The Pitfall of White Blood Cell Cystine Measurement to Diagnose Juvenile Cystinosis.

Cystinosis is an autosomal recessive lysosomal storage disease, caused by mutations in the CTNS gene, resulting in multi-organ cystine accumulation. Three forms of cystinosis are distinguished: infantile and juvenile nephropathic cystinosis affecting kidneys and other organs such as the eyes, endocrine system, muscles, and brain, and adult ocular cystinosis affecting only the eyes. Currently, elevated white blood cell (WBC) cystine content is the gold standard for the diagnosis of cystinosis. We present a patient with proteinuria at adolescent age and corneal cystine crystals, but only slightly elevated WBC cystine levels (1.31 ½ cystine/mg protein), precluding the diagnosis of nephropathic cystinosis. We demonstrate increased levels of cystine in skin fibroblasts and urine-derived kidney cells (proximal tubular epithelial cells and podocytes), that were higher than the values observed in the WBC and healthy control. CTNS gene analysis shows the presence of a homozygous missense mutation (c.590 A > G; p.Asn177Ser), previously described in the Arab population. Our observation underlines that low WBC cystine levels can be observed in patients with juvenile cystinosis, which may delay the diagnosis and timely administration of cysteamine. In such patients, the diagnosis can be confirmed by cystine measurement in slow-dividing cells and by molecular analysis of the CTNS gene.

Histopathology of Middle East respiratory syndrome coronovirus (MERS-CoV) infection - clinicopathological and ultrastructural study.

AIMS: The pathogenesis, viral localization and histopathological features of Middle East respiratory syndrome - coronavirus (MERS-CoV) in humans are not described sufficiently. The aims of this study were to explore and define the spectrum of histological and ultrastructural pathological changes affecting various organs in a patient with MERS-CoV infection and represent a base of MERS-CoV histopathology. METHODS AND RESULTS: We analysed the post-mortem histopathological findings and investigated localisation of viral particles in the pulmonary and extrapulmonary tissue by transmission electron microscopic examination in a 33-year-old male patient of T cell lymphoma, who acquired MERS-CoV infection. Tissue needle biopsies were obtained from brain, heart, lung, liver, kidney and skeletal muscle. All samples were collected within 45 min from death to reduce tissue decomposition and artefact. Histopathological examination showed necrotising pneumonia, pulmonary diffuse alveolar damage, acute kidney injury, portal and lobular hepatitis and myositis with muscle atrophic changes. The brain and heart were histologically unremarkable. Ultrastructurally, viral particles were localised in the pneumocytes, pulmonary macrophages, renal proximal tubular epithelial cells and macrophages infiltrating the skeletal muscles. CONCLUSION: The results highlight the pulmonary and extrapulmonary pathological changes of MERS-CoV infection and provide the first evidence of the viral presence in human renal tissue, which suggests tissue trophism for MERS-CoV in kidney.

Testosterone- and Cortisol-secreting Oncocytic Adrenocortical Adenoma in the Pediatric Age-group.

Oncocytic tumors are epithelial neoplasms that occur in various organs, including adrenal glands. Oncocytic adrenocortical adenomas and carcinomas are uncommon but well-known pathological entities in adults. However, generally oncocytic tumors, particularly in the adrenal glands, are very rare in the pediatric age-group. Most oncocytic adrenal tumors are not functional. We present a rare case of right-sided, functional oncocytic adrenocortical adenoma in a 5-year-old boy, who presented with clinical manifestations of precocious puberty and Cushing syndrome. Laparoscopic adrenalectomy showed a well-defined mass weighing 8.4 g and measuring 3 cm in maximum dimension. Histological examination demonstrated no features suggestive of aggressive biological behavior. The patient showed no evidence of recurrent or metastatic disease and continued to have normal serum hormonal levels 28 months following the surgery. In this report, we discuss the clinicopathological characteristics of this rare pathological entity and briefly review the literature on functional oncocytic adrenal tumors in the pediatric population.

Diminished accuracy of biomarkers of fibrosis in low replicative chronic hepatitis B.

BACKGROUND: We evaluated the diagnostic accuracy of aspartate aminotransferase (AST)-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4), AST/alanine aminotransferase (ALT) ratio (AAR), and age-platelet index (API) for significant fibrosis (Metavir F2-4) in low-replicative (HBV DNA <20,000 IU/mL) chronic hepatitis B virus (HBV) patients. METHODS: The sensitivity, specificity, and area under the receiver-operating characteristic curve (AUROC) of HBeAg-negative, low-replicative (n = 213) and high-replicative (HBV DNA ≥20,000 IU/mL, n = 153) patients was assessed. RESULTS: Overall, 113 patients (30.9%) had F2-4 fibrosis. Of the low and high-replicative patients, 40 (18.8%) and 73 (47.7%) had F2-4, respectively (P < 0.0001). APRI ≥0.5 less frequently identified F2-4 fibrosis in low vs. high-replicative patients (48.7% vs. 69.6%, P = 0.032) and AAR identified it more frequently in low-replicative patients (37.5% vs. 19.4%, P = 0.037). FIB-4 and API were not different (P > 0.05) for identifying F2-4 fibrosis in low and high-replicative patients. Higher specificities were seen at the lowest cut-offs in low vs. high-replicative states for APRI (≥0.5, 98% vs. 68.9%), AAR (84.3% vs. 76.6%), FIB-4 (≥1.45, 97.5% vs. 87.8%) and API (>4, 94.8% vs. 93.8%). At ROC-defined thresholds, APRI (≥0.33), AAR (≥0.93), FIB-4 (≥0.70) and API (>2) showed greater AUROCs for F2-4 diagnosis in low replicative (0.80, 0.62, 0.81 and 0.71, respectively) vs. high-replicative patients (0.73, 0.52, 0.67 and 0.69, respectively). CONCLUSION: All 4 biomarkers in both, low and high-replicative HBV demonstrate modest accuracy for fibrosis diagnosis at conventional cut-offs. Lowering the cut-offs may increase the diagnostic relevance of these biomarkers, particularly for APRI and FIB-4 in low-replicative disease.

Rare genetic variant in the CFB gene presenting as atypical hemolytic uremic syndrome and immune complex diffuse membranoproliferative glomerulonephritis, with crescents, successfully treated with eculizumab.

BACKGROUND: Complement factor B gene (CFB) is an important component of the alternate pathway of complement activation that provides an active subunit that associates with C3b to form the C3 convertase, which is an essential element in complement activation. Among the complement-associated disorders, mutations and pathogenic variants in the CFB gene are relatively rare phenomena. Moreover, mutated CFB affiliation with immune-complex diffuse membranoproliferative glomerulonephritis (IC-MPGN) and atypical hemolytic uremic syndrome (aHUS) are considered a highly rare occurrence. CASE PRESENTATION: We describe the clinical presentation, course, and pathological findings in a 7-year-old boy who has confirmed CFB heterozygous variants with pathological features compatible with IC-MPGN. Mutational analysis revealed a heterozygous variant p.Glu566Arg in exon 13 of the CFB gene. The patient did not respond to steroids and mycophenolate mofetil (MMF) therapy but responded clinically and biochemically to eculizumab treatment. This is the first case report of CFB alteration associated with IC-MPGN and aHUS that was successfully treated with eculizumab. CONCLUSIONS: Heterozygous variants in the CFB gene can be pathogenic and associated with IC-MPGN and aHUS. Early diagnosis and prompt management can be essential in preventing end-stage renal disease. Eculizumab may provide an effective modality of treatment.

Magnetic Fluorescent Nanoformulation for Intracellular Drug Delivery to Human Breast Cancer, Primary Tumors, and Tumor Biopsies: Beyond Targeting Expectations.

We report the development of a chemotherapeutic nanoformulation made of polyvinylpyrrolidone-stabilized magnetofluorescent nanoparticles (Fl-PMNPs) loaded with anticancer drugs as a promising drug carrier homing to human breast cancer cells, primary tumors, and solid tumors. First, nanoparticle uptake and cell death were evaluated in three types of human breast cells: two metastatic cancerous MCF-7 and MDA-MB-231 cells and nontumorigenic MCF-10A cells. While Fl-PMNPs were not toxic to cells even at the highest concentrations used, Dox-loaded Fl-PMNPs showed significant potency, effectively killing the different breast cancer cells, albeit at different affinities. Interestingly and superior to free Dox, Dox-loaded Fl-PMNPs were found to be more effective in killing the metastatic cells (2- to 3-fold enhanced cytotoxicities for MDA-MB-231 compared to MCF-7), compared to the normal noncancerous MCF-10A cells (up to 8-fold), suggesting huge potentials as selective anticancer agents. Electron and live confocal microscopy imaging mechanistically confirmed that the nanoparticles were successfully endocytosed and packaged into vesicles inside the cytoplasm, where Dox is released and then translocated to the nucleus exerting its cytotoxic action and causing apoptotic cell death. Furthermore, commendable and enhanced penetration in 3D multilayered primary tumor cells derived from primary lesions as well as in patient breast tumor biopsies was observed, killing the tumor cells inside. The designed nanocarriers described here can potentially open new opportunities for breast cancer patients, especially in theranostic imaging and hyperthermia. While many prior studies have focused on targeting ligands to specific receptors to improve efficacies, we discovered that even with passive-targeted tailored delivery system enhanced toxic responses can be attained.

Predictors of significant fibrosis in chronic hepatitis B patients with low viremia.

BACKGROUND AND AIM: The data on the prevalence and predictors of significant fibrosis (≥F2, METAVIR) in chronic hepatitis B virus (HBV) patients with low viremia are limited. We aimed to assess both the prevalence predictors of ≥F2 fibrosis in hepatitis B envelope antigen-negative patients with HBV DNA <20,000 IU/mL. METHODS: Hepatitis B envelope antigen-negative patients (n=213) with mean HBV DNA <2000 IU/mL (n=97) and HBV DNA 2000 to 20,000 IU/mL (n=116) were included and all had liver biopsy. Variables significantly associated with ≥F2 fibrosis on an univariate analysis were included in a multivariate logistic regression model. RESULTS: Overall, 40 (18.8%) patients had ≥F2 fibrosis, with no difference between those with mean HBV DNA <2000 IU/mL (19.6%) compared with patients with HBV DNA of 2000 to 20,000 IU/mL (18.1%; P=0.782). Fibrosis ≥F2 was similar in patients with HBV DNA <2000 versus 2000 to 20,000 IU/mL in relation to varying alanine aminotransferase thresholds (P>0.05), and was less frequent in persistently normal alanine aminotransferase patients (13.6%) when compared with those with elevated or fluctuating levels (25.3%, P=0.030). Fewer patients under 40 years of age had ≥F2 fibrosis (12.5%) as compared with older ones (28.2%; P=0.004). Logistic regression analysis identified higher aspartate aminotransferase [odds ratio (OR), 6.21; 95% confidence interval (CI), 2.48-15.54; P<0.0001], lower albumin (OR, 0.86; 95% CI, 0.78-0.95; P=0.002), platelet count (OR, 0.99; 95% CI, 0.98-0.99; P=0.013), and age (OR, 1.05; 95% CI, 1.01-1.09; P=0.024) as independent predictors of significant fibrosis. CONCLUSIONS: A small but significant minority of HBV patients with low viremia harbor significant fibrosis, although its rate is not different in those with viremia above or below 2000 IU/mL. Our findings may guide in decisions regarding liver biopsy and treatment in this category of patients.

Acute diffuse proliferative post-infectious glomerulonephritis in renal allograft--a case report and literature review.

PVN is a well-known cause of renal allograft dysfunction and failure. The diagnosis is established by examination of tissue from the renal graft, and confirmed by immunohistochemical or in situ hybridization techniques. Electron microscopy can be utilized as an ancillary modality to identify the viral particles ultrastructurally. The tubular epithelial cells are the primary target of PV cytopathic effect; however, PV-associated glomerular changes have also been described. Immune-type electron-dense deposits in the TBMs have been described in the setting of PVN, and rarely, likewise have glomerular subepithelial hump-like deposits. Diffuse immune-mediated proliferative glomerulonephritis in the setting of PVN has not been reported before. In this report, we describe an 11-yr-old kidney transplant recipient boy who developed immune-mediated glomerulonephritis with light microscopic, immunofluorescence, and ultrastructural features compatible with acute PIGN superimposing chronic PVN, discuss this unusual association and the possible mechanisms of antigen clearance in PVN and present a literature review.

Accuracy of international guidelines for identifying significant fibrosis in hepatitis B e antigen--negative patients with chronic hepatitis.

BACKGROUND & AIMS: Differing threshold levels of hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) are recommended by international guidelines for commencement of antiviral therapy. These guidelines advocate therapy for patients with significant fibrosis (METAVIR score ≥F2); we assessed the accuracy of these guideline-defined thresholds in identifying patients with ≥F2 fibrosis. METHODS: We applied the European (European Association for the Study of the Liver [EASL] 2012), Asian-Pacific (Asian-Pacific Association for the Study of the Liver [APASL] 2012), American (American Association for the Study of Liver Diseases [AASLD] 2009), and United States Panel Algorithm (USPA 2008) criteria to 366 consecutive hepatitis B e antigen-negative patients with liver biopsy samples: EASL, ALT >laboratory-defined upper limit of normal (ULN) and HBV DNA ≥2000 IU/mL (n = 171); APASL, ALT >2-fold laboratory-defined ULN and HBV DNA ≥2000 IU/mL (n = 87); AASLD, ALT >2-fold the updated ULN (0.5-fold ULN [corresponding to ≤19 U/L] for women and 0.75-fold the ULN [corresponding to ≤30 U/L] for men) and HBV DNA ≥20,000 IU/mL (n = 53); and USPA, ALT >updated ULN (>0.5-fold ULN for women and >0.75-fold ULN for men) and HBV DNA ≥2000 IU/mL (n = 173). RESULTS: Overall, 113 patients (30.9%) had ≥F2 fibrosis, which was more frequent among patients who fulfilled any guideline criteria (45.7% vs 17.9% for those who did not fulfill any criteria, P < .0001). In applying the EASL, AASLD, APASL, and USPA criteria, sensitivity and specificity values for detection of ≥F2 fibrosis were 45.6%, 58.5%, 56.3%, and 45.7% (P = .145) and 82.1%, 73.8%, 77.1%, and 82.4% (P = .366), respectively. The EASL criteria (area under the receiver operating characteristic [AUROC] curve, 0.66; 95% confidence interval [CI], 0.61-0.71) and USPA criteria (AUROC, 0.66; 95% CI, 0.58-0.73) performed better than APASL (AUROC, 0.64; 95% CI, 0.59-0.69; P = .421) and significantly better than the AASLD criteria (AUROC, 0.59; 95% CI, 0.54-0.64; P = .013). CONCLUSIONS: In hepatitis B e antigen-negative patients with chronic hepatitis, the EASL, AASLD, APASL, and USPA criteria identify patients with ≥F2 fibrosis with low levels of accuracy. However, the EASL and USPA criteria are the most accurate for identification of these patients.

Mucormycosis and Cryptococcosis with Gastrointestinal Involvement in a Patient with Poorly Managed Diabetes.

Mucormycosis and cryptococcosis are invasive fungal infections that mostly infect immunocompromised patients and are associated with high mortality rates. Here, we report a case of a 54-year-old male with poorly controlled diabetes mellitus who was initially admitted with a complaint of right frontal headache and vomiting for 5 days. The patient was found to have paranasal sinuses mucormycosis, and later developed gastrointestinal cryptococcosis. A multidisciplinary approach and early management are important to avoid any delay in managing these life-threatening infections. To the best of the authors' knowledge, this is the first case reporting concurrent invasive fungal infections in a patient.

Brunner's glands hamartoma with pylorus obstruction: a case report and review of literature.

Proliferative lesions of the Brunner's glands are uncommonly encountered lesions of the small intestine, originating from the deeply seated mucosal and submucosal Brunner's glands, mainly in the duodenum. The vast majorities of these lesions are benign and include Brunner's glands hyperplasia (adenomas/nodules) and hamartomas. The etiology and pathogenesis of these lesions are not fully understood, and the diagnosis can sometimes be challenging. We report a case of Brunner's gland hamartoma in a 57-year-old man who presented with chronic dyspepsia, hematemesis and weight loss. Endoscopic and radiological investigations show a submucosal polypoid lesion at the first part of the duodenum. Routine endoscopic biopsies demonstrated normal duodenal mucosa. The lesion considered endoscopically unresectable and was surgically resected. Frozen section examination and intraoperative consultation showed unremarkable duodenal mucosa and histologically bland Brunner's glands.

A cutaneous metastasis of unresectable rectal adenocarcinoma: A case report and literature review.

BACKGROUND: Colorectal cancer is ranked third among the most commonly diagnosed malignancies and fourth among the leading causes of cancer death in the world. However, only a few case reports are found in the literature regarding skin metastasis originating from rectal cancer, which usually shows widespread disease and poor prognosis. Approximately, 0.8% of the patients will have skin lesion as the first indication of a silent internal malignancy, which is rare. CASE REPORT: We report a complicated case of a 45-year-old male patient who referred to our highly specialized governmental hospital for diversion loop colostomy as well as biopsies of rectal and inguinal skin areas followed by palliative radiation therapy to the pelvis. Histopathological exam of rectal biopsies revealed moderately differentiated rectal adenocarcinoma, while the skin of the right inguinal area showed metastatic cutaneous rectal adenocarcinoma. Unfortunately, palliative radiation therapy was not started as the patient passed away secondary to respiratory failure which ended by cardiopulmonary arrest. CONCLUSION: A patient who is having new or evolving skin lesions with an oncology history should be well investigated as cutaneous metastasis is a strong possibility.

Vulvar apocrine adenocarcinoma: a case with nodal metastasis and intranodal mucinous differentiation.

Primary vulvar adenocarcinomas are rare tumors, and their histogenesis is not fully understood. They are classified into extramammary Paget's disease, sweat gland carcinomas, and "breast-like" adenocarcinomas of the vulva. The latter resemble adenocarcinomas arising in the breast morphologically and immunophenotypically. Rare cases of adenocarcinoma with apocrine features have been reported, and whether these neoplasms originate from the "native apocrine" sweat glands or from "anogenital mammary-like" glands are still debatable. The presence of normal mammary-like glands in the vicinity of the tumor, the transitional malignant morphological features from normal mammary-like glands and the tumor, the breast-like histological features of the tumor, and the expression of estrogen and progesterone receptors generally suggest an origin from anogenital mammary-like glands. Absence of these features points toward native apocrine sweat glands as the source of these neoplasms. In this report, we present a patient who was initially diagnosed with Paget's disease of the right vulva, which was treated by hemi-vulvectomy, and who later presented with primary vulvar apocrine adenocarcinoma with metastasis to the inguinal lymph nodes and intranodal mucinous/colloidal differentiation: a feature, to the best of our knowledge, not reported before. We also reviewed the histogenesis of the vulvar adenocarcinomas, with emphasis on the morphological features that separate the tumors arising from the anogenital mammary-like glands in the vulva from those arising from the native vulvar sweat glands.

Protocol Duodenal Graft Biopsies Aid Pancreas Graft Surveillance.

BACKGROUND: Histological evaluation of the pancreas graft is usually done on demand resulting in significant delays. This analysis reports on endoscopic protocol duodenal graft biopsies at regular intervals to determine feasibility, safety, and monitoring benefits. METHODS: Protocol duodenal graft biopsies in 27 consecutive pancreas transplants (10 simultaneous pancreas kidney [SPK], 17 pancreas after kidney [PAK]) with a follow-up of a minimum of 12 months were performed at days 14, 30, 90, 180, 360, 430. University of Pittsburgh Medical Center classification for intestinal rejection was used. C4d staining was performed when antibody-mediated rejection was suspected. RESULTS: Overall patient and pancreas graft survival was 100% and 93% at a mean follow-up of 2.8 years. One hundred sixty-seven endoscopic biopsy procedures were performed in 27 grafts without any complication. Biopsies revealed rejection in 3 (30%) SPK recipients and in 15 (82%) of PAK recipients as early as 14 days posttransplant. Two patients underwent PAK retransplantation diagnosed with acute rejection at day 180. All except 1 recipient being treated for rejection, showed histological improvement following antirejection treatment. Following transient treatment success, a total of 3 pancreas grafts were lost for immunological reason. One loss was immediate despite antirejection treatment, 1 secondary to nonresolving rejection at 7 months and the third due to recurrent rejection 15 months posttransplantation. Additionally, biopsies detected vascular (venous thrombosis) and overimmunosuppression (cytomegalovirus infection) complications. CONCLUSIONS: Protocol graft duodenal biopsies detect complications after whole-organ pancreas transplantation, are useful in guiding therapy, and carry potential for improving outcome.

Prevalence and 20-year epidemiological trends of glomerular diseases in the adult Saudi population: a multicenter study.

BACKGROUND: Recent international reports have shown significant changes in the incidence of different glomerular diseases. OBJECTIVE: Examine temporal and demographic trends of biopsy-diagnosed glomerular diseases in the adult population of Saudi Arabia over the last two decades. DESIGN: Medical record review. SETTINGS: Four tertiary medical centers in Saudi Arabia. PATIENTS AND METHODS: We identified all patients that underwent native kidney biopsy between 1998 and 2017. MAIN OUTCOME MEASURES: The frequency and the disease trends in four biopsy eras (1998-2002, 2003-2007, 2008-2011, and 2012-2017) for different glomerular diseases. SAMPLE SIZE AND CHARACTERISTICS: 1070 patients, 18-65 years of age; 54.1% female. RESULTS: Of 1760 patients who underwent native kidney biopsies, 1070 met inclusion criteria. Focal segmental glomerulosclerosis was the most common biopsy-diagnosed disease, with comparable frequencies over the four eras (23.6%, 19.8%, 24.1%, and 17.1, respectively [ P value for trend=.07]). The frequency of immunoglobulin A nephropathy increased progressively. The incidence of membranoproliferative glomerulonephritis declined significantly. Among the secondary types of glomerular diseases, systemic lupus erythematosus-associated lupus nephritis was the most common, followed by diabetic nephropathy. The prevalence of diabetic nephropathy increased from 1.4% in the first era to 10.2% in the last one. CONCLUSIONS: Trends in biopsy-diagnosed glomerular disease have changed. While focal segmental glomerulosclerosis remains the most common glomerular disease, there has been a significant rise in the prevalence of immunoglobulin A nephropathy and diabetic nephropathy. In contrast, membranoproliferative glomerulonephritis has declined. LIMITATIONS: Retrospective methodologies are vulnerable to lost data. CONFLICT OF INTEREST: None.

Alport's syndrome with focal segmental glomerulosclerosis lesion - Pattern to recognize.

The association between Alport's syndrome (AS) and focal segmental glomerulosclerosis (FSGS) in the same patient is complex and rarely reported. We report a case of a 42-year-old male presenting with proteinuria, microscopic hematuria, elevated serum creatinine and hypertension with unremarkable physical examination apart from obesity. The renal biopsy showed well-established FSGS pattern of injury with mild interstitial fibrosis and tubular atrophy, while the electron microscopic examination demonstrated glomerular basement membranes (GBM) changes compatible with AS. AS can be complicated by segmental glomerular scarring, which can mimic primary FSGS, while familial FSGS can result from mutations in collagen IV network of the GBM. This overlap can complicate histopathological interpretation of renal biopsy, which should be accompanied by mutational analysis for accurate diagnosis and proper therapeutic intervention.

Skin adnexal neoplasms--part 2: an approach to tumours of cutaneous sweat glands.

Tumours of cutaneous sweat glands are uncommon, with a wide histological spectrum, complex classification and many different terms often used to describe the same tumour. Furthermore, many eccrine/apocrine lesions coexist within hamartomas or within lesions with composite/mixed differentiation. In addition to the eccrine and apocrine glands, two other skin sweat glands have recently been described: the apoeccrine and the mammary-like glands of the anogenital area. In this review (the second of two articles on skin adnexal neoplasms), common as well as important benign and malignant lesions of cutaneous sweat glands are described, and a summary for differentiating primary adnexal neoplasms from metastatic carcinoma is outlined, striving to maintain a common and acceptable terminology in this complex subject. Composite/mixed adnexal tumours are also discussed briefly.

Cytokeratins 7 and 20 immunoexpression profile in goblet cell and classical carcinoids of appendix.

Goblet cell carcinoid (GCC) of the vermiform appendix is an uncommon neoplasm and its histogenesis is controversial. Whether GCC represents a morphological variant of classical appendiceal carcinoid or a mucin-producing adenocarcinoma is still conjectural. Little is known about the immunohistochemical expression of cytokeratins 7 (CK7) and 20 (CK20) in appendiceal neuroendocrine tumors. In this study, we compared the expression of CK7 and CK20 in 17 cases of appendiceal GCC and 25 cases of classical carcinoid. The tumors were also evaluated for Ki-67 proliferation index, mitotic activity, tumor necrosis, extracellular pools of mucin, obvious intestinal type adenocarcinomatous foci, angiolymphatic permeation, perineural/neural infiltration, and the depth of invasion of the appendix wall. Mesoappendiceal extension was present in 14 of 17 (82.3%) cases of GCC, whereas angiolymphatic and perineural/intraaneural involvement were found in 10 of 17 (58.8%) and 14 of 17 (82.3%) cases, respectively. The mitotic count ranged from 0 per 10 high power fields to 6 per 10 high power fields, with an average of 1.4 per 10 high power fields. Necrosis was not seen in any case and pools of extravasated mucin were present in 5 of 17 (29.4%) cases. Immunohistochemically, all 17 (100%) of GCC exhibited strong and diffuse immunopositivity for CK20, whereas expression of CK7 was present in 12 cases (70.5%), ranging from 5 to 50% of tumor cells being labeled. The Ki-67 labeling index ranged from 0 to 75% and showed no correlation to mitotic activity, angiolymphatic invasion or perineural/intraneural permeation. On the other hand, 25 cases of classical carcinoid tumors were consistently negative for CK7; however, 4 cases (16%) showed immunolabeling for CK20 in 25-50% of the tumor cells. The Ki-67 labeling index in classical carcinoids ranged from 0 to 5%. This study shows that in addition to the morphological differences, GCC (CK7/CK20-positive) and classical carcinoid (CK7/CK20-negative) differ in their expression of CK7 and CK20. In addition, GCC shows the same CK7/CK20 immunoexpression as colorectal adenocarcinoma. Goblet cell carcinoid should be regarded as a crypt cell or an amphicrine carcinoma rather than a variant of carcinoid tumor, a lesion that has benign connotations.

CK19 and CD99 immunoexpression profile in goblet cell (mucin-producing neuroendocrine tumors) and classical carcinoids of the vermiform appendix.

The immunoexpression of CK19 recently has been identified as a marker of poor prognosis in pancreatic endocrine tumors and hepatocellular carcinoma. Conversely, the loss of expression of CD99 has been suggested to play a role in the tumorigenesis and dedifferentiation and is associated with poor outcome in some malignancies. The purpose of this study was to explore CK19 and CD99 immunostaining in mucin-producing neuroendocrine (goblet cell) and classical carcinoids of the appendix. Eighteen goblet cell carcinoids (GCCs) and 20 classic carcinoids were stained with CK19, CD99, and Ki-67, and these results were correlated with known pathological features of aggression: extent of invasion, mitoses, necrosis, and histological pattern. All 18 GCCs were CK19 strongly positive, whereas 16/20 classic carcinoids were also CK19 positive. Fourteen of 18 GCCs and 14/20 classic carcinoids were CD99 positive. CK19/CD99 immunoexpression did not correlate with extent of tumor invasion and mesoappendiceal extension, mitotic activity, Ki-67 labeling index, presence of extracellular mucinous pools dissecting muscle, and angiolymphatic and perineural/neural invasion. There is no difference in the immunostaining for CK19 and CD99 between GCCs and classic carcinoids, and both types of neuroendocrine tumor show the same extent of expression of both markers.