Schistosomiasis and signet ring cell carcinoma of the rectum.

A definitive link between Schistosoma hematobium infection and squamous cell carcinoma of the bladder has been identified. A weaker association between S japonicum infection and colorectal neoplasia has been proposed, although reports are limited to case reports, a case series, and epidemiologic studies. Virtually all cases presented in the literature describe intestinal-type adenocarcinoma occurring in association with S japonicum. We here describe a 40-year-old male Filipino patient with signet ring cell carcinoma of the rectum and evidence of infection by S japonicum.

Expression of Siglec-11 by human and chimpanzee ovarian stromal cells, with uniquely human ligands: implications for human ovarian physiology and pathology.

Siglecs (Sialic acid-binding Immunoglobulin Superfamily Lectins) are cell surface signaling receptors of the I-type lectin group that recognize sialic acid-bearing glycans. CD33-related-Siglecs are a subset with expression primarily in cells of hematopoietic origin and functional relevance to immune reactions. Earlier we reported a human-specific gene conversion event that markedly changed the coding region for the extracellular domain of Siglec-11, associated with human-specific expression in microglia (Hayakawa T, Angata T, Lewis AL, Mikkelsen TS, Varki NM, Varki A. 2005. A human-specific gene in microglia. Science. 309:1693). Analyzing human gene microarrays to define new patterns of expression, we observed high levels of SIGLEC11 transcript in the ovary and adrenal cortex. Thus, we examined human and chimpanzee tissues using a well-characterized anti-Siglec-11 mouse monoclonal antibody. Although adrenal expression was variable and confined to infiltrating macrophages in capillaries, ovarian expression of Siglec-11 in both humans and chimpanzees was on fibroblasts, the first example of Siglec expression on mesenchyme-derived stromal cells. Cytokines from such ovarian stromal fibroblasts play important roles in follicle development and ovulation. Stable transfection of SIGLEC11 into a primary human ovarian stromal fibroblast cell line altered the secretion of growth-regulated oncogene α, interleukin (IL)-10, IL-7, transforming growth factor ß1 and tumor necrosis factor-α, cytokines involved in ovarian physiology. Probing for Siglec-11 ligands revealed distinct and strong mast cell expression in human ovaries, contrasting to diffuse stromal ligands in chimpanzee ovaries. Interestingly, there was a trend of increased Siglec-11 expression in post-menopausal ovaries compared with pre-menopausal ones. Siglec-11 expression was also found on human ovarian stromal tumors and in polycystic ovarian syndrome, a human-specific disease. These results indicate potential roles for Siglec-11 in ovarian physiology and human evolution.

Primary squamous carcinoma of the ovary likely arising from a monodermal cystic mucinous teratoma.

We present a 58-year-old woman with primary squamous carcinoma of the ovary likely arising from a monodermal cystic mucinous teratoma. Noninvolved ovary showed no Brenner tumor, endometriosis, transitional carcinoma, endometrioid adenocarcinoma, or typical multigerm layer classic mature teratoma. Moreover, no other primary site was possible because there were no prior or concomitant squamous carcinomas, or history of cervical intraepithelial neoplasia. The tumor showed strong positivity for p63 and CK5/6, reactivity that also extended from the squamous carcinoma into the basal-cell lining of the mucinous cyst of a likely monodermal teratoma. This basal-cell pattern was absent in a series of conventional benign and borderline cystic mucinous cystadenomas of the ovary, but clearly present in the mucinous cysts part of mature teratomas. We present this as a unique case of squamous carcinoma likely arising from a monodermal cystic mucinous teratoma. Moreover, we submit that the p63 and CK5/6 staining pattern may help to differentiate monodermal cystic mucinous teratoma from conventional cystic mucinous tumors.

Endometrioid carcinoma with a low-grade spindle cell component: a tumor resembling an adnexal tumor of probable Wolffian origin.

Endometrioid carcinoma is known to have many histopathologic variants, which may cause diagnostic difficulty. One rare variant resembles Wolffian adnexal tumor (female adnexal tumor of probable Wolffian origin). This pattern can produce a significant solid component within the tumor. Once the true endometrioid nature of the tumor is recognized, the tumor can appear deceptively high grade by International Federation of Gynecology and Obstetrics grading criteria, which take into account the percentage of the tumor showing solid growth. The English-language literature on this variant is scant, and its behavior is not well documented. We present a case of ovarian endometrioid carcinoma with a Wolffian adnexal tumor pattern that recurred 19 years after the original surgery; and the patient continues to remain well without evidence of disease 1 year following her second surgery, that is, 20 years of indolent behavior. This long clinical course shows evidence for low-grade behavior for this tumor.

A unique case of an indolent CD56-positive T-cell lymphoproliferative disorder of the gastrointestinal tract: a lesion potentially misdiagnosed as natural killer/T-cell lymphoma.

Primary intestinal natural killer (NK)/T-cell lymphoma (nasal-type) and enteropathy-associated T-cell lymphoma, type II, are CD56-positive lymphoproliferative disorders with very poor survival rates. We report a long-surviving patient with a CD56-positive T-cell lymphoproliferative disorder of the gastrointestinal tract that presented as vomiting, diarrhea, weight loss, and pain. This patient was referred to the university hospital as a case of peripheral T-cell lymphoma due to this CD56-positive lymphocyte population. There was no evidence of enteropathy; and the infiltrates were negative for CD8, Epstein-Barr virus, and T-cell receptor gene rearrangement. Despite its persistence for 8 years, the clinical course has remained indolent. This report confirms that patients may rarely present with a CD56-positive NK/T-cell-like proliferation of the gastrointestinal tract, yet follow an indolent clinical course. Thus, all pathologic features of enteropathy-associated T-cell lymphoma or NK/T-cell lymphoma should be present before making this diagnosis and exposing the patient to toxic chemotherapy.

Amphicrine carcinoma of the liver.

Amphicrine tumors are defined by evidence of both glandular and neuroendocrine differentiation in the same cell. These are extremely rare tumors, with only scattered case reports in the pancreas and stomach. We here report a case of amphicrine carcinoma occurring in apparent isolation in the liver. The tumor was characterized by signet ring cell morphology, mucicarmine, and periodic acid Schiff with diastase (PASD) positivity, and expression of chromogranin, synaptophysin, villin, and CDX2. No other tumor was identified by radiological or endoscopic examination of the gastrointestinal tract. The patient is disease-free 22 months after the resection. We speculate that this represents the first reported occurrence of primary amphicrine carcinoma of the liver.

Pulmonary langerhans cell histiocytosis diagnosed in a cervical lymph node: a case report.

BACKGROUND: Pulmonary Langerhans cell histiocytosis (PLCH) is usually confined to the lungs and is therefore an unexpected finding in a cervical lymph node. CASE: A 52-year-old male with a 40-pack-year smoking history presented to our clinic with cough, fever and cervical lymphadenopathy. Chest computed tomography (CT) showed bilateral pulmonary nodules and enlarged mediastinal lymph nodes, worrisome for an infectious or malignant process. Bronchioloalveolar lavage was nondiagnostic. Fine needle aspiration cytology of the enlarged cervical lymph node revealed atypical histiocytoid cells, suspicious for malignancy. Immunohistochemistry revealed CD1a- and S-100-positive Langerhans cells. These findings, along with the patient's extensive smoking history and characteristic radiographic nodules, favored a diagnosis of PLCH with cervical lymph node involvement. The patient was advised to cease smoking, and no therapy was administered. Months later, follow-up chest CT showed spontaneous resolution of the lung nodules. CONCLUSION: The demonstration of Langerhans cells by immunohistochemical staining of CD1a and S-100 on a fine needle aspiration cell block is a useful diagnostic adjunct. In this case, definitive cytology for Langerhans cells in the appropriate clinical and radiologic setting allowed us to arrive at the correct diagnosis of PLCH in a minimally invasive manner.

Terminal respiratory unit type lung adenocarcinoma is associated with distinctive EGFR immunoreactivity and EGFR mutations.

Approximately 10% to 20% of nonsmall cell lung cancer patients respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib. Responders are mostly nonsmokers and women with tumors displaying bronchioloalveolar features. Mutations of the tyrosine kinase domain of the EGFR gene have been associated with a clinical response to gefitinib. A recent study reported that the terminal respiratory unit (TRU)-type adenocarcinoma shares the clinical profile and EGFR mutations of gefitinib responders. EGFR immunoreactivity in this context has not been reported in the literature. We performed a detailed immunohistochemical analysis of EGFR expression on 124 consecutive lung resection specimens for malignancy, to survey the EGFR immunoreactivity in lung cancers in general and to correlate EGFR immunoreactivity with EGFR mutations and TRU-type histology. EGFR positivity was seen most frequently in squamous cell carcinomas (77%), followed by TRU-type adenocarcinomas (63%), large cell carcinomas (23%), and non-TRU-type adenocarcinomas (12%). A distinctive basally oriented cytoplasmic positivity was observed exclusively in TRU-type adenocarcinomas. EGFR mutation was identified in 6 of 54 cases studied and all 6 cases were TRU-type adenocarcinomas. Five of six cases with EGFR mutation were positive for EGFR immunostain with the basal cytoplasmic localization. In conclusion, EGFR immunoreactivity with basal cytoplasmic pattern was exclusively seen in TRU-type adenocarcinoma and a subset of these cases was seen with EGFR mutations in the responders to EGFR inhibitor therapy.

Strong PDGFRA positivity is seen in GISTs but not in other intra-abdominal mesenchymal tumors: Immunohistochemical and mutational analyses.

Mutation of the platelet-derived growth factor receptor-alpha (PDGFRA) gene has been well documented as an alternative oncogenic mechanism in a subset of gastrointestinal stromal tumors (GISTs) lacking c-kit mutations. However, the role of PDGFRA immunohistochemistry in the diagnosis of GISTs has not been well studied. We investigated PDGFRA immunoreactivity in GISTs and in other intra-abdominal mesenchymal tumors, and correlated PDGFRA expression with CD117 positivity and with the mutational status of PDGFRA and c-kit genes. In addition, expression of phosphorylated AKT, an activated downstream molecule in the PDGFRA and c-kit signaling pathways, was correlated with PDGFRA and CD117 status. A total of 39 GISTs and 20 other mesenchymal tumors in the abdomen were included in this study. Thirty-five of 39 GIST cases (89.7%) were positive for PDGFRA and 19 of these 35 positive cases were strongly positive. Five of 20 non-GIST lesions (25%) were positive for PDGFRA, but none of these cases were strongly positive. With one exception, PDGFRA-positive cases were also positive for CD117. Phosphorylated AKT positivity was not associated with the immunoreactivity or mutation of PDGFRA and c-kit, suggesting that the activation of AKT is probably independent of the activation of PDGFRA and c-kit in GISTs. Of 14 GISTs assayed, 4 had mutations in c-kit at exons 11 or 17, and 4 had mutations in PDGFRA at exons 12 or 18. Three of 4 GIST cases with PDGFRA mutations show epithelioid morphology and strong PDGFRA immunoreactivity with prominent perinuclear dotlike accentuation (so-called Golgi pattern). In conclusion, strong PDGFRA positivity with Golgi pattern is a useful adjunct in the diagnosis of GISTs with PDGFRA mutation.

Evaluation of tumor angiogenesis measured with microvessel density (MVD) as a prognostic indicator in nasopharyngeal carcinoma: results of RTOG 9505.

PURPOSE: The objective of this study was to evaluate tumor angiogenesis as measured by microvessel density (MVD) as an independent prognostic factor in patients with nasopharyngeal carcinoma (NPC) treated with radiotherapy alone. METHODS AND MATERIALS: Eligible patients included those with NPC treated with radiotherapy. Paraffin blocks of the primary tumor had a hematoxylin and eosin-stained section prepared at the block face. One representative section for tumor was stained for factor VIII-related antigen using a standard immunoperoxidase staining technique. MVD was determined by light microscopy in areas of invasive tumor containing the highest numbers of capillaries and microvessels per area. Individual microvessel counts were made on a 200x field within the area of most intense tumor neovascularization. Results were expressed as the highest number of microvessels identified within any single 200x field. Using a breakpoint of MVD <60 vs. > or =60, the distributions between the two MVD groups were compared by the method of Gray. Overall survival rates were estimated by the Kaplan-Meier method and compared by the log-rank test. A multivariate Cox proportional hazard model was employed to examine the relationship between MVD and disease outcomes while adjusting for other concomitant variables. RESULTS: One hundred sixty-six were eligible, of whom 123 had values determined for MVD. The MVD values ranged from 9 to 243 with a median of 70. In the multivariate analysis of overall survival, distant metastases, and local-regional failure, MVD did not significantly improve the model containing T stage, N stage, age, radiation dose, and World Health Organization class. CONCLUSIONS: We found no significant differences in overall survival, time to distant metastasis, or time to local-regional failure using a breakpoint of MVD <60 vs. MVD > or =60. The study was perhaps limited by the small size of the NPC samples.

Epithelioid gastrointestinal stromal tumor with PDGFRA activating mutation and immunoreactivity.

The authors report a unique case of an intra-abdominal, epithelioid mesenchymal tumor that had an activating mutation of PDGFRA and a strong PDGFRA immunoreactivity but lacked both c-kit mutation and c-kit protein (CD117) expression. IHC study showed that the tumor cells were diffusely and strongly positive for PDGFRA, vimentin, CD34, and Bcl-2 but completely negative for CD117 as well as for muscle, epithelial, endothelial, endocrine, mesothelial, neural, and melanocytic cell markers. Molecular study revealed a mutation at the juxtamembrane domain of exon 12 in PDGFRA gene with GTC to GAC transition at codon 561 (V561D), as shown in the previous mutational studies on gastrointestinal stromal tumor (GIST). This case likely represents an example of GIST with PDGFRA activating mutation and PDGFRA immunoreactivity without CD117 positivity, which has not been documented in the literature. STI 571 (imatinib mesylate [Gleevec]) might be an effective therapy in this case, since Gleevec targets both PDGFRA and c-kit oncoproteins.

A window-of-opportunity biomarker study of etodolac in resectable breast cancer.

Observational data show that nonsteroidal anti-inflammatory drug (NSAID) use is associated with a lower rate of breast cancer. We evaluated the effect of etodolac, an FDA-approved NSAID reported to inhibit cyclooxygenase (COX) enzymes and the retinoid X receptor alpha (RXR), on rationally identified potential biomarkers in breast cancer. Patients with resectable breast cancer planned for initial management with surgical resection were enrolled and took 400 mg of etodolac twice daily prior to surgery. Protein and gene expression levels for genes related to COX-2 and RXRα were evaluated in tumor samples from before and after etodolac exposure. Thirty subjects received etodolac and 17 subjects were assayed as contemporaneous or opportunistic controls. After etodolac exposure mean cyclin D1 protein levels, assayed by immunohistochemistry, decreased (P = 0.03). Notably, pre- versus post cyclin D1 gene expression change went from positive to negative with greater duration of etodolac exposure (r = -0.64, P = 0.01). Additionally, etodolac exposure was associated with a significant increase in COX-2 gene expression levels (fold change: 3.25 [95% CI: 1.9, 5.55]) and a trend toward increased ß-catenin expression (fold change: 2.03 [95% CI: 0.93, 4.47]). In resectable breast cancer relatively brief exposure to the NSAID etodolac was associated with reduced cyclin D1 protein levels. Effect was also observed on cyclin D1 gene expression with decreasing levels with longer durations of drug exposure. Increased COX-2 gene expression was seen, possibly due to compensatory feedback. These data highlight the utility of even small clinical trials with access to biospecimens for pharmacodynamic studies.

TTF-1 expression is specific for lung primary in typical and atypical carcinoids: TTF-1-positive carcinoids are predominantly in peripheral location.

Thyroid transcription factor (TTF)-1 expression in neuroendocrine tumors (NETs) has not been studied as widely as that in non-NETs, with the exception of small cell carcinomas, in which TTF-1 is highly sensitive but not specific for a primary lung tumor. The reported incidence of TTF-1 expression in pulmonary carcinoids has also been highly variable in the literature. To evaluate the expression of TTF-1 in NETs and potential value of TTF-1 in distinguishing pulmonary NETs from those of extrapulmonary origin, we performed an immunohistochemical study by using semiquantitative analysis on formalin-fixed, paraffin-embedded sections from 111 NETs, including 80 pulmonary (11 carcinoid tumorlets [TLs] or foci of neuroendocrine cell hyperplasia [NEH], 36 typical carcinoids [TCs], 17 atypical carcinoids [ACs], 16 large cell neuroendocrine carcinomas [LCNECs]), 13 thymic (3 TCs, 8 ACs, 2 LCNECs), 17 gastrointestinal or pancreatic (13 TCs, 4 ACs), and 1 ovarian (LCNEC). Pulmonary carcinoids were subdivided into those with central and those with peripheral location. TTF-1 positivity was seen exclusively in pulmonary NETs and was significantly higher in NEH or TLs (72.7%) than in TCs (27.8%), ACs (29.4%), and LCNECs (37.5%; P = 0.03). All extrapulmonary NETs were uniformly negative for TTF-1 staining. Interestingly, 12 of 14 TTF-1-positive pulmonary TCs and ACs had a peripheral location with spindle cell morphology, as did all cases of TL, a purported precursor of peripheral carcinoids. In conclusion, TTF-1 expression was 100% specific, though not so sensitive, for the lung primary in TCs and ACs and possibly also in LCNECs. Prevalent TTF-1 positivity in TLs and peripheral carcinoids suggest that they may be histogenetically distinct from the central carcinoids, which are typically composed of TTF-1-negative, more rounded cells.

Her2 amplification: correlation of chromogenic in situ hybridization with immunohistochemistry and fluorescence in situ hybridization.

Detecting Her2 gene amplification has become routine in predicting therapeutic responsiveness in patients with breast carcinoma. Fluorescence in situ hybridization (FISH) is a common technique for detecting Her2 amplification, yet dark field fluorescence microscopy remains problematic for many pathologists. Thus, a technique such as chromogenic in situ hybridization (CISH), in which the more familiar light microscopy can be used, is appealing. Paraffin-embedded sections from 61 breast carcinomas were tested for Her2 amplification by immunohistochemistry (IHC) and CISH. FISH was used to confirm CISH results. Excellent correlation was found between IHC and CISH except in cases considered negative (1+ on the DAKO scale) by IHC. CISH detected low-level Her2 amplification in 4 of 9 of these cases. Amplification was subsequently confirmed by FISH in all but 1 case. When compared with FISH, CISH was more sensitive than IHC for detecting low levels of Her2 gene amplification. Moreover, excellent concordance was found between FISH and CISH, supporting the conclusion that the CISH assay for Her2 gene amplification provides an accurate, effective, and practical alternative to FISH.

Simultaneous serous cystadenoma of the pancreas and mucinous cystadenoma of the appendix.

CONTEXT: Serous cystadenoma of the pancreas and mucinous tumors of the vermiform appendix are rare. To our knowledge, the simultaneous occurrence of these two tumors has not been reported. CASE REPORT: Here, we report an adult female who presented with signs and symptoms of appendicitis. A preoperative CT scan confirmed the findings of appendicitis and also showed an incidental large mass in the head of the pancreas. The patient underwent uneventful appendectomy. Her pathology revealed an acutely inflamed appendix with a benign mucinous cystadenoma at the tip. Several months after her recovery, a Whipple procedure was performed. Pathologic examination showed a 5x5 cm serous cystadenoma of the head of the pancreas without evidence of malignancy. Two years later, the patient is alive and well without evidence of tumor recurrence. CONCLUSIONS: Cystadenomas of the pancreas and appendix are unusual and their simultaneous occurrence is a rare event.

Contrast-Enhanced Magnetic Resonance Imaging to Assess Tumor Histopathology and Angiogenesis in Breast Carcinoma.

Contrast-enhanced magnetic resonance imaging (cMRI) is a potentially powerful new tool in the early diagnosis and staging of patients with breast carcinoma. Rapid contrast enhancement is suggestive of carcinoma and likely related to high tumor vascularity. We have developed a new cMRI technique that combines anatomic and kinetic information to help characterize breast carcinomas. Signal enhancement ratio (SER) patterns (which quantitate the kinetics of contrast enhancement using a three time point high-resolution method) were correlated in tumors from 32 patients with histopathology and tumor angiogenesis as measured by intratumoral microvessel density (iMVD). Early signal enhancement with rapid washout of intravenous contrast (i.e., corresponding to high SER values) correlated with high tumor vascularity. We found that TARGET MRI with SER analysis has potential as a tool for characterizing breast carcinoma in vivo. It enables anatomic visualization of tumor and appears to add biologic information as well, such as level of tumor angiogenesis.

Epithelioid hemangioendothelioma of the lung diagnosed by transesophageal endoscopic ultrasound-guided fine needle aspiration: a case report.

BACKGROUND: Epithelioid hemangioendothelioma is a rare vascular tumor of the lung and is also known as intravascular sclerosing bronchoalveolar tumor. Although it has relatively low malignant potential, extensive pulmonary involvement and systemic metastasis have been described. The cytologic features of these tumors are not very well defined, with only few case reports describing the cytologic findings of epithelioid hemangioendothelioma of the lung on fine needle aspiration. CASE: Endoscopic ultrasound-guided fine needle aspiration of a hilar mass was performed on a 25-year-old female. The cytology showed loosely cohesive sheets and clusters of epithelioid cells. The cellular features included large, irregular nuclei with nucleoli and a moderate amount of vacuolated cytoplasm. Rare cells had a suggestion of cytoplasmic lumen formation. Histologic examination of tissue fragments on the cell block revealed a tumor composed of rounded to spindled epithelioid cells in a background of light blue stroma. The endothelial differentiation was evidenced by cytoplasmic vacuoles and lumens, some of which contained erythrocytes. The endothelial nature of these cells was confirmed by positive staining with factor VIII and CD34. CONCLUSION: The cytomorphologic features of epithelioid hemangioendothelioma described in the literature and observed in our case are distinctive and can help with the interpretation of cytologic smears and prevent misdiagnosis.

Examination of sources of diagnostic error leading to cervical cone biopsies with no evidence of dysplasia.

At our institution, 17% of cervical conization specimens are reported as negative for dysplasia or malignancy. To identify sources of error, we reviewed 53 negative conization specimens and their prior and follow-up cytology, biopsy, and endocervical curettage specimens. Examination of deeper-level sections and p16 immunostaining were performed on all conization specimens and selected biopsy specimens. Dysplasia was detected in 26% (14/53) of conization specimens. Twenty-eight percent (15/53) of cones were truly negative, and the presurgical material had been overcalled as high-grade squamous intraepithelial lesions (HSIL). Forty-five percent (24/53) of cones were truly negative and HSIL was confirmed in the presurgical material. Of these, 11% (6/53) showed subsequent evidence of residual dysplasia and 26% (14/53) were negative on further follow-up. Deeper-level sections, p16 immunostains, and consensus review may help identify squamous dysplasia in conization specimens and may prevent the overdiagnosis of HSIL on cervical biopsies.

Papillary renal carcinoma arising in an ectopic native kidney and status after renal transplant: a report of a unique case and review of the literature.

Renal ectopia is an uncommon developmental defect of upper urinary tract. Except for hydronephrosis and urinary calculus formation, it is believed that ectopic kidneys are not more susceptible to diseases compared to the normally positioned kidneys. Primary renal carcinoma in ectopic kidneys is rarely observed. Our literature review identified eight cases in nontransplanted patients; seven were clear-cell carcinoma and one was papillary renal carcinoma. On the other hand, native kidneys of renal transplant patients are fifteen times more likely to develop renal carcinoma than those of nontransplanted patients. Renal malignancy has never been reported in native ectopic kidneys of transplant recipients. We report the first case of a papillary renal carcinoma in a native ectopic kidney of a 30 year-old female, six-year status after renal transplantation.

Fine-needle aspiration of ganglioneuroma, maturing type (a.k.a., "borderline ganglioneuroblastoma") in the mediastinum of a young man: Case report and discussion of classification.

We report a very unusual case of a posterior mediastinal tumor in a young man, which we diagnosed by fine-needle aspiration cytology as most consistent with ganglioneuroma, maturing subtype. The cytopathologic features were interpreted using the classification of neuroblastic tumors as defined by the International Neuroblastoma Pathology Committee. Neuroblastic tumors are peculiar tumors that have capacity for maturation, and hence they present as a spectrum of tumors, ranging from the undifferentiated neuroblastoma, to ganglioneuroblastoma, to the mature version ganglioneuroma. The practicing surgical pathologist or cytopathologist who does not regularly encounter pediatric specimens may experience difficulty interpreting a specimen from one of these tumors. The following case report discusses application of these criteria to cytopathologic diagnosis of these tumors.