing malignancy in mammary fibroepithelial lesions.

Lymphocytic gastritis-like T cell lymphoma: molecular evidence of an unusual recurrence.

This report describes a patient with a gastric biopsy specimen showing histomorphological and immunohistochemical appearances indistinguishable from those usually present in lymphocytic gastritis, a rare condition of unknown aetiology with a distinctive phenotype. The patient had a history of a biopsy confirmed T cell non-Hodgkin lymphoma at two anatomical sites (bladder and stomach), which was subsequently treated. Molecular analysis of the T cell receptor (TCR) gamma chain gene rearrangements showed a distinct monoclonal T cell population in the bladder and gastric biopsies. The same analysis in the lymphocytic gastritis-like biopsy sample showed a monoclonal population with identical base pair size to that identified in the other specimens. This report highlights the importance of TCR gene rearrangement analysis in the diagnosis of unusual gastric inflammation, and the use of capillary electrophoresis based polymerase chain reaction in the follow up of lymphoproliferative disorders.

Cyclooxygenase-2 expression: a potential prognostic and predictive marker for high-grade ductal carcinoma in situ of the breast.

AIMS: To study cyclooxygenase-2 (COX-2) expression in ductal carcinoma in situ (DCIS) of the breast and its association with histological features. COX-2, an inducible prostaglandin synthase, has been shown to be important in mammary carcinogenesis, being associated with increased tumour size and unfavourable outcome in breast cancer. Animal studies indicate that COX-2 inhibition is effective in the prevention and treatment of mammary cancers. METHODS AND RESULTS: Fifty-one cases of DCIS diagnosed during 1990-2000 were reviewed. Immunohistochemistry for COX-2 was performed and the COX-2 staining scores were correlated with histological features. The majority of cases [41 of 51 (80%)] had positive COX-2 staining, of which 13 cases (25%) had strong staining. High nuclear grade DCIS was significantly associated with increased COX-2 staining (P = 0.04). CONCLUSIONS: High-grade lesions are known to be associated with a higher recurrence rate following excision and are often oestrogen receptor negative, and as such, may be less responsive to adjuvant tamoxifen therapy. There is a need to examine further the role of COX-2 expression in DCIS, as both a prognostic and predictive factor.