Clinico- pathologic presentation of hypersensitivity pneumonitis in Egyptian patients: a multidisciplinary study.

BACKGROUND: Hypersensitivity pneumonitis (HP) is a common diffuse parenchymal lung disease in Egypt which can be difficult to recognize due to the dynamic symptoms & associated environmental factors. METHODS: Forty-three Egyptian patients were enrolled in this study, presenting with dyspnea and cough, predominant ground-glass opacity (GGO) in high-resolution computed tomography (HRCT) where lung biopsy was needed to establish the diagnosis. RESULTS: The age range was 15 to 60 years. Females represented 90.7% (39 patients) while 9.3% (4 patients) of our patients were males. History of contact with birds was detected in 9 (20.9%) patients. Most of our patients (60.5%) didn't have exposure history, and only 8 patients (18.6%) were living in geographic areas in Egypt that are known for the exposure to environmental etiologic factors (cane sugar exhaust fumes). The most common HRCT pattern was GGO with mosaic parenchyma in 18 patients (41.86%), followed by GGO with centrilobular nodules in 9 patients (20.93%), then isolated diffuse GGO in 5 patients (11.62%), GGO with traction bronchiectasis in 4 patients (9.3%), GGO with consolidation in 3 patients (6.97%), GGO with reticulations in 2 patients (4.65%), and GGO with cysts in 2 patients (4.65%). The most common histologic finding was isolated multinucleated giant cells in 38 patients (88.3%) commonly found in airspaces (24 patients) and less commonly in the interstitium (14 patients), followed by interstitial pneumonia and cellular bronchiolitis in 36 patients (83.7% each), interstitial ill-formed non-necrotizing granulomas in 12 patients (27.9%), fibrosis in 10 patients (23.2%), and organizing pneumonia pattern in 4 patients (9.3%). CONCLUSION: The diagnosis of HP presenting with predominant GGO pattern in HRCT requires a close interaction among clinicians, radiologists, and pathologists. Some environmental and household factors may be underestimated as etiologic factors. Further environmental and genetic studies are needed especially in patients with negative exposure history.

Transformation of primary human hepatocytes in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Currently, there is limited knowledge of neoplastic transformation of hepatocytes in HCC. In clinical practice, the high rate of HCC local recurrence suggests the presence of different hepatocyte populations within the liver and particularly in the tumor proximity. The present study investigated primary human hepatocyte cultures obtained from liver specimens of patients affected by cirrhosis and HCC, their proliferation and transformation. Liver samples were obtained from seven HCC cirrhotic patients and from three patients with normal liver (NL). Immediately after surgery, cell outgrowth and primary cultures were obtained from the HCC lesion, the cirrhotic tissue proximal (CP, 1-3 cm) and distal (CD, >5 cm) to the margin of the neoplastic lesion, or from NL. Cells were kept in culture for 16 weeks. Morphologic analyses were performed and proliferation rate of the different cell populations compared over time. Glypican-3, Heppar1, Arginase1 and CD-44 positivity were tested. The degree of invasiveness of cells acquiring neoplastic characteristics was studied with a transwell migration assay. We observed that HCC cells maintained their morphology and unmodified neoplastic characteristics when cultured. Cells isolated from CP, showed a progressive morphologic transformation in HCC-like cells accompanied by modification of markers expression with signs of invasiveness. Absence of HCC contamination in the CP isolates was confirmed. In CD samples some of these characteristics were present and at significantly lower levels. With the present study, we are the first to have identified and describe the existence of human hepatocytes near the cancerous lesion that can transform in HCC in vitro.

Comparative effects of cocaine and cocaethylene on alveolar epithelial type II cells.

Abuse of cocaine (COC) and alcohol have been among the leading causes of non-prescription drug-related deaths in the USA and are known to cause acute and chronic lung diseases. The co-abuse of COC and alcohol results in the production of an active metabolite, cocaethylene (CE). The effects of COC and its metabolites on the respiratory system have been scarcely studied. This study was aimed at comparing the toxic effects of eqimolar concentration (1 mM) of COC and CE on alveolar epithelial type II cells. This was performed by measuring cell growth, viability, clonogenic activity, cell cycle and reactive oxygen species (ROS) generation. The treatment of CE and COC resulted in a significant inhibition of cell proliferation with the formation of an average of three colonies which measured about 1.74×10(-15) m each and 25 colonies each of about 5.73×10(-15) m, respectively, while untreated cells yielded 31 colonies of 8.75×10(-15) m (p<0.05). The treatments of CE and COC resulted in the reduction of the growth fraction of alveolar epithelial type II cells without significant decrease in viability. In addition, there was an approximately twofold increase in ROS generation as compared to the controls (p<0.05). Therefore, CE-induced inhibition of cellular proliferation may contribute to the pathogenesis of diffuse alveolar damage in co-abusers of COC and alcohol.

Lymph node involvement in immunohistochemistry-based molecular classifications of breast cancer.

BACKGROUND: Prognosis and treatment options differ for each molecular subtype of breast cancer, but risk of regional lymph node (LN) metastasis for each subtype has not been well studied. Since LN status is the most important predictor for prognosis, the aim of this study is to investigate the propensity for LN metastasis in each of the five breast cancer molecular subtypes. METHODS: Under an institutional review board-approved protocol, we retrospectively reviewed the charts of all pathologically confirmed breast cancer cases from January 2004 to June 2012. Five subtypes were defined as luminal A (hormone receptor positive, Ki-67 low), luminal B (hormone receptor positive, Ki-67 high), luminal human epidermal growth factor receptor 2 (HER2), HER2-enriched (hormone receptor negative), and triple negative (TN). RESULTS: A total of 375 patients with complete data were classified by subtype: 95 (25.3%) luminal A, 120 (32%) luminal B, 69 (18.4%) luminal HER2, 26 (6.9%) HER2-enriched, and 65 (17.3%) TN. On univariate analysis, age (<50), higher tumor grade, HER2+ status, tumor size, and molecular subtype were significant for LN positivity. Molecular subtype correlated strongly with tumor size (χ(2); P = 0.0004); therefore, multivariable logistic regression did not identify molecular subtype as an independent variable to predict LN positivity. CONCLUSIONS: Luminal A tumors have the lowest risk of LN metastasis, whereas luminal HER2 subtype has the highest risk of LN metastasis. Immunohistochemical-based molecular classification can be readily performed and knowledge of the factors that affect LN status may help with treatment decisions.

Significance of Ki-67 and p53 immunoexpression in the differential diagnosis of oral necrotizing sialometaplasia and squamous cell carcinoma.

Necrotizing sialometaplasia (NS) is a benign condition that usually involves the hard palate and can be mistaken for invasive squamous cell carcinoma (SCC). In this study, we have demonstrated that p53 and Ki-67 staining may assist in the differential diagnosis of NS from SCC. Thirteen cases of NS and 20 cases of oral cavity SCC were randomly selected from our surgical pathology archive from 1992 to 2009. Each case was additionally stained with Ki-67, p53, BCL-2, p16, and epidermal growth factor receptor (EGFR) antibodies. All 13 cases of NS were negatively stained for BCL-2, EGFR, and Ki-67. Three cases (23%) showed weak and focal positive nuclear staining for p53. Two cases (15%) showed positive staining for p16. In 16 well-differentiated SCC cases, p53 was positive in 12 cases (75%); BCL-2, p16, EGFR were positive in 3 cases (18%); and Ki-67 was positive in all cases (100%). In 4 moderately differentiated SCC cases, p53 expression was positive in all cases. Two tumors (50%) had a positive expression of BCL-2. Three cases (75%) had a positive p16 staining, and 1 (25%) had a positive EGFR staining. All cases were positive with high nuclear staining greater than 35% of cells for Ki-67. Ki-67 and p53 showed more intense staining and increased in moderately differentiated SCC comparing with well-differentiated SCC and NS. BCL-2, EGFR, and p16 had the same pattern of staining with the same extent in NS and SCCs. The diagnosis of NS may be difficult and may be supplemented via immunohistochemistry by demonstrating focal or absent p53, low to absent Ki-67 (<10% of cells). Although Ki-67 and p53 staining are generally more intense and are increased in malignancy, these findings may be helpful adjuncts in the differential diagnosis of NS from SCC in appropriate clinical setting.

Mycobacterium haemophilum and Histoplasma capsulatum coinfection in a renal transplant patient.

We report the case of a 22-year-old man who presented with a Mycobacterium haemophilum and Histoplasma capsulatum coinfection occurring 21 years after a living-donor-related renal transplant.

Intraductal papilloma of the breast in association with preoncogenic gene of breast cancer.

We reported a case of an African American woman who went to the hospital with palpable right breast lump with bloody nipple discharge at University of Texas Medical Branch at Galveston. The modalities of breast imagings included mammography and ultrasonography. The method used for viral identification was Linear Array HPV genotyping test. Intraductal papilloma revealed as high density tubular or rounded lobular masses with partially circumscribed, obscured margins and clustered punctate microcalcifications on mammograms. Ultrasound showed as intraductal masses with dilated ducts. The core biopsy demonstrated duct filled with papillary lesion and post excision revealed intraductal papilloma. HPV DNA types 16, 33, 58 and 71 were detected after use of Linear Array HPV genotyping test.

A t(1;9)(q10;q10) translocation with additional 6q23 and 9q22 rearrangements in a case of chondromyxoid fibroma.

Chondromyxoid fibroma (CMF) is a rare cartilaginous tumor of bone. It typically presents in the long tubular bones and to a lesser extent in the small bones of the hands and feet of young adults. To date, several cytogenetic abnormalities have been described in association with CMF. We studied a phalangeal CMF from a 13-year-old female by cytogenetic methods. We found a novel unbalanced translocation between the long arms of chromosomes 1 and 9, resulting in loss of 1p. In addition, rearrangements involving the 6q23 and 9q22 regions were also observed. To our knowledge, this is the first report in the literature describing this novel chromosomal translocation in CMF.

Detection of human papilloma virus subtypes 16 and P16(ink4a) in invasive squamous cell carcinoma of the fallopian tube and concomitant squamous cell carcinoma in situ of the cervix.

Squamous cell carcinoma (SCC) of the fallopian tube is rare and often diagnosed postoperatively. Cervical cancer is considered as a long-term sequaele, resulting from sexual transmitted infection with certain common high-risk human papilloma virus (HPV) types. The role of human papilloma virus in the development of the tubal SCC is unknown. We report an unusual case of SCC of the fallopian tube, synchronously occurring with cervical SCC in situ in a 49-year-old patient. Histological examination of the entire endometrium revealed no involvement Both tubal and cervical lesions showed the presence of high risk HPV 16 by PCR and increased expression of p16(INK4a) protein. Both SCC of the fallopian tube and cervical SCC in situ were positive for p63, while the non-involved tubal epithelium was positive for WT-1, but negative for p63. In conclusion, the concomitant occurrence of fallopian tube and cervical SCC can be explained by: (i) the 'field effect' of HPV infection resulting in the concomitant development of primary SCC in various sites of the female genital tract; (ii) the primary fallopian tube SSC metastasizing to the uterine cervix; or (iii) primary cervical SCC metastasizing to the fallopian tube. The detection of HPV 16 and p16(INK4a) in both the fallopian tube and cervicalSCCs strengthens the hypothesis of the 'field effect' of HPV infection.

Immunohistochemical characterization of subtypes of male breast carcinoma.

INTRODUCTION: Male breast cancer accounts for around 1% of all breast cancer cases but the incidence has risen in recent years. This study aimed to classify the molecular subtypes of male breast cancers based on the expression profile of immunomarkers and to evaluate their association with clinicopathological features and expression patterns of epidermal growth factor receptor (EGFR) and nuclear factor kappaB (NF-kappaB). METHODS: A total of 42 cases of male breast carcinoma were examined retrospectively using immunostains for estrogen receptor (ER), progesterone receptor (PR), cytokeratin 5/6 (CK5/6), EGFR, and NF-kappaB. Human epidermal growth factor receptor 2 (HER2) expression was evaluated by immunostaining and confirmed by fluorescent in situ hybridization (FISH). RESULTS: The luminal A subtype was the most common subtype in male breast cancer (83%, 35/42), which was followed by the luminal B subtype (17%, 7/42). Basal-like and HER2+/ER- subtypes were not identified in this group. All carcinomas expressed ER and 67% of them were PR+. High nuclear grades were more common in the luminal B subtype (71%, 5/7) than in the luminal A subtype (34%, 12/35). The luminal B subtype carcinomas expressed EGFR (42%, 3/7) and NF-kappaB (57%, 4/7) more frequently than the luminal A subtype did (17%, 6/35 and 37%, 13/35, respectively). CONCLUSIONS: In our study group, luminal A and B subtypes were the major subtypes of male breast carcinoma. The immunophenotypical features of male breast cancer differ from those of its female counterpart. Luminal B subtype tended to have high nuclear grade and more frequent expression of EGFR and NF-kappaB.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia is an extremely rare pulmonary lesion, with only 39 cases reported in the literature. We report an additional case and review the literature. The patient is a 41-year-old man with a 5-year history of progressive dyspnea, cough, and wheezing. He was initially diagnosed as having bronchial asthma but did not respond to treatment of bronchodilators and inhaled steroids. Pulmonary function tests showed airflow obstruction. Chest computed tomography revealed a mosaic pattern of air trapping and thickening of bronchial walls. Open lung biopsy showed diffuse proliferation of pulmonary neuroendocrine cells within the bronchiolar epithelium, often bulging into or obliterating the bronchiolar lumen. These cells also breached the basement membrane, forming tumorlets. There was prominent peribronchiolar fibrosis and obliterative bronchiolitis. The pathologic evaluation of lung tissue is currently the gold standard in making a definitive diagnosis of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, and all the reported cases were diagnosed by either open lung biopsy or lobectomy.

Intranodal palisaded myofibroblastoma.

Intranodal palisaded myofibroblastoma (IPM) usually presents as a painless, slow-growing inguinal mass. Our review of 42 cases from 13 publications indicates that two thirds of IPMs occur between the ages of 45 and 55 years, the male-female ratio is 2:1, and there is a lack of ethnic predilection. Grossly, the IPM cut surface shows areas of hemorrhage. Five microscopic features are seen: (a) compressed remnants of lymphoid tissue at the periphery; (b) spindle cells with nuclear palisading; (c) intraparenchymal hemorrhage and erythrocyte extravasation; (d) so-called amianthoid fibers; and (e) intracellular and extracellular fuchsinophilic bodies that stain positive for smooth muscle actin. Immunohistochemically, IPM is positive for smooth muscle actin and cyclin D1 and negative for S100, glial fibrillary acidic protein, CD34, and desmin, and it shows a low proliferative index of Ki-67. Electron microscopy demonstrates features of myofibroblasts and smooth muscle cells. Excellent prognosis is seen after surgical treatment, with an approximately 6% recurrence rate and no malignant transformation.

Immunohistochemical and ultrastructural analysis of a poorly differentiated pediatric age Sertoli-Leydig cell tumor.

Ovarian Sertoli-Leydig cell tumors (SLCT) are rare in young women. They are divided into six categories based on the degree of differentiation and the presence of heterologous elements. Less than 15% of these tumors are poorly differentiated. A 14-year-old obese African-American girl presented with amenorrhea, progressive abdominal pain, and increasing abdominal girth. Pelvic CT revealed a 10 x 9 x 9 cm right adnexal mass which was resected successfully. The gross appearance was dark tan and red with central hemorrhage and necrosis. Microscopically, this was poorly differentiated with compact aggregates of moderate size oval to elongated cells separated by zones of edematous stroma containing scattered spindle shape cells. Areas of ill-formed tubules and primitive cords were present. Clusters of Leydig cells were observed. The oval and spindle cells showed multiple mitoses and were diffusely positive for inhibin and patchy but strong positivity for calretinin. Both preoperative and postoperative studies revealed no metastases. Serum alpha-fetal protein (AFP), androgen, and dihydroepiandrosterone sulfate (DHEA-S) were elevated.

Cytogenetic and molecular studies of an unusual case of multiple primary alveolar rhabdomyosarcomas: low-level chromosomal instability and reciprocal translocation t(6;11).

Cytogenetic and molecular studies have shown that approximately 80% of cases of alveolar rhabdomyosarcoma (ARMS) have consistent chromosomal translocation of either t(2;13) or t(1;13), resulting in either PAX3-FKHR or PAX7-FKHR gene fusions. However, 20% of the cases diagnosed histologically are negative for these fusion genes. The clinical and pathological properties of the so-called fusion gene negative tumors remain to be defined. We present an unusual case of a 7-year-old boy who developed three separate primary ARMS over a 5-year period, with the first tumor diagnosed at the age of 12 months. The tumors were negative for the characteristic translocations, t(2;13) or t(1;13), but showed evidence of low-level chromosomal instability and a reciprocal chromosomal translocation t(6;11)(q27;q13). PCR amplification of the p53 gene, exons 2-11, followed by DNA sequencing did not detect any germline p53 mutation. These clinical and cytogenetic features have not been reported previously in ARMS. The findings suggest that cytogenetic abnormalities of chromosome 6 may be associated with the development of early onset multiple ARMS in a subgroup of pediatric patients as seen in this case.

Histopathologic and immunohistochemical characterization of a primary papillary thyroid carcinoma in the lateral cervical lymph node.

Lymph nodes in the neck are known to occasionally contain benign epithelial inclusions and can be rare primary site of various tumors usually occurring in other organs. Papillary thyroid carcinoma in the lateral neck lymph node with co-existing ectopic thyroid inclusions has not been reported previously. A 41-year-old male patient, who had normal thyroid function and no history of neck irradiation, was seen with a slowly enlarging mass in the right lateral neck. At surgery the cervical mass was found to be separate from the thyroid proper without any attachments in between. Papillary thyroid carcinoma and co-existing thyroid inclusions were identified within the lateral cervical lymph node. Immunohistochemistry detected strong and diffuse cytoplasmic positivity with antibodies against CK19 and CK903 in papillary thyroid carcinoma. Benign thyroid follicles within the lymph node were only weakly and focally stained. Thorough examination confirmed no malignancy in the total thyroidectomy specimen. Furthermore, small foci of metastatic papillary carcinoma were identified in two ipsilateral lymph nodes from neck dissection specimen. These findings suggest development of primary papillary thyroid carcinoma from malignant transformation of benign intranodal thyroid inclusions.

Mimicks of pancreatic malignancy in patients with chronic pancreatitis: correlation of computed tomography imaging features with histopathologic findings.

Differentiation of chronic pancreatitis and pancreatic carcinoma can be a clinical and radiologic dilemma. Several patients with chronic pancreatitis can undergo unnecessary major abdominal surgery for benign lesions. This pictorial review illustrates the computed tomographic findings and histopathologic features of lesions mimicking pancreatic neoplasm in patients with chronic pancreatitis. Several benign lesions can simulate pancreatic malignancy in patients with chronic pancreatitis. Knowledge of the computed tomographic appearance of these benign entities is important to prevent unnecessary surgeries.

Nodular mucinosis of the breast: a case report with pathologic, ultrasonographic, and clinical findings and review of the literature.

Nodular mucinosis is an extremely rare breast lesion. This benign mass usually presents clinically as a poorly circumscribed, subareolar, myxoid mass in young female patients. We report a case of this rare breast lesion and discuss its clinical, radiologic, and histopathologic features. A 21-year-old white woman presented with a mass in the left breast of 6 months' duration. She had never been pregnant or had any history of breast feeding, surgery, trauma, or use of exogenous hormones or a family history of breast cancer. Clinical breast examination demonstrated a 1 cm "rubbery" mass directly under and continuous with the left nipple. The skin that covered the mass had an edematous and irregular appearance without erythema or drainage from the nipple. Ultrasonography demonstrated a 1-cm, nonintraductal, circumscribed, homogeneous, isoechoic mass that was continuous or part of the base of the left nipple. The mass was smooth, with a thin echogenic rim. Doppler flow showed some vascularity. These findings suggested a benign breast lesion, including a fibroadenoma or nipple adenoma. Despite reassurance, the patient desired excision of the lesion. Gross examination revealed a nodular, rubbery-firm, ovoid, pink, polypoid mass that measured 1.5 x 0.9 x 0.8 cm. Microscopic examination showed a well-circumscribed tumor with a nodular appearance, which consisted of an accumulation of pink myxoid tissue and contained spindle cells with bland-appearing nuclei, no mitosis, and mild cellularity. The pink myxoid tissue was stained with Hale colloidal iron and Alcian blue. The Alcian blue stain was removed by pretreatment with hyaluronidase. The spindle cells stained with vimentin and smooth muscle actin; however, they did not express smooth muscle myosin or cytokeratin. This report presents and discusses the pathologic, ultrasonographic, and clinical findings of this rare entity.