Postoperative survival following perioperative MAGIC versus neoadjuvant OE02-type chemotherapy in oesophageal adenocarcinoma.

The optimal management of resectable oesophageal adenocarcinoma is controversial, with many centres using neoadjuvant chemotherapy following the Medical Research Council (MRC) oesophageal working group (OE02) trial and the MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. The more intensive MAGIC regimen is used primarily in gastric cancer but some also use it for oesophageal cancer. A database of cancer resections (2001-2013) provided information on survival of patients following either OE02 or MAGIC-type treatment. The data were compared using Kaplan-Meier analysis. Straight-to-surgery patients were also reviewed and divided into an 'early' cohort (2001-2006, OE02 era) and a 'late' cohort (2006-2013, MAGIC era) to estimate changes in survival over time. Subgroup analysis was performed for responders (tumour regression grade [TRG] 1-3) versus non-responders (TRG 4 and 5) and for anatomical site (gastro-oesophageal junction [GOJ] vs oesophagus). An OE02 regimen was used for 97 patients and 275 received a MAGIC regimen. Those in the MAGIC group were of a similar age to those undergoing OE02 chemotherapy but the proportion of oesophageal cancers was higher among MAGIC patients than among those receiving OE02 treatment. MAGIC patients had a significantly lower stage following chemotherapy than OE02 patients and a higher median overall survival although TRG was similar. On subgroup analysis, this survival benefit was maintained for GOJ and oesophageal cancer patients as well as non-responders. Analysis of responders showed no difference between regimens. 'Late' group straight-to-surgery patients were significantly older than those in the 'early' group. Survival, however, was not significantly different for these two cohorts. Although the original MAGIC trial comprised few oesophageal cancer cases, our patients had better survival with MAGIC than with OE02 chemotherapy in all anatomical subgroups, even though there was no significant change in operative survival over the time period in which these patients were treated. The use of the MAGIC regimen should therefore be encouraged in cases of operable oesophagogastric adenocarcinoma.

Evaluation of touch preparation cytology during frozen-section diagnoses of pulmonary lesions.

BACKGROUND: Intraoperative frozen section (FS) examination in thoracic surgery is a reliable method for diagnosis and staging of pulmonary lesions and provides a valuable guide in directing the extent of the ongoing surgical procedure. However, the contribution of touch preparation cytology (TPC) to FS diagnosis remains unclear. Aim To assess the utility of routinely performed TPC during FS diagnoses of pulmonary lesions. METHODS: In this study FS and TPC for all patients who had undergone FS diagnoses of pulmonary lesions in a 6-year period were reviewed by two pathologists. RESULTS: A total of 155 consecutive patients underwent intraoperative FS procedure, and 110 of those cases had TPC available for review. TPC was diagnostic or contributory to FS diagnosis in 97 (88%) cases, and non-contributory in 13 cases, mainly due to low or inadequate cellularity. TPC provided useful information regarding tumour subtyping, but it was less sensitive in the diagnosis of mucinous neoplasms and was less specific in the assessment of bronchial resection margins. In granulomatous lesions with or without necrosis, TPC was diagnostic in 10 (91%) cases. In five cases (including four cases of tuberculosis), TPC was the only diagnostic tool since FS was not completed. In conclusion, TPC showed high sensitivity and specificity rates and was contributory to FS diagnosis of pulmonary lesions. TPC provides a fast, less-expensive method of diagnosis, utilises a minimal amount of tissue, and can save processing of fresh frozen tissues in certain situations such as tuberculous lesions.

Tumour regression and ERCC1 nuclear protein expression predict clinical outcome in patients with gastro-oesophageal cancer treated with neoadjuvant chemotherapy.

AIMS: Neoadjuvant chemotherapy followed by surgery is the standard of care for patients with gastro-oesophageal adenocarcinoma. Previously, we validated the utility of the tumour regression grade (TRG) as a histopathological marker of tumour downstaging in patients receiving platinum-based neoadjuvant chemotherapy. In this study we profiled key DNA repair and damage signalling factors and correlated them with clinicopathological outcomes, including TRG response. METHODS AND RESULTS: Formalin-fixed human gastro-oesophageal cancers were constructed into tissue microarrays (TMAs). The first set consisted of 142 gastric/gastro-oesophageal cancer cases not exposed to neoadjuvant chemotherapy and the second set consisted of 103 gastric/gastro-oesophageal cancer cases exposed to preoperative platinum-based chemotherapy. Expressions of ERCC1, XPF, FANCD2, APE1 and p53 were investigated using immunohistochemistry. In patients who received neoadjuvant chemotherapy, favourable TRG response (TRG 1, 2 or 3) was associated with improvement in disease-specific survival (P=0.038). ERCC1 nuclear expression correlated with lack of histopathological response (TRG 4 or 5) to neoadjuvant chemotherapy (P=0.006) and was associated with poor disease-specific (P=0.020) and overall survival (P=0.040). CONCLUSIONS: We provide evidence that tumour regression and ERCC1 nuclear protein expression evaluated by immunohistochemistry are promising predictive markers in gastro-oesophageal cancer patients receiving neoadjuvant platinum-based chemotherapy.

The sensitivity of cytologic evaluation of pleural fluid in the diagnosis of malignant mesothelioma.

Pleural malignant mesothelioma (MM), which is an aggressive neoplasm with a high mortality, frequently manifests initially as pleural effusions. The sensitivity of cytologic examination for its diagnosis varies widely in literature and most of the figures are from earlier studies with conventional cytologic preparations. The objective of this study was to provide the current evidence on the role and sensitivity of cytologic examination of pleural fluid in the diagnosis of MM. We reviewed the cytologic findings in pleural effusions of a large series of histologically proven MM (234 cases) diagnosed in our institution between 2001 and 2008. Of all cases, 154 (66%) had cytologic material examined. A specific diagnosis of MM was rendered or suspected in 53% (79 patients). The lowest sensitivity (20%) was noticed in sarcomatoid MM cases. MM was favored over adenocarcinoma in 97% of patients with positive cytologic findings that have been confirmed with immunohistochemistry. In this series, five cases were inadequate and five cases were initially reported as atypical, whereas 65 cases (44%) were reported as negative for malignancy. On review of the cytology slides, only four cases were upgraded from benign to suspicious compared to four cases downgraded from suspicious to atypical but no significant improvement to the diagnosis could be made on revision. These data suggested that a cytologic diagnosis contributed useful information in patients with epithelioid and biphasic pleural MM. Limitations of the cytologic examination of MM should also be acknowledged.

Cytological assessment of conventional transbronchial fine needle aspiration of lymph nodes.

OBJECTIVES: Transbronchial fine needle aspiration (TBNA) is a minimally invasive bronchoscopic technique that allows pathological examination of mediastinal and hilar lymph nodes. The aim of this study was to assess the cytopathological outcome of TBNA. METHODS: One hundred and eighty-seven patients who underwent TBNA of mediastinal and hilar lesions from May 2000 to June 2007 were reviewed. RESULTS: TBNA results were considered to be adequate if the cytological material revealed a malignant lesion or sufficient number of benign lymphoid cells. In the current study, 40 cases (21.9%) were reported as inadequate. When inadequate tests were excluded, the overall sensitivity and accuracy of TBNA in the diagnosis of malignant lesions were 83.5% and 88.0% respectively. The lowest sensitivity was noted in lymph node involvement by lymphoma. Regarding the workload associated with TBNA cytology, we found that the average number of conventionally prepared cytological slides per case was high (17 slides per case). CONCLUSION: Our results confirm that conventional TBNA is a sensitive and useful technique but it is relatively expensive and the protocols should be adapted to allow appropriate material to be collected for ancillary diagnostic tests.

Biomarkers of response to therapy in oesophago-gastric cancer.

Cancer of the oesophagus, gastro-oesophageal junction (GOJ) and stomach remains a major health problem worldwide. The evidence base for the optimal management of patients with operable oesophago-gastric cancer is evolving. Accepted approaches include preoperative chemotherapy followed by surgery (oesophageal cancer), chemo-radiotherapy alone (oesophageal cancer) and perioperative chemotherapy (gastric and gastro-oesophageal adenocarcinomas). The underlying principles behind neoadjuvant therapy are to improve resectability of the tumour by tumour shrinkage/downstaging and to treat occult metastatic disease as early as possible. The response rate to cytotoxic therapy is about 40% in oesophago-gastric cancer. Available evidence suggests that a favourable histopathological response to cytotoxic therapy may be a useful positive predictive marker in oesophago-gastric cancer. However, the ability to predict tumour response in routine clinical practice is difficult and is an area of intense investigation. There is evolving evidence for the role of predictive biomarkers in cancer in general and oesophago-gastric cancer in particular. We provide an overview on the current status of radiological and biological predictive biomarkers. We have focussed on clinical translational investigations and, where appropriate, provided pre-clinical insights. Whether predictive markers will be routinely incorporated in clinical practice remains to be seen as biomarker research is expensive and the data generated from these investigations are complex. It is clear that a concerted international effort between academia and industry is critical if personalised medicine as a practical reality for our cancer patients is to be realised.

Expression of mesothelial markers in malignant mesotheliomas: an immunohistochemical evaluation of 173 cases.

OBJECTIVE: To see the distribution of Calretinin, thrombomodulin, CK5/6 and HBME-1 markers in various subtypes of mesotheliomas and extend the published data on this topic. The positivity of adenocarcinoma specific markers (CEA and BerEP4) in malignant mesotheliomas have also been evaluated. METHODS: Various markers in 173 cases of malignant mesotheliomas received over a period of 8 years were evaluated by immunohistochemistry. RESULTS: In majority of malignant mesotheliomas i.e., epithelioid and biphasic types, the positive staining patterns complement the gold standard histologic diagnosis. However, in a small minority mainly sarcomatoid variant, heavy reliance cannot be placed on these markers. CEA and BerEP4 are useful negative markers of mesotheliomas, although occasionally these are positive in clear cut mesotheliomas. CONCLUSIONS: Specificity of various markers in malignant mesotheliomas should be assessed according to histologic subtypes. The existing generation of markers is not reliable in diagnosis of sarcomatoid mesotheliomas. Fortunately this forms only a small group of mesothelial malignancy. In common epithelioid and biphasic variants calretinin, thrombomodulin, CK5/6, HBME-1 are sensitive positive markers whereas CEA and BerEP4 are negative markers of malignant mesotheliomas.

Spectrum of cutaneous appendage tumors at Aga Khan University Hospital.

OBJECTIVE: To determine the frequency of various types of cutaneous appendage tumors in our practice. METHOD: This is a partly retrospective and partly prospective study conducted at the Department of Pathology, Histopathology Section, The Aga Khan University Hospital, Karachi between 1st January 1997 and 31st December 2001. RESULTS: One hundred sixty six skin appendage tumors were diagnosed during the study period. 87.3% were benign, while 12.6% were malignant. Male female ratio was almost equal. Mean age was 41.72 years. 37.34% showed eccrine differentiation, 14.45% showed apocrine differentiation and 41.56% showed pilosebaceous differentiation, 6.62% exhibited mixed differentiation. The 5 commonest tumors were pilomatricoma, nodular hidradenoma (eccrine acrospiroma), syringocystadenoma papilleferum, eccrine poroma and eccrine spiradenoma. The commonest malignant tumors were porocarcinoma and sebaceous carcinoma. Pilomatricoma were common in children. CONCLUSION: Most of our findings roughly correlate with the western published data. However, commonest site for eccrine poromas in our study was head and neck. Also, not a single case of eccrine spiradenoma was seen in the first two decades of life. These findings differ significantly from western data.

Morphological pattern of salivary gland tumours.

OBJECTIVE: To delineate the spectrum of salivary gland tumors in our setup. SETTING: The Aga Khan University Medical Centre, Karachi. METHOD: Tumors were analysed considering histological type, age and sex of the patients and anatomic location. The diagnosis of individual tumours was based on the 1991 World Health Organisation Classification. RESULTS: During the span of eight years (1991-1998), 379 cases of salivary gland tumours were diagnosed. Of these, 205 (65.7%) were male and 174 (34.3%) were female. The median age at the time of diagnosis was 35 years. The median age for patients with malignant lesions (44 years) was 12 years older than those with benign tumours (34 years). Overall, malignant tumours were seen more frequently in males, however benign tumours were distributed equally between the two sexes. The most common site was parotid gland (82.85%). Only five cases of minor salivary gland tumours were seen. The most frequently diagnosed benign salivary gland neoplasm was pleomorphic adenoma (84.5%), followed by Warthin's tumours (6.18%), Mucoepidermoid carcinoma was the most commonly encountered malignant lesion (56.9%), followed by adenoid cystic carcinoma (19.6%). CONCLUSION: Plemorphic adenoma was the most common benign salivary gland tumour and mucoepidermoid carcinoma was the most frequent malignant neoplasm. Parotid gland was the most common site of origin in both benign and malignant tumours. The overall relative frequency of salivary gland tumours in this series correlates with that reported in the international literature.

Clinicopathological profile of Wilms' tumor.

The profile of renal tumors in children less than 15 years of age during the period 1991-1997 is presented. Among the 37 children with kidney tumors, 29 (78.4%) had Wilms' tumor. There was also a 20-year-old female with Wilms' tumor. The median age at presentation was 2.6 years (range 2.5 months to 20 years). 66.7% of the cases diagnosed were < or = 3 years and 90% were < or = 6 years. Five cases were under one year of age. The male to female ratio was 2:1. Twenty-two cases (73.3%) were triphasic and 7 (23.3%) were biphasic. Only one case was monophasic with blastemal component. Five cases (16.7%) showed nephrogenic rests in the uninvolved renal parenchyma and one case had nephroblastomatosis. The tumor was favorable in 26 cases (86.7%) and unfavorable in 4. Fourteen cases were in-patients while 16 were outside referrals. The pathological (10 cases whose specimens were sent from other centers) and clinicopathological (13 hospitalized patients) staging showed 10 cases (43.5%) with stage 1, 4 cases (17.4%) with stage 2, and 7 cases (30.4%) with stage 3. In two cases (8.7%), there was stage 4 disease. The length of the follow-up period in the 13 hospitalized patients ranged from 7 days to 5 years 5 months (median 14 months). There was one recurrence and one death after 2 years of diagnosis.

Association of Epstein Barr Virus (EBV) with nasopharyngeal carcinoma (NPC).

AIM: To observe the frequency of nasopharyngeal carcinoma (NPC) and its association with Epstein Barr Virus (EBV) infection. SETTING: This study included consecutive cases of nasopharyngeal carcinoma, which were diagnosed in the Department of Pathology at the Aga Khan University Hospital, Karachi in the period of two years (1996-97). METHODS: These tumors were initially evaluated on H&E stained sections. The tumors showing evidence of keratinization were excluded from the study. The Epstein Barr Virus was detected with the help of Polymerase chain reaction in formalin fixed, paraffin embedded tissue sections. RESULTS: During the study period, seventeen cases of nasopharyngeal carcinoma were diagnosed which comprised 0.3% of all malignant tumors. The age ranged from 5 years to 70 years with male to female ratio of 2.4:1. The NPC was more prevalent in adults (71%) as compared to children (29%) under 15 years. Six cases (35%) exhibited positive signal for Epstein Barr Virus. CONCLUSION: Nasopharyngeal carcinoma is an infrequent tumor. The prevalence of Epstein Barr virus infection in nasopharyngeal carcinoma is quite low as compared to other regions of the world.

Morphological pattern of testicular tumors.

OBJECTIVE: To find out the mode of presentation, age distribution and the prevalence of various histological subtypes of testicular tumors. METHOD: All consecutive cases of testicular tumors diagnosed in the department of pathology, the Aga Khan University Hospital, Karachi, during the period of eight years (1991-98) were included in this study. Relevant clinical details such as age, clinical presentation and side of involvement of the testis were also recorded, where available. RESULTS: During the span of eight years (1991-98), 170 cases of testicular tumors were diagnosed at the Aga Khan University Hospital, Karachi. Most of the tumors were diagnosed in the third and fourth decade of life. Scrotal mass or swelling was the predominant mode of presentation. There was a slight predominance of right-sided testicular tumors. Germ cell tumors constituted 83.5% of all malignant testicular neoplasms. Amongst these seminoma was the most common (36.5%) tumor followed by mixed germ cell tumors (28.82%). Yolk-sac tumor was the commonest testicular neoplasm in children while lymphoma was the predominant neoplasm in the elderly population. CONCLUSION: The overall relative frequency of testicular malignancy in this series correlated with that reported in the international literature.

Central nervous system lymphomas: a histologic and immunophenotypic analysis.

OBJECTIVE: To observe the spectrum of non-Hodgkin's lymphomas involving the central nervous system including morphological subtypes and immunophenotypic status. SETTING: Retrospective analysis of eleven years (1986 to 1996) data from surgical pathology files of Department of Pathology. RESULTS: Forty-three cases of non-Hodgkin's lymphomas were diagnosed during the period of eleven years (from 1986 to 1996), all of which were diffuse types. A total of 1177 Central Nervous CNS biopsies were examined, out of which 937 cases were diagnosed as CNS neoplasms, the remaining were non-neoplastic in nature. Among 937 CNS neoplasms, 43 cases (4.6%) were reported as non-Hodgkin's lymphomas. As most of the cases were outside referrals, the primary or secondary nature of the lymphomatous process could not be assessed. Seventeen cases were intracranial, while 26 cases were spinal in location. Majority of the intracranial lymphomas were biopsied from the cerebrum (12 cases). Male to female ratio was 1:2. The median age for intracranial lymphomas was 50 years and for spinal lymphomas 29 years. There were 16 cases (37%) of diffuse large cell lymphomas; 7 cases (16%) of diffuse mixed small and large cell lymphomas; 3 cases (7%) of diffuse large cell immunoblastic lymphomas; 2 cases (4.6%) of lymphoblastic lymphomas and diffuse small non-cleaved cell lymphomas and one case of small lymphocytic lymphoma and diffuse small cleaved cell lymphoma. One case of T cell rich B cell lymphoma was also diagnosed in the thoracic spine as primary extranodal lymphoma. Eight cases were unclassifiable and in 2 cases the features were suggestive of lymphoma. Immunophenotypic analysis was performed in 20 cases, however, in 2 cases the results were inconclusive. Fifteen cases (83%) showed immunoreactivity for B cell markers and 3 cases showed T cell phenotype out of which one case was lymphoblastic lymphoma. CONCLUSION: CNS lymphomas were uncommon tumors and comprised 4.6% of the total CNS neoplasms in our study. Moreover, these CNS lymphomas accounted for 2.2% of the total non-Hodgkin's lymphomas, including both nodal and extranodal. There was a higher incidence of location of these lymphomas within the spinal cord than brain. Most of the lymphomas were of intermediate or high grade (75%) according to the working formulation. Immunophenotypical status revealed B-cell phenotype in 84% of the lymphomas, in which it was tested (JPMA 50:141, 2000).

Morphological pattern and frequency of thyroid tumors.

OBJECTIVE: The present study was done to evaluate the frequency of thyroid cancer and to find out the prevalence of histological types of thyroid tumor with respect to age and sex group. SETTING: This study included consecutive cases of malignant tumors of thyroid gland, which were diagnosed in the Department of Pathology at the Aga Khan University Hospital, Karachi during the period of three years (1995-1997). METHODS: These cases were evaluated on H & E stained sections from paraffin embedded 10% buffered formalin fixed tissue blocks. Special stains and immunohistochemical analysis were performed whenever required. RESULTS: A total of 8541 malignant tumors were diagnosed in a period of 3 years which included 103 (1.2%) cases of thyroid cancer. Thyroid tumors were more prevalent in females with female to male ratio of 2.6:1. Papillary carcinoma (69%) was the most common histological type of thyroid tumors, followed by follicular carcinoma (11.6%), medullary carcinoma (9.7%), anaplastic carcinoma (5.9%), non-Hodgkin's lymphoma (2.9%) and unclassified tumors (0.9%) in order of frequency. CONCLUSION: Thyroid cancer was more common in females. Papillary carcinoma was the most common histological type of thyroid tumors in females as well as in males. Papillary carcinoma was more prevalent in third, fourth and fifth decades of life while follicular and anaplastic carcinomas were more frequent after the fourth decade of life.