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 RXR α 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 β ‐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.

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.

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.

We report a distinct, primary testicular tumor with peritubular myoid cell differentiation. A 25-year-old man developed a well-circumscribed testicular tumor composed of cytologically bland spindled cells, which were strongly and diffusely positive for desmin, smooth muscle actin, muscle-specific actin, and smooth muscle myosin. In addition, S-100 was diffusely positive, and cytokeratin (CK5/6 and AE1/3) was focally positive. Calretinin, inhibin, and CD34 were all negative. This pattern of immunoreactivity was very similar to the normal adjacent peritubular myoid cells. Follow-up after radical orchiectomy showed benign behavior. We found reports of 6 similar intratesticular tumors demonstrating peritubular myoid cell–like differentiation and having favorable outcome. We believe that the myoid gonadal stromal tumor is a rare, yet distinct, testicular tumor separate from leiomyoma and deserves recognition.

Glomerular diseases (GDs) associated with chronic lymphocytic leukemia (CLL) are unusual [1]. Th e many causes of renal failure in patients with CLL include immune-complex deposition, hyperkalemia, amyloid deposition, sepsis, hemoglobinuria in the setting of hemolysis, uric acid nephropathy caused by tumor lysis syndrome (TLS) and therapy related complications. Th e most common clinical manifestations of these nephropathies include proteinuria, hematuria, electrolyte abnormalities (hyperkalemia) and progressive renal failure [2,3]. Th e most frequent GD associated with CLL is membranoproliferative glomerulonephritis (MPGN) (45%), followed by membranous glomerulonephritis (MGN) (20%), with occasional reports of proliferative, minimal change disease, immunotactoid glomerulopathy (ITG), and amyloid or

Glomerular diseases (GDs) in chronic lymphocytic leukemia (CLL) are rare clinical complications. The relationship between CLL and GD is difficult to prove, but may be supported by close temporal relationship, immunoglobulin (Ig) monoclonal glomerular deposition, parallel improvement, resolution, and/or relapse of both conditions. The complete remission of nephropathies in CLL has been observed after therapy with alkylating agents, monoclonal antibodies and prednisone. We present here a case of a 55-year-old male with 5-year history of CLL who developed nephrotic syndrome associated with progressive CLL. His leukemia presentation included lymphocytosis, splenomegaly and bulky lymphadenopathy. He had no B symptoms, weight loss, fevers, diaphoresis or chills. His past medical history was relevant for hypertension, benign prostatic hyperplasia, bronchitis, and skin basal cell carcinoma. Renal core-needle biopsy showed focal areas of glomerulosclerosis with areas of diffuse hypercellularity forming a lobular glomerulonephritis pattern and prominent subendothelial hyaline deposits mimicking wire-loop lesions (a Membrane Proliferative Glomeruli-Nephritis pattern, type 1). Electron microscopy revealed abundant subendothelial electron-dense deposits organized diffusely into elongated, non-branching microfibrils /microtubules forming tightly packed parallel arrays. The patient received treatment with high-dose methylprednisolone in combination with rituximab (HDMP-R) on a monthly basis for four cycles. The patient's nephrotic syndrome resolved completely after HDMP-R with normalization of both creatinine and proteinuria. In addition, he achieved a partial response with residual disease in the bone marrow and persistent anemia (bone marrow biopsy showed 40% cellularity with 40% CLL involvement). Because of the presence of residual disease the patient received additional treatment with Alemtuzumab (Campath-H1) 30 mg IV for a total of 26 doses. With this treatment he achieved a complete response (CR) with negative minimal residual disease (MRDneg) by multiparameter flow cytometry analysis in the bone marrow. He remains in CR -MRDneg with no evidence of recurrence of his hematologic or glomerular diseases for 2 years. In conclusion, GD associated with CLL is an unusual condition characterized by glomerular deposits of Ig and complement. To our knowledge, the case presented here is the first one of CLL with associated GD that has been successfully treated with a non-chemotherapy regimen that includes HDMP-R and consolidation with alemtuzumab. In our patient, both the renal function and CLL-related findings have normalized and the patient has remained in complete remission a long period. HDMP-R followed by alemtuzumab is a regimen that offers the safety and efficacy required to manage challenging cases of CLL with associated GD like the one presented here.

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.

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.

Benign lymphoid hyperplasia (pseudolymphoma) has been reported in the skin, lungs, orbit, and gastrointestinal tract, but only rarely in soft tissues. These lesions mimic lymphoma both clinically and histologically. We describe a case of a pseudolymphoma of the deep soft tissues of the lower extremity. The lesion was composed of nonencapsulated lymphoid tissue with involvement of adjacent fat and connective tissues and multiple variably sized well-polarized germinal centers. Immunohistochemical staining, flow cytometry, chromogenic in situ hybridization for κ/λ light-chain restriction, and polymerase chain reaction for T- and B-cell gene rearrangements all revealed a polyclonal population of T and B cells, consistent with a benign reactive process. So far as we know, pseudolymphoma of the deep soft tissues has been described only once previously in the medical literature.

BACKGROUND: Patients with hamartomatous polyposis syndromes have increased risk for colorectal cancer (CRC). Although progression of polyps to carcinoma is observed, pathogenic mechanisms remain unknown. The authors examined whether familial hamartomatous polyps harbor defects in DNA mismatch repair (MMR), and assayed for somatic mutation of PTEN, a gene inactivated in the germline of some hamartomatous polyposis syndrome patients. METHODS: Ten hamartomatous polyposis syndrome patients were genotyped for germline mutations. Epithelial and nonepithelial polyp DNA were assayed for microsatellite instability (MSI) and PTEN frameshift mutation. DNA MMR and PTEN protein expression were assessed in all polyps by immunohistochemistry. In addition, 99 MSI-high sporadic CRCs and 50 each of hMLH1(-/-) and hMSH3(-/-) cell clones were examined for PTEN frameshifts. RESULTS: Twenty-five (58%) of 43 hamartomatous polyposis syndrome polyps demonstrated dinucleotide or greater MSI in polyp epithelium, consistent with hMSH3 deficiency. MSI domains lost hMSH3 expression, and PTEN expression was lost in polyps from germline PTEN patients; sporadic hamartomatous polyps did not show any of these findings. PTEN analysis revealed wild type exon 7 and 8 sequences suggestive of nonexistent or rare events for PTEN frameshifts; however, MSI-high sporadic CRC showed 11 (11%) of 99 frameshifts within PTEN, with 4 tumors having complete loss of PTEN expression. Subcloning hMLH1(-/-) and hMSH3(-/-) cells revealed somatic PTEN frameshifts in 4% and 12% of clones, respectively. CONCLUSIONS: Nondysplastic epithelium from hamartomatous polyposis syndrome polyps harbors hMSH3 defects, which may prime neoplastic transformation. Polyps from PTEN+/- patients lose PTEN expression, but loss is not a universal early feature of all hamartomatous polyposis syndrome. However, PTEN frameshifts can occur in hMSH3-deficient cells, suggesting that hMSH3 deficiency could drive hamartomatous polyposis syndrome tumorigenesis. Cancer 2011;117:492-500. (C) 2010 American Cancer Society.

The risk for developing celiac disease is associated with the major histocompatibility complex class II human leukocyte antigen DQ2 and DQ8. We retrospectively reviewed the medical records of 127 consecutive cases of adult-onset celiac disease evaluated at a single United States center to determine the distribution of the associated human leukocyte antigen DQA1 and DQB1 alleles. The median patient age of diagnosis was 41 (range, 16-81) years. Ninety-five adults underwent human leukocyte antigen DQ typing. Eighty patients were DQ2 positive, 24 were DQ8 positive, and 11 were DQ2 and DQ8 positive. Four patients carried the uncommon, low-risk haplotype DQ2.2 (DQA1⁎02 and DQB1⁎02) without DQA1⁎05. Two patients did not carry human leukocyte antigen DQ2 or DQ8. All of the patients with atypical human leukocyte antigen DQ responded to a gluten-free diet. Although the majority of patients carry the human leukocyte antigen DQ2 or DQ8, gluten-dependent enteropathy periodically presents in adults with low-risk alleles.

The prognostic and predictive value of Her2/neu and the hormone receptors in patient with primary or metastatic breast cancer is essential for a favorable outcome of treatment. We have been experiencing increasing requests to test cytologic specimens for these markers in patients with metastatic breast carcinoma. A recent study threw some doubts on the validity of such testing using cell blocks. In this study we compared our immunohistochemical Her2/neu, ER and PR testing performed on 42 formalin‐fixed, paraffin‐embedded cell blocks from 27 fine needle aspirations (FNA) and 15 serous effusions of 42 patients with metastatic (n = 38) and primary (n = 4) breast carcinoma to the test results obtained on tissue sections. In seven cases the Her2/neu immunohistochemistry (IHC) results on cell blocks were also compared with Her2/neu fluorescence in situ hybridization (FISH) on tissue or cell block. The study revealed 100% correlation for positive and negative Her2/neu results. For ER testing the results showed 85.7% sensitivity, 100% specificity, 100% positive predictive value (PPV), and 85.7% negative predictive value (NPV). For PR testing the results showed 80% sensitivity, 100% specificity, 100% PPV, and 88.8% NPV respectively. In conclusion, IHC for Her2/neu, ER and PR performed on formalin‐fixed, paraffin‐embedded cell blocks prepared from fresh FNA and serous fluid is reliable in predicting the expression of these markers when correlated with IHC and FISH performed on the corresponding tumor tissue. Diagn. Cytopathol. 2011;39:328–332. © 2010 Wiley‐Liss, Inc.

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. Diagn. Cytopathol. 2012. © 2011 Wiley Periodicals, Inc.

Several parasitic species are well known to have carcinogenic properties, namely; Schistosoma hematobium (squamous cell carcinoma of the bladder) and the liver flukes Opisthorchis and Chlonorchis (cholangiocarcinoma). A large number of parasites are known to colonize the gastrointestinal tract. We sought to review the evidence that implicates these parasites in gastrointestinal neoplasia. Schistosoma japonicum, which is endemic primarily in east Asia, has been shown in multiple studies to convey a mildly increased risk of colorectal adenocarcinoma. The data supporting a causative role for Schistosoma mansoni in colorectal or other neoplastic processes are less convincing, limited primarily to small case-control studies and case series. Reports of possible associations between other gastrointestinal parasites (e.g., E. histolytica and A. lumbricoides) and neoplasia may be found in the literature but are limited to individual cases. We conclude that, other than S. japonicum and to a lesser extent S. mansoni, there is little evidence of an association between gastrointestinal parasites and neoplasia.

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.

Endometriosis is well known for creating diagnostic pitfalls for pathologists. It may produce masses mimicking neoplasms or cause diagnostic quandaries, particularly when the patient age, location, and/or epithelial appearance are atypical. This study reports a patient with endometriosis causing rectal bleeding and involving the cecum. It produced a mass clinically considered appendiceal. The endometriosis was focally lined by intestinal epithelium including Paneth cells. In the deep endometriotic glands embedded within intestinal wall, direct fusion of the intestinal and the endometrial epithelium-the benign intestinal epithelium apparently colonizing the endometriotic foci-was found. The mass effect, plus deep-seated intestinal epithelium, closely mimicked invasive well-differentiated mucinous carcinoma. This is yet another peculiar presentation of endometriosis with potential for misinterpretation as a more serious condition, specifically well-differentiated mucinous carcinoma of the cecum or appendix.

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 β1 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.