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Background:Multiple myeloma (MM) is a disease of malignant plasma cells (PC) with poor survival. Disease progression and treatment relapse are attributed to MM cancer stem cells (CSCs) and signaling molecules such as MUC1 and XBP1. The prognostic value of the expression of CSC associated biomarkers, MUC1 and XBP1 in MM, has not been explored previouslyMethod:In this study, we determined the immunohistochemical expression of CSC markers (ALDH1, CD117 and CD34), MUC1 and XBP1in 128 MM formalin-fixed paraffin-embedded bone marrow archival blocks. The expression of biomarkers was assessed for association with clinicopathological variables and the overall survival of patients. Descriptive & initial univariate survival analyses were performed using Kaplan Meier curves. Univariate and multivariable analyses were performed using simple and multiple Cox regression models. The results are reported as crude & adjusted hazard ratios with 95% confidence intervals. Results :Expression of ALDH1 and CD117 was found in 51% and 48% of the tumors, respectively. ALDH1 expression was associated with 1.83 years of reduced survival for patients with CD56 negative tumors. MUC1 expression was observed in 62%, whereas XBP1 was expressed in 48% tumors. Combinatorial group analysis of XBP1 and MUC1 stratified patients into two prognostic groups. Cases with tumors negative for expression of MUC1 and XBP1 (XBP1- / MUC1-) were categorized as a good prognostic group with increased survival of 3.42 years compared to cases with tumors expressing both (Worst prognosis, XBP1+/MUC1+). The adjusted hazard ratio showed a four-fold increased risk of mortality associated with the concordant expression of MUC1 and XBP1 in patients who were >65 years of ageConclusion: Concordant expression of MUC1 and XBP1 in MM defines a subset of patients with adverse outcomes. Of these, patients diagnosed at >65 years of age have a significantly higher risk of death.

Low- and middle-income countries sustain the majority of pediatric cancer burden, with significantly poorer survival rates compared to high-income countries. Collaboration between institutions in low- and middle-income countries and high-income countries is one of the ways to improve cancer outcomes.Patient characteristics and effects of a pediatric neuro-oncology twinning program between the Hospital for Sick Children in Toronto, Canada and several hospitals in Karachi, Pakistan over 7 years are described in this article.A total of 460 patients were included in the study. The most common primary central nervous system tumors were low-grade gliomas (26.7%), followed by medulloblastomas (18%), high-grade gliomas (15%), ependymomas (11%), and craniopharyngiomas (11.7%). Changes to the proposed management plans were made in consultation with expert physicians from the Hospital for Sick Children in Toronto, Canada. On average, 24% of the discussed cases required a change in the original management plan over the course of the twinning program. However, a decreasing trend in change in management plans was observed, from 36% during the first 3.5 years to 16% in the last 3 years. This program also led to the launch of a national pediatric neuro-oncology telemedicine program in Pakistan.Multidisciplinary and collaborative efforts by experts from across the world have aided in the correct diagnosis and treatment of children with brain tumors and helped establish local treatment protocols. This experience may be a model for other low- and middle-income countries that are planning on creating similar programs.

Background Complete diagnostic autopsy (CDA) is considered to be the gold-standard procedure that aids in determination of cause of death in stillbirths and neonatal deaths. However, CDA is not routinely practiced in South Asian countries due to religious beliefs, lack of expertise, and lack of resources. Minimally invasive tissue sampling (MITS) has been recommended as a less mutilating and less expensive alternative to CDA for obtaining tissues for analysis. The present study aims to evaluate the yield of lung tissue and histological findings using MITS as part of a cause of death analysis for stillborns and preterm neonatal deaths. Methods Data were collected during an observational multicenter prospective study called the Project to Understand and Research Preterm birth and Stillbirth (PURPOSe) conducted in India and Pakistan. After obtaining written informed consent from parents, the eligible stillbirths and neonatal deaths were subjected to MITS using a standard protocol. The tissues were obtained from both lungs for histological and microbiological analysis. Results At both sites, a total of 453 stillbirths and 352 neonatal deaths underwent MITS. For stillbirths and neonatal deaths, the yield of lung tissue using MITS was high (92%). Intrauterine fetal distress and respiratory distress syndrome were the leading lung pathologies reported in stillbirths and neonatal deaths, respectively. Conclusions MITS appears to be a reasonable alternative to CDA in obtaining and evaluating lung tissue to inform accurate cause of death analysis in stillbirth and preterm deaths.

Multiple myeloma (MM) is a heterogeneous disease of the bone marrow (BM). Its association with Epstein-Barr virus (EBV) remains enigmatic. Aim of our study was to determine expression of latent membrane protein 1 (LMP1), aldehyde dehydrogenase 1 (ALDH1), CD117 and their association with 5-year survival in MM patients. Seven percent of cases expressed LMP1 in MM cells with no association with survival. Whereas, LMP1 expression in CD138- non-neoplastic cells was observed in 80% of the cases, conferring a survival advantage of 1.75 years (mean 3.75 ± 0.28, 95% CI 3.19-4.3). LMP1 in CD138- non-neoplastic cells was associated with CD117 expression in MM cells. Combinatorial analysis of LMP1 and CD117 stratified patients into good prognostic group LMP1+/CD117- (mean survival 4.16 ± 0.39 years) and a worst prognostic group; LMP1-/CD117+ (mean survival 1.02 ± 0.29 years). Our study showed that LMP1 expression in CD138- non-neoplastic cells of BM in MM patients confers a survival advantage.

Cedrus deodara have been used traditionally in ayurvedic system against peptic ulcer. Present work is concerned with the determination of histopathological effects in ethanol induced ulcer on rats (Wistar Strain) treated with Cedrus deodara root oil at a dose of 200mg/kg and comparison of its antiulcer activity against control, positive control and standard anti-ulcer drug (Omeprazole). The aim was to find out the antiulcer effect of Cedrus deodara root oil and to observe histopathology of liver, kidney as well. 120 Albino rats were taken and divided into four groups i.e. A, B, C and D designated as control, positive control, standard and treated groups respectively. Normal and intact general architecture of mucosa and submucosa layers of stomach observed. No significant changes observed in thickness of epithelium, no inflammatory cells were present on the mucosa and submucosal layer and gastric glands were normal. Liver of albino rats, showed no dilation and congestion in central as well as portal vein. Kidney of albino rats exhibited no shrinkage in glomeruli, no congested and dilated renal corpuscles, neither hemolysis nor congested and dilated renal tubules were seen. It is concluded that C. deodara root oil has anti-ulcer properties without effecting kidney and liver tissues.

Glioblastoma is an aggressive primary central nervous system tumour that usually has a poor prognosis. Generally, the typical imaging features are easily recognisable, but the behaviour of glioblastoma multiforme (GBM) can often be unusual. Several variations and heterogeneity in GBM appearance have been known to occur. In this pictorial essay, we present cases of pathologically confirmed GBM that illustrate unusual locations and atypical features on neuroimaging, and review the relevant literature. Even innocuous-looking foci, cystic lesions, meningeal-based pathology, intraventricular and infra-tentorial masses, multifocal/multicentric lesions and spinal cord abnormalities may represent GBM. We aim to highlight the atypical characteristics of glioblastoma, clarify their importance and list the potential mimickers. Although a definitive diagnosis in these rare cases of GBM warrants histopathological confirmation, an overview of the many imaging aspects may help make an early diagnosis.

Nipple adenoma (NA) is a rare benign breast neoplasm that seldom co-exists with breast carcinoma (BC). Majority of these BC are separate from NA, and their origin from NA is an extremely rare event. We herein describe a case of 65-year-old female who had a painless lump for 15 years which increased in size and ulcerated for last six months. Microscopic examination of the wedge biopsy of nipple showed features of NA at superficial aspect and invasive carcinoma from it at the deeper aspect. The patient underwent mastectomy and axillary clearance, which revealed a 4-cm invasive breast carcinoma, no special type with axillary lymph node involvement. The patient received adjuvant chemotherapy, radiotherapy and adjuvant hormonal therapy. The patient is alive and disease-free after 36 months. NA should be carefully evaluated for co-existent BC because it completely changes the treatment plan and prognosis.

Paragangliomas are rare tumours derived from the neural crest cells. Most common site for these tumours is the adrenal medulla, where they are called as pheochromocytomas. Biliary system is an extremely uncommon site for extra-adrenal paraganglioma. We report the case of a 55 year old female who presented with one-month history of jaundice and right upper quadrant discomfort. Imaging showed a well-defined rounded mass at porta hepatis with arterial enhancement causing compression over the proximal common bile duct, resulting in moderate intrahepatic biliary dilatation. The patient underwent radical excision of common bile duct and roux-en-y hepaticojejunostomy. Final histopathology confirmed paraganglioma. Approximately 10% of the patients may present with extra-adrenal disease, but biliary paraganglioma are extremely rare. Only few cases have been reported in literature and the management usually involves the surgical excision. ---Continue

Liver biopsies are common in clinical practice for a variety of reasons in the work-up of diverse disorders ranging from congenital disorders like ‘storage diseases’ to inflammatory conditions in particular for grading and staging of ‘chronic hepatitis’ to autoimmune disorders affecting intrahepatic bile ducts. Another common challenge on core needle biopsies of the liver is to differentiate ‘hepatocellular carcinoma’ from liver metastases which may originate from a large number of organs in both genders. As liver transplantation is getting pace biopsies from live allografts are also becoming common. As for gall bladder, almost all biopsy specimens are ‘cholecystectomies’, performed due to gall stones, and only occasionally associated dysplasia or malignancy is seen. Pancreatic biopsies or resections are also not uncommon for both more commonly seen ‘pancreatic adenocarcinoma’ arising from pancreatic ducts to ‘neuroendocrine tumours’. In this chapter all common and relatively uncommon entities from this anatomical region are described with salient light microscopic features and ancillary testing where necessary.

Haematolymphoid pathology is one of the most diverse and challenging area of diagnostic pathology by virtue of the immense diversity and complexity of immune system itself. Precise categorization of haematolymphoid neoplasms also invariably require immunophenotyping by ‘immunohistochemistry (IHC)’ or/and ‘flow cytometry’ in addition to molecular genetic testing by FISH or PCR. Common biopsy sites include ‘lymph node’ from all regions, extra-nodal sites in particular from GIT, though no site is exempt as well as ‘bone trephine’. In this chapter both non-neoplastic and neoplastic lesions are covered, though major focus is on salient microscopic features both at architectural and cellular level along with judicious use of IHC and other ancillary testing of haematolymphoid neoplasms to differentiate these from close mimicries on one hand and from atypical reactive patterns on the other.

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive intrathoracic neoplasm that typically offer poor prognosis. In general, development of MPM is linked with a history of asbestos exposure. Herein we report a 56-year-old female patient with MPM, who presented with complains of chest pain, cough, shortness of breath and weight loss. The patient’s radiological work-up demonstrated right sided plural effusion with circumferential plural thickening and loss of lung volume. Histopathological features in tandem with immunohistochemical (IHC) study were consistent with the diagnosis of MPM. Our study illustrate that MPM is an uncommon and highly aggressive malignancy associated with poor prognosis. Keywords: Malignant pleural mesothelioma, Chemotherapy, Asbestos exposure

Case reports and case series documenting unfortunate patients with more than one malignant neoplasm are rare but well established. While majority of such patients have two malignancies, cases with three or even four malignant neoplasms in the same patient have been published in literature. A number of factors influencing carcinogenesis have been implicated in such cases including exposure to large amounts of radiation, chemotherapy for the original malignancy; prolonged history of heavy smoking and exposure to other environmental carcinogens; aging; and underlying genetic alterations. Concomitant multiple malignant neoplasms may be synchronous-two or more malignant neoplasms histologically distinct from each other, arising in the same site and detected simultaneously (for example during the same hospital admission) or detected one after the other in sequence in a period less than 6 months; or metachronous-two or more malignant neoplasms of similar or distinct histologic type detected at different times (after an interval of greater than 6 months) in different anatomic sites. Any combination of malignant tumors can occur in the same patient for example carcinomas with other carcinomas, carcinomas with Non-Hodgkin or Hodgkin lymphomas, carcinomas with mesotheliomas, carcinomas with sarcomas etc. We have reported several cases with multiple malignancies during our practice, and these cases were composed of the different combinations described above. The aim of the present study is to document 10 such cases of combined carcinoma and Non Hodgkin lymphoma in the same patient which were diagnosed in our section.

Insulinomas are rare, usually benign, solitary tumours accounting for 60% of islet cell tumours. These tumours can be difficult to localize preoperatively due to their small size. We present a challenging case of a 40 year old male with frequent hypoglycaemic spells and endogenous hypoglycaemia who presented as a diagnostic dilemma. Patient had an occult insulinoma with inconclusive CT Abdomen, MRI Abdomen and Octreotide scan. The final localization of the tumour was made by selective arterial calcium stimulation testing (SCAT), done for the first time in Pakistan at Aga Khan University Hospital. This was followed by successful distal pancreatectomy as localizd by SACT yielding a well differentiated neuroendocrine tumour. After surgery patient made a robust recovery with no further hypoglycaemic symptoms. Hence successful localization and management of occult insulinomas can be challenging but can be achieved with the advent of newer invasive modalities.

Aim: To present an epidemiological and histological perspective of diseases of the gastrointestinal tract (including liver and biliary tract) at the Section of Histopathology, Department of Pathology, AKUH, Karachi, Pakistan. Materials and Methods: All consecutive endoscopic biopsies and resections between October 1 and December 31, 2012 were included. Results: A total of 2,323 cases were included. Carcinoma was overwhelmingly the commonest diagnosis on esophageal biopsies (69.1%); chronic helicobacter gastritis (45.6%) followed by adenocarcinoma (23.5%) were the commonest diagnoses on gastric biopsies; adenocarcinoma (27.3%) followed by ulcerative colitis (13.1%) were the commonest diagnoses on colonic biopsies; acute appendicitis (59.1%) was the commonest diagnosis on appendicectomy specimens; chronic viral hepatitis (44.8%) followed by hepatocellular carcinoma (23.4%) were the commonest diagnoses on liver biopsies; chronic cholecystitis was the commonest diagnosis (over 89%) on cholecystectomy specimens. Conclusions: Squamous cell carcinoma comprised 88.8% of esophageal cancers. About 67% were in the lower third and 56.5% were moderately differentiated; mean ages 49.8 years for females and 55.8 years for males; 66% cases were from South West Pakistan. Over 67% patients with gastric adenocarcinoma were males; mean ages 59 and 44 years in males and females respectively, about 74% gastric carcinomas were poorly differentiated; and 62.2% were located in the antropyloric region. About 63% patients with colorectal adenocarcinoma were males; mean ages 46.1 and 50.5 years for males and females respectively; tumor grade was moderately differentiated in 54%; over 80% were located in the left colon. In 21.2% appendicectomies, no acute inflammation was found. Acute appendicitis was most common in young people. Hepatitis C (66.3%) was more common than hepatitis B (33.7%); about 78% cases of hepatocellular carcinoma occurred in males; females comprised 76.7% patients with chronic cholecystitis; and 77.8% patients with gall bladder carcinoma. All resection specimens showed advanced cancers. Most cancers occurred after the age of 50 years.

Fungal cerebral abscesses are rare and usually seen in immunocompromised individuals. We report a case and review published literature of Madurella mycetomatis as an agent of cerebral abscess. We found contiguous head and neck infections to be the principal cause of cerebral maduromycosis caused by M. mycetomatis. Early recognition of Madurella spp. as the causative agent is essential to avoid cerebral spread.

Context There are no recent authoritative data about incidence and prevalence of various types of cancers in Pakistan. Aim To determine the frequency of malignant tumors seen in our practice and provide a foundation for building a comprehensive cancer care strategy. Materials and methods 10,000 successive cases of solid malignant tumors reported in 2014 were included. All cases had formalin fixed, paraffin embedded specimens available and diagnosis was based on histological examination of H and E stained slides plus ancillary studies at the Section of Histopathology, Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi. The latest WHO classifications were used along with the latest CAP protocols for reporting and the most updated TNM staging. Results There were 9,492 (94.9%) primary tumors while 508 (5.1%) were metastatic. Some 5,153 (51.5%) were diagnosed in females and 4,847 (48.5%) in males. The commonest malignant tumors in females were breast (32%), esophagus (7%), lymphomas (6.8%), oral cavity (6.7%) and ovary (4.8%), while in males they were oral cavity (13.9%), lymphomas (12.8%), colorectum (7.9%), stomach (6.9%) and esophagus (6.6%). Malignant tumors were most common in the 5th, 6th and 7th decades. About 8% were seen under 20 years of age. Conclusions Oral cavity and gastrointestinal cancers continue to be extremely common in both genders. Breast and esophageal cancers are prevalent in females. Lung and prostate cancer are less common than in the west. Ovarian cancer was very common but cervix cancer was less so.

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare malignant thyroid tumor showing thymic or related branchial pouch differentiation. The tumors are composed predominantly of spindle cells along with focal epithelial component and ductular formations. SETTLE occurs in young patients, with indolent growth and a tendency to develop delayed blood-borne metastases. We herein report two cases of SETTLE with a follow-up period of 64 months and 30 months, respectively.

We present a case of a 14-year-old girl who was diagnosed with Burkitt lymphoma in 2014. She was managed with chemotherapy and remained in remission for 3 years. On her surveillance imaging in 2017, a left-sided renal neoplastic mass was incidentally discovered. She underwent nephrectomy and pathology of the resected specimen revealed small cell tumour of the kidney with features favouring renal Ewing sarcoma/primitive neuroectodermal tumour. Molecular genetic analysis by fluorescence in situ hybridisation was performed which showed translocation of 22q12, thereby confirming the diagnosis. This is a rare secondary malignancy and an unusual association. This case highlights the importance and diagnostic dilemmas of rare secondary tumours in patients with such haematological malignancies and discusses its possible pathogenetic aspects.

Ameloblastic fibrosarcoma (AFS) is a rare malignant odontogenic tumour regarded as the malignant counterpart of ameloblastic fibroma. It is characterized by a benign epithelial component within a malignant fibrous stroma. AFS is a locally aggressive neoplasm with extremely low potential for metastasis. We report an extremely rare, rapidly progressive, and fatal case originating in the posterior mandible of a 20-year old female patient. Initially histopathologically diagnosed as a benign lesion, it rapidly recurred with apparent transformation into a high-grade sarcoma over a period of 6 months. Subsequent intracranial and pulmonary metastases were noted, and the patient died within 15 months of initial consultation. This case emphasizes the need for a high element of suspicion about clinically ambiguous lesions. We recommend more extensive or radical, primary excisions in lesions that have a known potential for recurrence or malignancy.

Lymphoma is a malignant tumour arising from lymphoid tissue, with the majority of cases being in the lymph nodes, however, in 1/4th of cases, these tumours are found in extralymphoid tissue. Lymphoid tissue is also found in organs having mucosa, such as the digestive tract, salivary gland and in tracheal tissue. This collection of lymphoid tissue is known as mucosa-associated lymphoid tissue (MALT), and non-Hodgkin lymphoma involving this extralymphoidal lymph tissue is known as MALT lymphoma. It was first reported by Isaacson and Wright in 1983, however, it was not included as a working diagnosis in clinical use until it was reclassified as ‘marginal zone B-cell lymphoma’ in a 1994 Revised European American Lymphoma (REAL) classification. It is rarely seen in the head and neck region, and we report the sixth case of MALT lymphoma of the base of the tongue. A 61-year-old man presented with dysphagia and the feeling of a lump in his throat for 5 months.

New treatments for inflammatory bowel disease are of interest due to high rate of remission failure. Natural products have been effective in IBD therapeutics as they have multiple constituents. The aim of the present study was to evaluate the effect of Flaxseed extract (Fs.Cr) on ulcerative colitis and identify the possible mechanisms involved. Colitis was induced by intrarectal administration of 6% AA in BALB/c mice. Colonic mucosal damage was assessed after 24h by calculating disease activity index (DAI), macroscopic and histological damage scores, biochemical measurement of myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), and total glutathione activities. Since cytokines are involved in exacerbating inflammatory cascade with emerging role of innate immune cytokines in IBD therapeutics, we hence assessed the effect on the levels of TNF-α, IFN-γ and IL-17, at 6, 12 and 24h by ELISA. Fs.Cr ameliorated the severity of AA colitis as evident by improved DAI, macroscopic damage and the histopathological scores along with restoration of goblet cells. Fs.Cr decreased MDA and MPO activities and enhanced antioxidant activity compared to the AA group. Finally, Fs.Cr in doses (300 and 500mg/kg) decreased TNF-α and IFN-γ levels at all time points with simultaneous increase in IL-17 levels at 24h as compared to the AA group. These results suggest that Fs.Cr ameliorates the severity of AA colitis by reducing goblet cell depletion, scavenging oxygen-derived free radicals, reduce neutrophil infiltration that may be attributed due to decreasing IFN-γ and TNF-α and increasing IL-17 levels.

Aim To report the histologic findings on Whipple resection specimens and thus determine the extent and spread of carcinomas of ampullary region and head of pancreas in our population. Setting Section of Histopathology, Department of Pathology, Aga Khan University Hospital (AKUH), Karachi, Pakistan. Materials and methods A case series of 311 consecutive Whipple resection specimens received between January 1,2003 and December 31, 2014. Specimens processed for histologic sections and representative sections submitted and histologically examined as per established and standard protocols. All relevant tumor parameters including histologic type, histologic grade, pathologic T and N stage and tumor size were assessed. Epidemiologic data were also recorded. All findings were analysed using SPSS 19.0 software. Results Ampullary (periampullary) carcinomas were much more common than carcinomas of the head of the pancreas, especially in males, with an average age of 53 years. Mean tumor size was 2.5 cms, over 54% were well differentiated. A large majority were pT2 or pT3 and N0. Carcinomas of pancreatic head were also more common in males, mean age was 55 years, mean tumor size was 3.5 cms, and over 65% were moderately differentiated. The majority were T2 or T3 and pN1. Prognostically, significant statistical correlation was seen with tumor grade and pathologic T and N stage (p values statistically significant). However, tumor size was not statistically significant. Conclusions Ampullary carcinomas are more common compared to pancreatic carcinomas. Majority of ampullary carcinomas were well differentiated while majority of pancreatic carcinomas were moderately differentiated. Large majority of both types of cases were pT2 or T3. Histologic tumor grade and pathologic T and N stage are significantly related to prognosis in Pakistani patients with ampullary and pancreatic cancers.

Congenital infantile fibrosarcoma (CIFS) is a soft tissue sarcoma of infants mainly involving lower extremities usually presenting during the first year of life. A subset of cases occur in the head and neck, but scalp involvement is exceptionally rare. We report clinicopathological features of three cases of CIFS involving the scalp diagnosed between 2011 and 2012. The ages of the three patients at the time of diagnosis ranged from 12 to 90 days (mean 48 days). All were males and presented with scalp swelling at birth which grew rapidly in size. The tumor was located in the left temporal region in two cases and the right temporoparietal region in one case. On imaging, underlying bone involvement was noted in two cases. The mean size of the resected tumors was 8 cm. All cases exhibited a cellular tumor arranged in sheets of uniform oval to spindle cells, increased mitosis, and hemangiopericytoma-like vessels. All patients are alive after a mean follow-up of 39.6 months. Recurrence was seen in one case due to incomplete excision. No metastasis was seen in any of the cases. CIFS of the scalp is rare and carries a good prognosis. Underlying bone erosion is rare but was noted seen in two of our cases. A male predominance was seen in our cases.

Introduction: Multiple myeloma (MM) is a plasma cell (PC) disorder of the elderly, affecting predominantly males. Therapeutic advancement during the last decade has improved overall survival. Crosstalk between malignant PCs and the microenvironment is considered to play an important role in the development of resistance to treatment and relapse. Epstein Barr virus (EBV) is the first B-lymphotropic herpes virus identified for its association with human tumors. Reports relating an association of EBV to MM are few and inconsistent. It has been proposed that initiation of viral lytic cycle in EBV infected B cells is preceded by X-Box binding Protein-1 (XBP-1) mediated differentiation, resulting in a subset of EBV expressing infected PCs. Increased incidence of EBV expressing MM cases have been observed in immune-compromised patients. However, the significance of EBV in the bone marrow (BM) of MM patients has not been fully elucidated. The aim of our study was to evaluate prevalence of EBV in association with MUC1, XBP-1, ALDH1, and B-cell lineage markers (CD20, CD45, CD56, and CD138) in bone marrow trephine biopsies of patients with MM and to assess if there was any association with prognosis in a cohort of 151 MM patients at a single tertiary teaching hospital institution in Pakistan. Methodology: Formalin-fixed, paraffin-embedded trephine blocks of 151 MM cases diagnosed from 2007-2015 were evaluated for immunohistochemical (IHC) expression of MUC1, XBP-1, and EBV along with stem cell marker (ALDH1) and B-cell lineage markers (CD20, CD45, CD56, and CD138). Clinicopathologic details and follow-up data were collected from patients' medical records. Data was analyzed on SPSS 19. Five-year survival was estimated by Kaplan Meier curve for patients with follow-up available for 5 years or more (n=75). Results: Mean age at diagnosis was 57 years (range 30-89) with male preponderance (68.2%). Women (60.4%) with MM presented at an earlier age (median age 55 years, range 42-78) and difference in age of presentation was found to be significant (p value 0.04). Bone lesions were identified in 68.9% of patients at presentation. Stage I, II, and III disease was identified in 32.4%, 23.4%, and 44.1 % of patients, respectively (ISS staging system). Relapse was observed in 79.6% of patients and was significantly correlated with the expression of XBP-1 (p value 0.035). CD56 was expressed in 60.3% of cases and was significantly associated with cases diagnosed after the age of 57 years (p value 0.003). Expression of MUC1 was observed in 62.3% of tumors and 70% of MUC1-positive tumors also expressed XBP-1 (p value 0.06). Although the number of cases expressing EBV in the MM tumor cell population was only 7.2%, we detected EBV in 80.2% of the cases in the adjacent non-neoplastic cells with conspicuous expression in megakaryocytes. Five-year survival analysis (n=75) showed that expression of EBV+ in non-neoplastic cells was associated with significantly improved outcome with an advantage of 1.8 years (95% CI 3.32-4.4) as compared to EBV- cases (p value < 0.005). Among the XBP-1+ tumors, lack of EBV expression in non-neoplastic cells significantly correlated with adverse outcome (95%CI, 0.70-2.6) (p value < 0.005). Conclusions: To the best of our knowledge, this is the first study reporting expression of EBV in non-neoplastic cell population in BM trephines of MM patients. Salient conclusions of our study are as follows: 1. Expression of EBV in the surrounding tumor microenvironment of trephine biopsies of patients with MM is associated with a significant survival advantage; 2. Patients with MM in Pakistan present at a comparatively earlier age; 3. XBP1 expression was associated with relapse. Citation Format: Sheerien Rajput, Khurram Minhas, Iqbal Azam, Sadia Habib, Azhar Hussain, El-Nasir Lalani. Expression of EBV in the non-neoplastic cell population in trephine biopsies of patients with multiple myeloma is associated with a significant survival advantage [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 53.

Continued advances in the field of histo pathology (and cyto pathology) over the past two decades have resulted in dramatic changes in the manner in which these disciplines are now practiced. This is especially true in the setting of a large university hospital where the role of pathologists as clinicians (diagnosticians), undergraduate and postgraduate educators, and researchers has evolved considerably. The world around us has changed significantly during this period bringing about a considerable change in our lifestyles and the way we live. This is the world of the internet and the world-wide web, the world of Google and Wikipedia, of Youtube and Facebook where anyone can obtain any information one desires at the push of a button. The practice of histo (and cyto) pathology has also evolved in line with these changes. For those practicing this discipline in a poor, developing country these changes have been breathtaking. This is an attempt to document these changes as experienced by histo (and cyto) pathologists practicing in the biggest center for Histopathology in Pakistan, a developing country in South Asia with a large (180 million) and ever growing population. The Section of Histopathology, Department of Pathology and Microbiology at the Aga Khan University Hospital (AKUH) in Karachi, Pakistan’s largest city has since its inception in the mid-1980s transformed the way histopathology is practiced in Pakistan by incorporating modern methods and rescuing histopathology in Pakistan from the primitive and outdated groove in which it was stuck for decades. It set histopathology in Pakistan firmly on the path of modernity and change which are essential for better patient management and care through accurate and complete diagnosis and more recently prognostic and predictive information as well.

Background: Carcinoma of the male breast is responsible for less than 1% of all malignancies in men but the incidence is rising. Invasive ductal carcinoma is the most common histological subtype while invasive lobular carcinoma is responsible for only 1.5% of the total cases of which pleomorpic lobular carcinoma is an extremely rare variant. We report the case of a gentleman with node positive, pleomorphic lobular carcinoma of the breast. Case presentation: An elderly gentleman with a past history of type 2 diabetes and long term ethanol use presented to us with a self-discovered palpable lump in the left breast. Physical examination revealed bilateral gynaecomastia along with a well circumscribed subareolar mass and palpable lymphadenopathy in the ipsilateral axilla. The breast nodule revealed atypical cells on fine needle aspiration biopsy and the patient underwent a modified radical mastectomy after systemic surveillance was negative for metastatic disease. The lesion was reported as grade III pleomorphic lobular carcinoma with a lack of E-cadherin expression on immunohistochemistry and the neoplastic cells exhibited strong positivity for estrogen receptor in the absence of Her2 gene amplification. Six out of the eleven dissected regional lymph nodes showed evidence of disease. The patient completed 4 cycles of adjuvant chemotherapy without evidence of recurrent disease and was subsequently lost to follow up. Conclusions: Although invasive lobular carcinomas comprise 12% of all female breast cancers, they are very rare in males due to lack of acini and lobules in the normal male breast. Pleomorphic lobular carcinoma, an aggressive variant of ILC is even rarer in males. Chronic consumption of ethanol by our patient may have resulted in some degree of hepatic impairment with resultant hyperestrogenism. This in theory may have been the cause of his gynaecomastia, resultant breast cancer and is a plausible explanation for development of the invasive lobular subtype in a male. The prognosis and clinicopatholocial features of pleomorphic lobular carcinoma in men are less clearly defined due to its rarity. Additional studies are hence necessary to improve our understanding of this disease in males.

To describe the clinicopathological spectrum of Lymphangioma Circumscriptum (LC).Observational case series.Department of Pathology and Microbiology, AKUH, Karachi, from 2002 to 2012.All reported cases of LC were retrieved from medical record. Clinical and pathological features were noted. Frequency percentages were determined.There were 29 cases of LC predominantly males (62%). The mean age was 27.17 ±15.5 years. The commonest sites was anal/perianal region (24%) followed by extremities (17%) and tongue, (14%). Vulval LC was seen in 3 patients. Two cases were described on scrotum. The lesions were most commonly suspected as viral warts, mole or polyp (in anal region). Vesicles with erosions and bleeding and localized growth were the usual clinical presentations. Four of the patients presented with swelling since birth. All were treated with surgical excision. Microscopic examination revealed acanthotic squamous epithelium with papillomatosis. The subepithelial region had collections of lymphatic channels composed of ectatic dilated vessels with serum and inflammatory cells in their lumina. The lymphatic channels were seen in deeper layers along with lymphocytic aggregates.Lymphangioma circumscriptum is a malformation of abnormal lymphatic channels with feeding cisterns in subcutaneous tissue. It is a benign lesion usually occurring in anal/perianal region and confused with warts. Surgical excision is preferred mode of treatment.

Melanotic neuroectodermal tumour of infancy is a rare, mostly benign but locally aggressive tumour of neural crest cell origin occurring in infants. The most commonly affected anatomic site is the maxilla. Such tumours of the brain and skull are very rare. We present the case of an 8 months old baby girl whose presenting complaint was a swelling in the scalp for 6 months. She was otherwise asymptomatic. CT imaging confirmed the presence of an osteolytic tumour in the anterior parasagittal skull with dural involvement. The tumour was surgically excised enbloc. The patient has been well at 2 years follow-up without any evidence of recurrence.

Infiltrating ductal carcinoma is the most common form of invasive breast cancer. It accounts for 80% of all types of breast cancer. We report an unusual presentation of histologically proven case of infiltrating ductal carcinoma of breast presented clinically as a small palpable areolar dermal lesion. Well defined hypoechoic cystic lesion in areolar dermis was present on ultrasound with a negative mammogram.

Juvenile dermatomyositis (JDM) is an important subtype of dermatomyositis characterized by inflammation of muscle, skin and gastrointestinal tract. A 14-year-old girl, with a history of fever, joint pain, easy fatigability and a rash since the age of 3 years is described. Physical examination, laboratory evaluation, electromyography (EMG) and muscle biopsy were suggestive of a chronic inflammatory process involving the muscles, most likely dermatomyositis. The report highlights the importance of a muscle biopsy as the gold standard for diagnosing dermatomyositis.

We report a case of diffuse fibrous pseudotumour/fibromatous periorchitis, in a 43 year old male, that completely encased the right testis and was adjacent to a hydrocoele cavity. Although fibrous pseudotumours of this region are uncommon, they are reported to be the second most common benign paratesticular lesion after adenomatoid tumours. These comprise approximately 6 percent of paratesticular lesions, and are accepted as reactive lesions secondary to trauma, hydrocoele, infections or inflammation. Fibrous pseudotumours have a peak incidence in the third decade of life but can occur at any age. Clinically these lesions mimic malignancy resulting in the treatment by radical orchidectomy. Fibrous pseudotumours should be considered in differential diagnosis when one encounters a predominantly fibrocollagenous lesion.

Invasive papillary carcinomas of the Extrahepatic Bile Ducts (EBD) are uncommon (4-5%). The course is less aggressive than conventional adenocarcinomas of the extrahepatic bile ducts. Non-invasive and minimally invasive papillary carcinomas are even rarer, behave as in-situ carcinomas and are associated with excellent long-term prognosis. A variety of lesions of the EBD that show papillary architecture should be distinguished from papillary carcinoma. Here, we report a case of papillary carcinoma of the common bile duct showing minimal invasion. Separation of invasive from non-invasive or minimally invasive papillary carcinoma is critical in estimating the patient outcome.

Hepatic angiosarcomas are rare tumours with poor prognosis, with patients usually dying within 6 months. Metastases mainly occur in lymph nodes, spleen, lungs, bones and adrenals. Metastasis to small intestine is even rarer. Similarly, primary or metastatic angiosarcomas in small intestine are extremely rare, often present with recurrent gastrointestinal bleeding and anemia, and have an extremely poor prognosis. Both primary or metastatic intestinal angiosarcomas may exhibit epithelioid morphology. It may be very difficult to differentiate between primary and secondary cases in intestine and especially when the tumour exhibits epithelioid morphology.

Post-Transplant Lymphoproliferative Disorder (PTLD) is a lymphoma, which develops as a result of immunosuppression in a recipient of a solid organ or bone marrow allograft. Majority are associated with Ebstein-Barr Virus (EBV) infection, are mostly B-cell type and less often T-cell type. We report a case of T-cell PTLD, occurring in a renal transplant recipient.

Synchronous or metachronous occurrence of esophageal, gastric and colonic cancers is a very rare occurrence, although there are several case reports in literature. A case of a 41 years old man with metachronous cancers of colon and stomach is reported.

Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology characterised pathologically by the presence of non-caseating granulomas in involved organs. Sarcoidosis most frequently involves the lungs followed by eye and skin. Presentation as retroperitoneal and lung mass is rare in sarcoidosis. We describe an unusual case of sarcoidosis where the patient presented with large retroperitoneal and lung masses, and was treated as tuberculosis.

We report the case of a young adult who presented with a painful foot due to chondroblastoma associated with an aneurismal bone cyst. Chondroblastoma is a rare benign cartilaginous neoplasm that accounts for approximately 1% of all bone tumors and characteristically arises in the epiphysis of a long bone, particularly the humerus, tibia, and femur. Chondroblastoma can affect people of all ages. It is, however, most common in children and young adults between the ages of 10 and 20 years. Association of chondroblastoma with aneurysmal bone cyst is well documented however this association has only once been reported in the cuboid. Imaging techniques should be supplemented with an open biopsy for the final diagnosis. Management with curettage, use of high speed burr and bone grafting has shown very good outcomes.