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.

Serial changes in the expression of breast cancer-related proteins in response to neoadjuvant chemotherapy.

BACKGROUND: Tumour expression of cyclooxygenase-2 (COX-2), epidermal growth factor receptor (EGFR), erythroblastic leukaemia viral oncogene homologue-2 (ErbB2), Ki-67 and p53 in breast cancer are associated with poorer outcomes. We investigated in vivo changes of these proteins with neoadjuvant chemotherapy. PATIENTS AND METHODS: Four core biopsies were taken from 100 breast cancer patients at baseline, during and upon completion of neoadjuvant chemotherapy. Immunohistochemical expression of these proteins were evaluated and correlated with clinicopathological features, clinical response and progression-free survival (PFS). RESULTS: There was a statistically significant change from positivity to negativity in COX-2 expression with chemotherapy (P = 0.002), predominantly in clinical responders (P = 0.002). COX-2-positive tumours that remained positive had shorter PFS than those that turned negative. Estrogen receptor (ER)+ and COX-2+ tumours at baseline that remained COX-2+ fared worse than those that became COX-2 negative (PFS 27 versus 52 months, P = 0.002). No significant changes in IHC expression were observed for ER, progesterone receptor, ErbB2, EGFR, p53 or Ki67. CONCLUSIONS: Chemotherapy induced change in COX-2 expression from positivity to negativity predominantly among clinical responders and is associated with longer PFS. Interaction between COX-2 and ER was observed, suggesting that some hormone receptor-positive patients may benefit from combining COX-2 inhibition with hormonal therapy.

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation.

Protocadherins constitute the largest subgroup in the cadherin superfamily of cell adhesion molecules. Their major functions are poorly understood, although some are implicated in nervous system development. As tumor-specific promoter methylation is a marker for tumor suppressor genes (TSG), we searched for epigenetically inactivated TSGs using methylation-subtraction combined with pharmacologic demethylation, and identified the PCDH10 CpG island as a methylated sequence in nasopharyngeal carcinoma (NPC). PCDH10 is broadly expressed in all normal adult and fetal tissues including the epithelia, though at different levels. It resides at 4q28.3--a region with hemizygous deletion detected by array-CGH in NPC cell lines; however, PCDH10 itself is not located within the deletion. In contrast, its transcriptional silencing and promoter methylation were frequently detected in multiple carcinoma cell lines in a biallelic way, including 12/12 nasopharyngeal, 13/16 esophageal, 3/4 breast, 5/5 colorectal, 3/4 cervical, 2/5 lung and 2/8 hepatocellular carcinoma cell lines, but not in any immortalized normal epithelial cell line. Aberrant methylation was further frequently detected in multiple primary carcinomas (82% in NPC, 42-51% for other carcinomas), but not normal tissues. The transcriptional silencing of PCDH10 could be reversed by pharmacologic demethylation with 5-aza-2'-deoxycytidine or genetic demethylation with double knockout of DNMT1 and DNMT3B, indicating a direct epigenetic mechanism. Ectopic expression of PCDH10 strongly suppressed tumor cell growth, migration, invasion and colony formation. Although the epigenetic and genetic disruptions of several classical cadherins as TSGs have been well documented in tumors, this is the first report that a widely expressed protocadherin can also function as a TSG that is frequently inactivated epigenetically in multiple carcinomas.

TRPV4 plays a role in breast cancer cell migration via Ca2+-dependent activation of AKT and downregulation of E-cadherin cell cortex protein.

TRPV4 belongs to the 'Transient Receptor Potential' (TRP) superfamily. It has been identified to profoundly affect a variety of physiological processes, including nociception, heat sensation and inflammation. Unlike other TRP superfamily channels, its role in cancers are unknown until recently when we reported TRPV4 to be required for cancer cell softness that may promote breast cancer cell extravasation and metastasis. Here, we elucidated the molecular mechanisms mediated by TRPV4 in the metastatic breast cancer cells. TRPV4-mediated signaling was demonstrated to involve Ca2+-dependent activation of AKT and downregulation of E-cadherin expression, which was abolished upon TRPV4 silencing. Functionally, TRPV4-enhanced breast caner cell transendothelial migration requires AKT activity while a combination of transcriptional and post-translational regulation contributed to the TRPV4-mediated E-cadherin downregulation. Finally, mass spectrometry analysis revealed that TRPV4 is required for the expression of a network of secreted proteins involved in extracellular matrix remodeling. In conclusion, TRPV4 may regulate breast cancer metastasis by regulating cell softness through the Ca2+-dependent AKT-E-cadherin signaling axis and regulation of the expression of extracellular proteins.

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.

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.

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 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.

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.

Correlation of viral RNA, alanine aminotransferase, and histopathology in hepatitis C virus-associated hepatitis.

BACKGROUND: Hepatitis C virus (HCV) infection is usually monitored by the level of alanine aminotransferase (ALT) and histopathological changes in liver biopsy specimens. However, accumulating data indicate these parameters are not always correlated with disease progression or the response of HCV infection to therapy. MATERIALS AND METHODS: Using the Amplicor PCR Monitor Test Kit (Roche Diagnostic Systems, Branchburg, NJ), HCV RNA level was measured in 38 patients with positive anti-HCV antibodies and in 21 of those patients after interferon treatment. The grade and stage of histological changes on hematoxylin and eosin-stained sections of liver biopsy specimens were evaluated on a scale of 1 to 4. In each case, the HCV RNA level was compared with the histological grade or stage and level of ALT and statistically analyzed by Student's t-test. RESULTS: ALT level did not correlate with pretreatment and posttreatment levels of HCV RNA or histopathological changes. However, there was a statistically significant correlation between HCV RNA and histological grade (P,.05). CONCLUSION: HCV RNA measurement is a better means of determining and monitoring HCV infection than either ALT level or histopathological characteristics and may provide insight into hepatic injury caused by HCV infection even without an invasive liver biopsy.

Mixed columnar cell and tall cell variant of papillary carcinoma of thyroid: a case report and review of the literature.

Columnar cell and tall cell carcinomas are newly described variants of papillary thyroid carcinoma associated with aggressive clinical behaviour. Although several cases of tall cell and columnar cell variants have been reported, only a single detailed case report of a mixed tall cell and columnar cell variant has been described in the English-language literature. We report another such composite tumour with predominant columna cell features in an elderly female. The tumour showed extrathyroidal extension with intraluminal superior thyroid vein invasion and lymph node metastasis. DNA ploidy analysis showed a diploid DNA content with no increase of S-phase fraction. Immunohistochemistry showed focal positivity for p53 and Ki-67 at the infiltrating margins of the tumour and diffuse positivity for proliferating cell nuclear antigen. The adverse clinical course warrants aggressive treatment and careful follow-up.

Periosteal chondrosarcoma: a case report and review of the literature.

Periosteal chondrosarcoma occurs predominantly in the long tubular bones. The long-term survival rate is better and there are fewer local recurrences than with central chondrosarcoma. A case of periosteal chondrosarcoma is reported with a review of the literature. A 13-year-old girl presented with swelling of the distal right thigh of 3 weeks' duration. Radiographs and computed tomographic scan of the lesion showed a soft tissue mass, measuring 6 x 6 cm, with matrix calcification arising from the surface of the bone. An open biopsy followed by en bloc resection of the tumor was performed. The histologic features were those of a chondrosarcoma. An 8-year follow-up period has shown no local recurrence or distant metastases. The differential diagnosis of periosteal chondrosarcoma includes periosteal (chondroblastic) osteosarcoma and periosteal chondroma. Controversy exists as to whether periosteal chondrosarcoma is an entity distinct from periosteal osteosarcoma. The clinicopathologic features in this case and in the cases reported in the literature support the contention that periosteal chondrosarcoma is indeed distinct.

Skeletal metastases from a granulosa-cell tumor of the ovary: report of a case diagnosed by fine-needle aspiration cytology.

We report on the fine-needle aspiration cytological findings of a metastatic granulosa-cell tumor of the ovary to bone. The patient had undergone resection of a primary ovarian granulosa-cell tumor 15 yr prior to her last admission. Recently she injured her right hip, sustained after a fall. CT examination revealed hypodense lesions involving the posterior body and the right pedicle of the L1 vertebra. The aspirate from the bone yielded a highly cellular smear, composed of round to oval cells with scanty cytoplasm. Many of the cells revealed the presence of nuclear grooves. In areas, the cells were arranged in clusters resembling Call-Exner bodies. The rarity of skeletal metastases from granulosa-cell tumors can cause diagnostic difficulty in diagnosing this entity. Accurate clinical data, radiological findings, and cytological features are important in arriving at the correct diagnosis.

Fine needle aspiration cytology of mixed tall and columnar cell papillary carcinoma of the thyroid. A case report.

BACKGROUND: We report the first case of a composite tumor (tall cell and columnar cell variants) of papillary thyroid carcinoma (PTC) diagnosed by fine needle aspiration. It is important to differentiate these uncommon aggressive variants from the usual indolent papillary carcinomas. CASE: Fine needle aspiration cytology was obtained from a rare composite tumor of tall cell and columnar cell variants of papillary thyroid carcinoma. The smears showed a cellular aspirate with scattered single tumor cells and several tissue fragments arranged in a papillary pattern. The tumor cells had abundant nuclear grooves and intranuclear pseudoinclusions. Several of the fragments showed columnar cells with nuclear pseudostratification, and a few clusters displayed tall columnar cells with basal nuclei and abundant cytoplasm. A rare cluster exhibited composite features of tall cell and columnar cell variants. CONCLUSION: Columnar cell and tall cell variants of PTC manifest aggressive clinical behavior. The differential diagnosis of columnar cell variant includes medullary carcinoma of thyroid and metastatic adenocarcinoma. Immunohistochemical stains for calcitonin and thyroglobulin play an important role in difficult cases. The tall cell variant needs to be differentiated from Hürthle cell papillary neoplasm of thyroid, which displays prominent nucleoli and lacks the characteristic nuclear features of PTC. The preoperative diagnosis of these aggressive variants' is important in planning the most appropriate type of treatment.

MR imaging features of fibroepithelial ureteral polyp in a patient with duplicated upper urinary tract.

We describe the magnetic resonance (MR) imaging features of a rare case of fibroepithelial polyp (FEP) in a duplicated upper urinary tract. The FEP appeared as a T2-hyperintense and T1-isointense filling defect within the dilated lower moiety ureter. Post gadolinium-enhanced images revealed enhancement of the FEP without ureteral wall-thickening or enhancement. Retrograde ureterography confirmed the findings, and the patient underwent ureterotomy and removal of the polyp. Histopathological findings were consistent with an FEP. It may be possible to differentiate FEP from an ureteric carcinoma based on MR imaging features. MR imaging may be useful for preoperative diagnosis of a benign ureteric tumour, and may thus prevent an unnecessary nephroureterectomy.

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.

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.

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.

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.