Roles of Ki67 in Breast Cancer - Important for Management?

BACKGROUND: The three standard biomarkers used in breast cancer are the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The Ki-67 index, a proliferative marker, has been shown to be associated with a poorer outcome, and despite absence of standardization of pathological assessment, is widely used for therapy decision making. We aim to study the role of the Ki-67 index in a group of Asian women with breast cancer. MATERIALS AND METHODS: A total of 450 women newly diagnosed with Stage 1 to 3 invasive breast cancer in a single centre from July 2013 to Dec 2014 were included in this study. Univariable and multivariable logistic regression was used to determine the association between Ki-67 (positive defined as 14% and above) and age, ethnicity, grade, mitotic index, ER, PR, HER2, lymph node status and size. All analyses were performed using SPSS Version 22. RESULTS: In univariable analysis, Ki -67 index was associated with younger age, higher grade, ER and PR negativity, HER2 positivity, high mitotic index and positive lymph nodes. However on multivariable analysis only tumour size, grade, PR and HER2 remained significant. Out of 102 stage 1 patients who had ER positive/PR positive/HER2 negative tumours and non-grade 3, only 5 (4.9%) had a positive Ki-67 index and may have been offered chemotherapy. However, it is interesting to note that none of these patients received chemotherapy. CONCLUSIONS: Information on Ki67 would have potentially changed management in an insignificant proportion of patients with stage 1 breast cancer.

Diabetic Mastopathy: A Case Report and Literature Review.

Diabetic mastopathy is a rare fibroinflammatory breast disease characterized by lymphocytic lobulitis, ductitis, and perivasculitis with stromal fibrosis. This lesion often presents as a discretely palpable uni- or bilateral mass in long-standing type I diabetes and other autoimmune diseases. We report a case of insulin-dependent diabetic mastopathy, which presented clinically as an indeterminate breast lump suspicious for malignancy. The patient is a 36-year-old woman who had type 1 insulin-dependent diabetes mellitus. Mammography and ultrasonography raised a suspicion of malignancy, and an excisional biopsy was performed. A previous biopsy had shown no evidence of malignancy. Histopathological examination now showed dense keloid-like stromal fibrosis with epithelioid-like and spindly myofibroblasts and a characteristic lymphocytic infiltration around blood vessels in and around lobules and ducts, features consistent with diabetic mastopathy. The literature is briefly reviewed.

Mucosal malignant melanoma of the maxillary sinus.

Mucosal malignant melanoma (MMM) is an aggressive tumour occurring in the upper respiratory tract. It is rare compared to malignant melanoma of the skin. We report a case of a 53-year-old man with left paranasal swelling. A biopsy showed high-grade spindle cell tumour. Subsequently a subtotal maxillectomy was performed. Histopathological examination revealed a hypercellular tumour composed of mixed spindle and epitheloid cells with very occasional intracytoplasmic melanin pigment. The malignant cells were immunopositive for vimentin, S-100 protein and HMB-45. It was diagnosed as mucosal malignant melanoma (MMM). This article illustrates a rare case of MMM where the diagnosis may be missed or delayed without proper histopathological examination that include meticulous search for melanin pigment and appropriate immunohistochemical stains to confirm the diagnosis. Malignant melanoma can mimic many other types of high-grade malignancy and should be considered as a differential diagnosis in many of these instances.

Gene expression in human oral squamous cell carcinoma is influenced by risk factor exposure.

Oral squamous cell carcinoma (OSCC) is a world health problem and is associated with exposure to different risk factors. In the west, smoking and alcohol consumption are considered to be the main risk factors whilst in India and southeast Asia, betel quid (BQ) chewing is predominant. In this study, we compared the gene expression patterns of oral cancers associated with BQ chewing to those caused by smoking using Affymetrix microarrays. We found that 281 genes were differentially expressed between OSCC and normal oral mucosa regardless of aetiological factors including MMP1, PLAU, MAGE-D4, GNA12, IFITM3 and NMU. Further, we identified 168 genes that were differentially expressed between the BQ and smoking groups including CXCL-9, TMPRSS2, CA12 and RNF24. The expression of these genes was validated using qPCR using independent tissue samples. The results demonstrate that whilst common genes/pathways contribute to the development of oral cancer, there are also other gene expression changes that are specific to certain risk factors. The findings suggest that different carcinogens activate or inhibit specific pathways during cancer development and progression. These unique gene expression profiles should be taken into consideration when developing biomarkers for future use in prognostic or therapeutic applications.

Multifocal nodal and extranodal Rosai-Dorfman disease initially diagnosed as histiocytic lymphoma.

Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy (SHML), is a systemic disease involving nodal and extranodal tissues. We report a 48-year-old female with recurrent nasal obstruction due to polypoidal masses involving the nasal sinuses, turbinates and septum bilaterally, and lumps in the right infra-orbital region and region of the right lacrimal sac. A 4 cm right upper neck mass was also noted, which was initially diagnosed as histiocytic lymphoma. Histopathology of the nasal and infraorbital lesions revealed fibro-inflammatory masses containing histiocytic cells with large vesicular nuclei and abundant foamy cytoplasm exhibiting emperipolesis and lymphophagocytosis, admixed with scattered plasma cells and lymphocytes. These histiocytes revealed immunohistochemical positivity for S-100 protein and CD68, but were negative for CDla. The findings supported a diagnosis of RDD. This report serves to remind pathologists and clinicians of the extranodal manifestations of RDD and its potential confusion with lymphomas.

Small cell variant of anaplastic large cell lymphoma with positive immunoreactivity for CD99.

A 13 year old boy presented with a huge mass on his right arm of 6 months duration. Histopathological examination revealed sheets of malignant small round blue cells with immunopositivity for LCA, CD43, CD45Ro, CD30, EMA, ALK-1 and CD99, and negativity for CD20, TdT, myogenin, myoD1, NSE, bcl-6, bcl-2 and CD10. Fluorescent In-Situ Hybridization (FISH) testing excluded the diagnosis of Ewing's sarcoma/PNET. Pathologists need to be aware of the diagnosis of a small cell variant of ALCL, as well as of the fact that CD99 expression commonly occurs in cases of ALK-positive ALCL, in order to distinguish this entity from Ewing's sarcoma/PNET.

Clear cell "sugar" tumour of the lung: a case report.

We report a case of clear cell "sugar" tumour of the lung (CCTL) occurring in a 26-year-old lady. The patient was asymptomatic and the lesion was picked up in the course of a pre-employment medical examination. A well-defined 5 cm nodule in the right lower lobe was detected on routine chest X-Ray. Microscopical examination of the coin lesion showed clear cells containing abundant diastase-sensitive intracytoplasmic glycogen, as demohstrated with periodic acid-Schiff stains. Tumour immunoreactivity for HMB-45 and non-reactivity for cytokeratin support the histological diagnosis. To our knowledge, this is the first reported case of CCTL in Malaysia.

The Midlands Trial of Empirical Amiodarone versus Electrophysiology-guided Interventions and Implantable Cardioverter-defibrillators (MAVERIC): a multi-centre prospective randomised clinical trial on the secondary prevention of sudden cardiac death.

AIMS: MAVERIC was a randomised clinical trial designed to test the possibility of prospectively identifying patients who would benefit most from the implantable cardioverter-defibrillator (ICD) by electrophysiology (EP) study in the context of secondary prevention of sudden cardiac death (SCD) through comparing EP-guided interventions (anti-arrhythmic drugs, coronary revascularization, and ICD) against empirical amiodarone therapy. METHODS: Two hundred and fourteen survivors of sustained ventricular tachycardia (VT), ventricular fibrillation (VF) or SCD were randomized to either treatment strategy, pre-stratified for haemodynamic status at index event, and followed up for a median of 5 years. RESULTS: Of the 106 amiodarone arm patients, 89 (84%) received the drug and 5 (5%) received an ICD after crossing over. Of the 108 EP arm patients, 31 (29%) received an ICD, 46 (43%) received anti-arrhythmic drugs only (mainly amiodarone or sotalol) and 18 (17%) received coronary revascularization but no ICD. No significant differences in survival or arrhythmia recurrence existed between the two treatment arms after 6 years. However, ICD recipients had a lower mortality than non-ICD recipients, regardless of allocated treatment (hazard ratio=0.54, p=0.0391). CONCLUSIONS: Prospective selection of patients to receive the ICD by EP study did not improve survival compared with empirical amiodarone therapy among survivors of VT, VF or SCD, whereas ICD implantation improved survival regardless of allocated treatment. On this basis, routine EP study has no role in the management of such patients, who should be offered empirical ICD therapy according to the results of other secondary prevention ICD trials.

Ovarian sex cord-stromal tumors in children and adolescents.

PURPOSE: To develop diagnostic standards and a risk-adapted therapeutic strategy for ovarian sex cord-stromal tumors (OSCST). PATIENTS AND METHODS: Fifty-four patients were prospectively enrolled as follow-up patients onto the German Maligne Keimzelltumoren protocols. Surgical protocols and histopathology were reviewed centrally (53 patients with complete data). Surgery included ovariectomy in 18 patients, salpingo-ovariectomy in 34 patients, and hysterectomy in one patient. Patients with stage IA tumors were followed-up at regular intervals, whereas nine patients with stage IC and six patients with stage II to III tumors were treated with cisplatin-based chemotherapy. RESULTS: International Federation of Gynecology and Obstetrics stage was IA in 27 patients, IC in 21 patients, II in three patients, and III in three patients. After a median follow-up of 59 months (range, 6 to 193 months), event-free survival +/- SD was 0.86 +/- 0.05 (47 of 54 patients) and overall survival was 0.89 +/- 0.05 (49 of 54 patients). Prognosis correlated with stage (event-free survival +/- SD: IA, 1.0 [27 of 27 patients]; IC, 0.76 +/- 0.09 [16 of 21 patients]; and II/III, 0.67 +/- 0.19 [four of six patients]; P =.02). Ten of 15 patients treated with chemotherapy, including four of six stage II to III patients, are alive after a median follow-up of 33 months. CONCLUSION: On the basis of a standardized clinical and histopathologic assessment, risk-adapted therapeutic strategies for OSCST can be evaluated. Considering our experience, we would recommend that stage IA tumors be followed up at regular intervals, whereas we would recommend cisplatin-based chemotherapy in stage IC tumors with preoperative rupture or malignant ascites, especially those with high mitotic activity. Finally, cisplatin-based chemotherapy also seems to be effective in advanced-stage tumors.

Therapy of advanced ovarian juvenile granulosa cell tumors.

BACKGROUND: Gonadal sex cord-stromal tumors are rare tumors that develop from the gonadal non-germ cell component such as granulosa, Sertoli or Leydig cells. Among these, juvenile granulosa cell tumors (JGCT) constitute the largest subgroup of ovarian sex cord-stromal tumors during childhood and adolescence. In local disease (FIGO stage I), the beneficial role of tumor-ovarectomy is well established. In contrast, life expectancy in patients with advanced JGCT (FIGO stage >/= II) is short even after complete tumor resection. The current literature provides only limited and inconclusive data regarding the value of adjuvant chemotherapy in such patients with advanced disease. PATIENTS AND METHODS: Therefore, we analyzed the patients with FIGO stage >/= II JGCT who were prospectively documented as follow-up patients of the German MAKEI trials for non-testicular germ cell tumors and received the recommended cisplatin-based chemotherapy in an adjuvant setting. From 1988 until 2000, 7 patients (age, 4;2 - 18;11 years, median 14;8 years) were registered. Three patients were stage IIc, one stage IIIa, and three stage IIIc. 5 patients underwent laparatomy with adnectomy, which was complete in only two patients. Two patients received laparoscopic tumor resection, which was incomplete in both. All patients received 4 or 6 cycles of adjuvant cisplatin-based three-agent chemotherapy in analogy to the current therapeutic concept applied in malignant germ cell tumors. One patient with a large tumor and multiple peritoneal metastases additionally received 40 Gy abdominal irradiation. RESULTS: All patients achieved complete clinical remission after initial surgery and adjuvant chemotherapy. 4 out of 7 patients are currently remaining in first continuous complete remission after 15 to 111 months follow-up. One patient developed a metachronous tumor of the contralateral ovary after 126 months follow-up and is still alive but currently in therapy of another recurrence. Another patient suffered a tumor recurrence after 12 months but achieved a second complete remission with cisplatin chemotherapy after a follow-up of currently 4 months. One patient achieved complete clinical remission but suffered a diffuse peritoneal tumor recurrence with massive ascites and finally died as a result of tumor progression. In summary, at the time of this report 6 of 7 patients are alive after a median of 47 (15 - 138) months. CONCLUSION: This analysis clearly demonstrates that advanced JGCT can be successfully treated with surgery followed by adjuvant cisplatin-based chemotherapy. Therefore, this study reveals encouraging therapeutic perspectives in these otherwise fatal tumors that merit further investigation in a prospective cooperative trial.

Failure to infect congenitally immunodeficient SCID and NUDE mice with Rhinosporidium seeberi.

Congenitally T and B cell-deficient SCID mice and T cell-deficient NUDE mice, with BALB/c mice as immunologically normal controls, were inoculated with Rhinosporidium seeberi. At 3 and 16 weeks after inoculation, no evidence of rhinosporidiosis was detected. The reasons for the failure to establish rhinosporidiosis in immunodeficient or normal mice remain obscure.

The impact of teleradiology in clinical practice--a Malaysian perspective.

Teleradiology is the most mature and rapidly evolving specialty in telemedicine. The use of teleradiology has grown tremendously during the past few years. This article describes the role of teleradiology in health care along with a brief history of its development in tandem with advances in telecommunications and computer technologies. Teleradiology standards, image acquisition, data compression, transmission and image interpretation are summarised. The impact of teleradiology in the practice of radiology, traces the evolution of the modality especially in the Malaysian perspective and its current and future role are discussed.

Cystic lesion of the parotid gland with squamous metaplasia mistaken for squamous cell carcinoma. A case report.

BACKGROUND: The diverse range of diseases that affect the salivary glands may lead to problems and pitfalls in cyto-diagnosis. While false negative diagnosis of cystic salivary gland tumors is well known, false positive cytodiagnosis in nonneoplastic salivary cysts is less well documented. CASE: An 85-year-old female presented with a painless left parotid gland swelling of three months' duration. Fine needle aspiration cytology yielded fluid, smears of which showed keratinizing squamous cells with nuclear atypia leading to a cytologic diagnosis of cystic squamous cell carcinoma. A total radical parotidectomy followed. Histopathologic study showed cystic dilatation of many of the salivary ducts, which were lined with metaplastic squamous epithelium that showed atypia. There was no evidence of squamous cell carcinoma. CONCLUSION: Squamous metaplasia is known to occur in benign salivary gland lesions, such as pleomorphic adenoma and Warthin's tumors, as well as in salivary duct cysts and necrotizing sialometaplasia. However, atypical squamous metaplasia of salivary duct cysts mimicking squamous cell carcinoma on cytology is unusual.

Potential impact of antiarrhythmic drugs versus implantable defibrillators on the management of ventricular arrhythmias: the Midlands trial of empirical amiodarone versus electrophysiologically guided intervention and cardioverter implant registry data.

BACKGROUND: Survival was prolonged in selected patients with sustained ventricular arrhythmias who received implantable cardioverter defibrillators (ICDs) in the antiarrhythmics versus implantable defibrillators (AVID) study. The Midlands trial of empirical amiodarone versus electrophysiologically guided intervention and cardioverter implant in ventricular arrhythmias (MAVERIC) registry is a population based trial. OBJECTIVE: To determine the number of patients who satisfy the AVID criteria because of the high cost of ICDs. DESIGN: Observational study, based on a continuing trial. SETTING: All coronary care units in the Midlands region in the United Kingdom (population 9.1 million). PATIENTS: Patients presenting to a coronary care unit with sustained ventricular arrhythmias not related to an acute myocardial infarction are entered onto the registry. Those who consent to the MAVERIC study are randomised to receive either empirical amiodarone or electrophysiologically guided treatment. Demographic data, details of clinical presentation, and echocardiographic findings are collected. These data have been used to calculate the number of patients who satisfy the AVID criteria and would benefit from ICD implantation. The financial implications have been calculated for the region and nationally. RESULTS: 132 patients were entered onto the registry during the first five months of the MAVERIC study; 69 patients fulfilled the AVID criteria. Extrapolation of these data over a 12 month period suggests implantation of at least 166 new ICDs (compared with 23 implants in 1996). This would increase the UK ICD implant rate from five to at least 18 per million of the population, costing the National Health Service 24.1 Pounds million per annum. CONCLUSION: Application of the AVID criteria in the UK will cause a great increase in the ICD implant rate, with serious financial implications.

Gastric strongyloidiasis in a Malaysian patient.

Strongyloides stercoralis infection is of low prevalence in Malaysia. We report an unusual case presenting primarily with gastric symptoms. The patient was a 72 years old Chinese male admitted for progressive weight loss and abdominal bloating. Gastroscopic examination revealed mucosal prepyloric elevations in the gastric mucosa. Gastric strongyloidiasis was confirmed by the presence of adult forms, as well as ova and larval rhabditiform stages of the worm in the gastric mucosal crypts. We believe that this is the first histologically documented case of gastric strongyloidiasis in Malaysia.

Trans (elaidic) fatty acids adversely affect the lipoprotein profile relative to specific saturated fatty acids in humans.

Although dietary trans fatty acids can affect plasma lipoproteins negatively in humans, no direct comparison with specific saturated fatty acids has been reported, even though trans fatty acids were designed to replace saturates in foods and food processing. In this study, dietary trans 18:1 [elaidic acid at 5.5% energy (en)] was specifically exchanged for cis 18:1, 16:0 or 12:0 + 14:0 in 27 male and female subjects consuming moderate fat (31% en), low cholesterol (<225 mg/d) whole food diets during 4-wk diet periods in a crossover design. The trans-rich fat significantly elevated total cholesterol and LDL cholesterol relative to the 16:0-rich and 18:1-rich fats and uniquely depressed HDL cholesterol relative to all of the fats tested. Trans fatty acids also elevated lipoprotein (a) [Lp(a)] values relative to all dietary treatments. Furthermore, identical effects on lipoproteins were elicited by 16:0 and cis 18:1 in these subjects. The current results suggest that elaidic acid, one of the principal trans isomers produced during industrial hydrogenation of edible oils, adversely affects plasma lipoproteins. Thus, the negative effect of elaidic acid on the lipoprotein profile of humans appears to be unmatched by any other natural fatty acid(s).

Impact of saturated and trans fatty acid enriched oil blends on atherosclerosis in rabbits fed cholesterol-free diets.

Thirty six-male New Zealand White rabbits subdivided into four dietary groups (9 animals per group) were fed high fat (36% en), cholesterol-free diets for nine months. The dietary oil blends were formulated to contain high levels of the target fatty acids namely trans-rich (partially hydrogenated soybean oil; TRANS), cis monounsaturated-rich (rapeseed, sunflower seed oil and palm olein; MONO), palmitic-rich (palm olein; POL) and lauric-myristic rich (coconut, palm kernel and corn oils; LM). Ad libitum feeding of the rabbits resulted in normal growth throughout the nine months and no differences in the final body weights of the animals were evident at autopsy. Plasma total cholesterol was significantly elevated only by the LM enriched diet compared with all other treatments; values were comparable between the other three treatment groups. Changes in the total cholesterol were not reflected in the VLDL and LDL lipoproteins. However, HDL-cholesterol was significantly lowered by the TRANS diet compared with all other dietary groups. HDL-cholesterol was also significantly increased by the LM diet in comparison to the POL-diet. Both adipose and liver triglyceride fatty acid compositions tended to reflect the type of fatty acids fed the animals. Trans fatty acids were evident only in animals fed the trans diet and it was apparent that the trans fatty acids competed with linoleic acid for incorporation into these tissues. Increased concentrations of lauric and myristic fatty acids in the LM-fed animals were also evident. In the POL and high MONO fed rabbits, palmitic and oleic fatty acids (respectively) were concentrated in the adipose and liver. The diets, however, failed to induce severe atherosclerosis in this study. This can be explained, in part, by the lack of dietary cholesterol and the use of plant (rather than animal) proteins in our dietary formulations. The effect of these important atherosclerosis modulators in association with these fatty acids requires further evaluation.