Papillary squamous cell carcinoma of the cervix: Two cases and a review of the literature.

OBJECTIVE: Papillary squamous cell carcinoma of the cervix (PSCC) is a rare and distinct form of cervical carcinoma. Detecting stromal invasion on biopsy is difficult due to the papillary growth of the tumor. Here we present two cases that highlight the diagnostic and clinical challenges of PSCC. CASE 1: A 50-year-old woman found to have carcinoma on a routine pap-smear. The patient was diagnosed with PSCC on colposcopic biopsy and underwent a radical hysterectomy, bilateral salpingo-oophorectomy and pelvic lymph node dissection. Her final pathology demonstrated PSCC with no evidence of stromal invasion. At her 3-month follow up visit, she was noted to have a tumor recurrence at the vaginal cuff, again with no stromal invasion. She is currently undergoing definitive radiation therapy with sensitizing cisplatin. CASE 2: An 82-year-old woman presented with post-menopausal bleeding and was found to have an exophytic mass. Biopsies were taken and showed PSCC with no stromal invasion identified. She underwent a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy. Final pathology indicated no invasion. She is currently being followed for persistent vaginal dysplasia. CONCLUSION: PSCC is a rare tumor that has previously been described as less aggressive than classical squamous cell carcinoma. These two cases demonstrate the complex behavior of the disease. Case 1 highlights that PSCC may recur even when stromal invasion cannot be confirmed pathologically.

Novel epigenetic changes in CDKN2A are associated with progression of cervical intraepithelial neoplasia.

OBJECTIVE: To conduct a comprehensive mapping of the genomic DNA methylation in CDKN2A, which codes for the p16(INK4A) and p14(ARF) proteins, and 14 of the most promising DNA methylation marker candidates previously reported to be associated with progression of low-grade cervical intraepithelial neoplasia (CIN1) to cervical cancer. METHODS: We analyzed DNA methylation in 68 HIV-seropositive and negative women with incident CIN1, CIN2, CIN3 and invasive cervical cancer, assaying 120 CpG dinucleotide sites spanning APC, CDH1, CDH13, CDKN2A, CDKN2B, DAPK1, FHIT, GSTP1, HIC1, MGMT, MLH1, RARB, RASSF1, TERT and TIMP3 using the Illumina Infinium array. Validation was performed using high resolution mapping of the target genes with HELP-tagging for 286 CpGs, followed by fine mapping of candidate genes with targeted bisulfite sequencing. We assessed for statistical differences in DNA methylation levels for each CpG loci assayed using univariate and multivariate methods correcting for multiple comparisons. RESULTS: In our discovery sample set, we identified dose dependent differences in DNA methylation with grade of disease in CDKN2A, APC, MGMT, MLH1 and HIC1, whereas single CpG locus differences between CIN2/3 and cancer groups were seen for CDH13, DAPK1 and TERT. Only those CpGs in the gene body of CDKN2A showed a monotonic increase in methylation between persistent CIN1, CIN2, CIN3 and cancers. CONCLUSION: Our data suggests a novel link between early cervical disease progression and DNA methylation in a region downstream of the CDKN2A transcription start site that may lead to increased p16(INK4A)/p14(ARF) expression prior to development of malignant disease.

Gastro-intestinal stromal tumor (GIST) complicating a colonic interposition: a novel case report.

BACKGROUND: Gastrointestinal stromal tumor (GIST) is a rare tumor comprising 0.1-0.3% of all gastrointestinal (GI) malignancies. Stomach followed by small intestine is the most common sites of involvement, implicated in 95% of the cases. We present a case of GIST complicating a colonic interposition. To the best of the author's knowledge, this is the first reported case of GIST complicating a colonic interposition. CASE PRESENTATION: A 47 year old African American male presented to the emergency department with intermittent, severe chest pain. Past medical history was significant for alkali (NaOH) ingestion during 1980 for which esophageal resection and a colonic pull-through was performed. A CXR revealed a widened mediastinum and CT scan chest revealed showed a large (11.4 × 8.3 × 12.1 cm) vascular mediastinal mass. At endoscopy, a large, ulcerated, cratered and friable mass was found at 29 cm extending to 36 cm at which point the lower anastomosis of the colonic pull through was present. Multiple endoscopic biopsies were obtained which showed that the tumor was immunoreactive with CD117, CD34 and DOG1 while markers of carcinoma, melanoma and lymphoma were negative. In light of the pathology report, the immunohistochemistry and the CT scans, the tumor was classified as a stage 4 GIST of colonic interposition. CONCLUSIONS: GIST can complicate unusual locations such as colonic interposition and should be kept in the differential diagnosis of such unusual presentations.

Granulomatous mastitis: changing clinical and imaging features with image-guided biopsy correlation.

OBJECTIVES: To review clinical presentation, revisit patient demographics and imaging findings in granulomatous mastitis and determine the optimal biopsy method for diagnosis. METHODS: A retrospective study was performed to review the clinical presentation, imaging findings and biopsy methods in patients with granulomatous mastitis. Twenty-seven patients with pathology-proven granulomatous mastitis were included. RESULTS: The average age at presentation was 38.0 years (range, 21-73 years). Seven patients were between 48 and 73 years old. Twenty-four patients presented with symptoms and three patients were asymptomatic. Nineteen patients were imaged with mammography demonstrating mammographically occult lesions as the predominant finding. Twenty-six patients were imaged with ultrasound and the most common finding was a mass lesion. Pathological diagnosis was made by image-guided biopsy in 44 % of patients. The imaging features of granulomatous mastitis on mammography are infrequently described. CONCLUSIONS: Our study demonstrates that granulomatous mastitis can occur in postmenopausal or asymptomatic patients, although previously reported exclusively in young women with palpable findings. Presentation on mammography as calcifications requiring mammographically guided vacuum-assisted biopsy has not been previously described. The diagnosis of granulomatous mastitis can easily be made by image-guided biopsy and surgical excision should be reserved for definitive treatment. KEY POINTS: • Characterizes radiographic appearance of granulomatous mastitis in postmenopausal or asymptomatic patients. • Granulomatous mastitis can present exclusively as calcifications on mammography. • The diagnosis of granulomatous mastitis is made by image-guided biopsy techniques.

Inhibition of the TWEAK/Fn14 pathway attenuates renal disease in nephrotoxic serum nephritis.

Previously it was shown that the TNF superfamily member TWEAK (TNFSF12) acts through its receptor, Fn14, to promote proinflammatory responses in kidney cells, including the production of MCP-1, RANTES, IP-10 and KC. In addition, the TWEAK/Fn14 pathway promotes mesangial cell proliferation, vascular cell activation, and renal cell death. To study the relevance of the TWEAK/Fn14 pathway in the pathogenesis of antibody-induced nephritis using the mouse model of nephrotoxic serum nephritis (NTN), we induced NTN by passive transfer of rabbit anti-glomerular antibodies into Fn14 knockout (KO) and wild type (WT) mice. Severe proteinuria as well as renal histopathology were induced in WT but not in Fn14 KO mice. Similarly, a pharmacologic approach of anti-TWEAK mAb administration into WT mice in the NTN model significantly ameliorated proteinuria and improved kidney histology. Anti-TWEAK treatment did not affect the generation of mouse anti-rabbit antibodies; however, within the kidney there was a significant decrease in glomerular immunoglobulin deposition, as well as macrophage infiltrates and tubulointerstitial fibrosis. The mechanism of action is most likely due to reductions in downstream targets of TWEAK/Fn14 signaling, including reduced renal expression of MCP-1, VCAM-1, IP-10, RANTES as well as Fn14 itself, and other molecular pathways associated with fibrosis in anti-TWEAK treated mice. Thus, TWEAK/Fn14 interactions are instrumental in the pathogenesis of nephritis in the NTN model, apparently mediating a cascade of pathologic events locally in the kidney rather than by impacting the systemic immune response. Disrupting TWEAK/Fn14 interactions may be an innovative kidney-protective approach for the treatment of lupus nephritis and other antibody-induced renal diseases.

Dysregulated nephrin in diabetic nephropathy of type 2 diabetes: a cross sectional study.

BACKGROUND: Podocyte specific proteins are dysregulated in diabetic nephropathy, though the extent of their expression loss is not identical and may be subject to different regulatory factors. Quantifying the degree of loss may help identify the most useful protein to use as an early biomarker of diabetic nephropathy. METHODOLOGY/PRINCIPAL FINDINGS: Protein expression of synaptopodin, podocin and nephrin were quantified in 15 Type 2 diabetic renal biopsies and 12 control patients. We found statistically significant downregulation of synaptopodin (P<0.0001), podocin (P = 0.0002), and nephrin (P<0.0001) in kidney biopsies of diabetic nephropathy as compared with controls. Urinary nephrin levels (nephrinuria) were then measured in 66 patients with Type 2 diabetes and 10 healthy controls by an enzyme-linked immunosorbent assay (Exocell, Philadelphia, PA). When divided into groups according to normo-, micro-, and macroalbuminuria, nephrinuria was found to be present in 100% of diabetic patients with micro- and macroalbuminuria, as well as 54% of patients with normoalbuminuria. Nephrinuria also correlated significantly with albuminuria (rho = 0.89, p<0.001), systolic blood pressure (rho = 0.32, p = 0.007), and correlated negatively with serum albumin (rho = -0.48, p<0.0001) and eGFR (rho = -0.33, p = 0.005). CONCLUSIONS/SIGNIFICANCE: These data suggest that key podocyte-specific protein expressions are significantly and differentially downregulated in diabetic nephropathy. The finding that nephrinuria is observed in a majority of these normoalbuminuric patients demonstrates that it may precede microalbuminuria. If further research confirms nephrinuria to be a biomarker of pre-clinical diabetic nephropathy, it would shed light on podocyte metabolism in disease, and raise the possibility of new and earlier therapeutic targets.

Sea urchin spine arthritis in the foot.

We present a case of sea urchin spine arthritis (SUSA) in a 33-year-old woman who sustained penetrating trauma to the interphalangeal (IP) joint of the hallux while snorkeling in Japan. Serial radiographs and MRI were obtained over a period from 7 weeks to 10 months following injury. At 7 weeks radiographs revealed periarticular osteopenia and subtle marginal erosion, similar to the appearance of tuberculous arthritis. Over the ensuing months, radiographs and MRI documented progressive marginal and periarticular erosions with synovitis, despite preservation of cartilage space and restoration of bone mineral density. Delayed radiographs and imaging features mimic gouty arthropathy. Only the history points to the proper diagnosis, which was confirmed by histopathology, demonstrating necrobiotic granuloma with central fibrinoid necrosis following synovectomy and arthrodesis. The majority of previous case reports affected the hand, with few cases in the feet. In all, radiographic illustrations were limited and demonstrated only minimal osteolysis and periosteal reaction. No other report included MRI or serial radiographs over a long period to illustrate the natural progression of the disease.

Performance of implementing guideline-driven cervical cancer screening measures in an inner-city hospital system.

OBJECTIVE: : In 2006, the American Society for Colposcopy and Cervical Pathology updated evidence-based guidelines recommending screening intervals for women with abnormal cervical cytology diagnosis. In our low-income inner-city population, we sought to improve performance by uniformly applying the guidelines to all patients. We report the prospective performance of a comprehensive tracking, evidence-based algorithmically driven call back, and appointment scheduling system for cervical cancer screening in a resource-limited inner-city population. MATERIALS AND METHODS: : Outreach efforts were formalized with algorithm-based protocols for triage to colposcopy, with universal adherence to evidence-based guidelines. During implementation from August 2006 to July 2008, we prospectively tracked performance using the electronic medical record with administrative and pathology reports to determine performance variables such as the total number of Pap tests, colposcopy visits, and the distribution of abnormal cytology and histology results, including all cervical intraepithelial neoplasia 2, 3 diagnoses. RESULTS: : A total of 86,257 gynecologic visits and 41,527 Pap tests were performed system-wide during this period of widespread and uniform implementation of standard cervical cancer screening guidelines. The number of Pap tests performed per month varied little. The incidence of CIN 1 significantly decreased from 117 (68.4%) of 171 during the first tracked month to 52 (54.7%) of 95 during the last tracked month (p = 0.04). The monthly incidence rate of CIN 2, 3, including incident cervical cancers, did not change. The total number of colposcopy visits declined, resulting in a 50% decrease in costs related to colposcopy services and approximately a 12% decrease in costs related to excisional biopsies. CONCLUSIONS: : Adherence to cervical cancer screening guidelines reduced the number of unnecessary colposcopies without increasing numbers of potentially missed CIN 2, 3 lesions, including cervical cancer. Uniform implementation of administrative-based performance initiatives for cervical cancer screening minimizes differences in provider practices and maximizes performance of screening while containing cervical cancer screening costs.

Risk factors for persistent cervical intraepithelial neoplasia grades 1 and 2: managed by watchful waiting.

OBJECTIVE: : This study examines risk factors for persistent cervical intraepithelial neoplasia (CIN) and examines whether human papillomavirus (HPV) testing predicts persistent lesions. MATERIALS AND METHODS: : Women with histologically diagnosed CIN 1 or CIN 2 (n = 206) were followed up every 3 months without treatment. Human papillomavirus genotyping, plasma levels of ascorbic acid, and red blood cell folate levels were obtained. Cervical biopsy at 12 months determined the presence of CIN. Relative risk (RR) was estimated by log-linked binomial regression models. RESULTS: : At 12 months, 70% of CIN 1 versus 54% of CIN 2 lesions spontaneously regressed (p < .001). Levels of folate or ascorbic acid were not associated with persistent CIN at 12 months. Compared with HPV-negative women, those with multiple HPV types (RRs ranged from 1.68 to 2.17 at each follow-up visit) or high-risk types (RRs range = 1.74-2.09) were at increased risk for persistent CIN; women with HPV-16/18 had the highest risk (RRs range = 1.91-2.21). Persistent infection with a high-risk type was also associated with persistent CIN (RRs range = 1.50-2.35). Typing for high-risk HPVs at 6 months only had a sensitivity of 46% in predicting persistence of any lesions at 12 months. CONCLUSIONS: : Spontaneous regression of CIN 1 and 2 occurs frequently within 12 months. Human papillomavirus infection is the major risk factor for persistent CIN. However, HPV testing cannot reliably predict persistence of any lesion.

A novel cutaneous vasculitis syndrome induced by levamisole-contaminated cocaine.

In order to describe the clinical and serologic features of a cutaneous vasculitis due to cocaine contaminated with the adulterant levamisole, we report four new cases of this syndrome along with 12 previously reported cases identified through a PubMed Literature search (1964 to March 2011). Of the 16 patients described, the average age was 43, with a female predominance (81% of patients). Over half of patients had involvement of the earlobes, and the rash frequently affected the extremities in a "retiform" pattern. Leukopenia or neutropenia was reported in 56% of patients. Ninety-three percent were anti-neutrophil cytoplasmic antibody positive, and 63% tested positive for anti-phospholipid antibodies. The predominant pattern seen on histopathological examination of the skin was small vessel vasculitis and/or a thrombotic vasculopathy. Treatment in these patients varied widely, with several patients showing improvement or resolution of the rash without specific therapy following cessation of illicit drug use. This new cutaneous vasculitis syndrome can be recognized by its characteristic rash and skin pathology, together with leukopenia and autoantibody production. Certain clinical features can be attributed to the adulterant levamisole, though cocaine as well may play a role in its pathogenesis.

Influence of neutropenia on the course of serotype 8 pneumococcal pneumonia in mice.

Polymorphoneutrophils (PMNs) are important effector cells in host defense against pneumonia. However, PMNs can also induce inflammation and tissue damage. To investigate the contribution of PMNs to host defense against pneumococcal pneumonia, we determined the effect of the PMN-depleting rat monoclonal antibody RB6-8C5 (RB6) on survival and inflammatory and cellular response in the lungs to a lethal intranasal infection with a serotype 8 pneumococcus in BALB/c mice. Control mice received rat immunoglobulin G (rIgG). Strikingly, the survival of RB6-treated mice was significantly prolonged compared to that of rIgG-treated mice. Although the numbers of CFU in the lungs were statistically similar in both groups 4, 24, and 32 h after infection, rIgG-treated mice developed higher levels of bacteremia, and histopathological examination of the lungs of infected mice revealed marked differences between RB6- and rIgG-treated mice. RB6-treated mice had focal, perivascular lesions without accompanying parenchymal inflammation, and rIgG-treated mice had diffuse, interstitial parenchymal inflammation. Lung homogenates from the rIgG-treated mice had more leukocytes and significantly more total and apoptotic PMNs as determined by fluorescence-activated cell sorter analysis with Annexin V and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining of lung tissue samples. Studies with a pneumolysin-deficient mutant of the serotype 8 strain we used also demonstrated the prolonged survival of RB6- compared to rIgG-treated mice. Taken together, our findings suggest that PMNs enhance the likelihood of early death and alter the pathological response to pneumococcal lung infection in BALB/c mice with serotype 8 pneumonia without significantly affecting bacterial clearance or the cytokine response.

Modulation of the lung inflammatory response to serotype 8 pneumococcal infection by a human immunoglobulin m monoclonal antibody to serotype 8 capsular polysaccharide.

The human monoclonal antibody to serotype 8 pneumococcal capsular polysaccharide D11 [immunoglobulin M(kappa)] protects wild-type and complement component 4 knockout (C4 KO) mice against lethal intratracheal challenge with serotype 8 pneumococcus, but it does not promote polymorphonuclear leukocyte (PMN)-mediated pneumococcal killing in vitro. In this study, we investigated the effect of D11 on the blood and lung bacterial burdens and the serum and lung expression of inflammatory chemokines and cytokines in an intratracheal challenge model with serotype 8 pneumococcus in C4 KO mice. Pneumococcus was not detected in the blood of D11-treated mice, whereas control mice had high-grade bacteremia with >10(7) CFU. Control mice had a >5-log increase in lung CFU and D11-treated mice manifested a nearly 3-log increase in lung CFU compared to the original inoculum 24 h after infection. Serum and lung levels of soluble macrophage inflammatory protein 2 (MIP-2) and interleulin-6 (IL-6) as measured by an enzyme-linked immunosorbent assay were lower in D11-treated mice than in control mice 24 h after infection. Real-time PCR was performed to examine lung mRNA chemokine and cytokine expression. The results showed that D11-treated mice had significantly less gamma interferon, MIP-2, IL-12, monocyte chemoattractant protein 1/JE, and tumor necrosis factor alpha expression than control mice 24 h after infection. Histopathology and immunohistochemical staining of lung tissues revealed that D11-treated mice had less inflammation, fewer PMNs, and less myeloperoxidase staining than control mice 24 h after infection. These findings suggest that the efficacy of certain serotype-specific antibodies against pneumococcal pneumonia could be associated with modulation of the lung inflammatory response and a reduction in host damage.

Detection of cervical human papillomavirus infection by in situ hybridization in fetuses from women with squamous intraepithelial lesions.

OBJECTIVE: To evaluate for human papillomavirus (HPV) infection in the cervix of fetuses from mothers with documented squamous intraepithelial lesions. METHODS: Fetal cervical epithelium was obtained from the Human Fetal Tissue Repository as per Institutional Review Board protocol. Fetal cervical epithelium was dissected, fixed in formalin, and embedded in paraffin. Sections were tested by in situ hybridization using a wide-spectrum HPV DNA probe. Cases were specimens from mothers with low- and high-grade squamous intraepithelial lesions, and controls were specimens from women with no documented squamous intraepithelial lesions. RESULTS: A total of 14 controls and 10 cases were evaluated for HPV DNA. No reactivity was detected in the controls. Two cases showed focal intracellular reactivity with the HPV DNA probe. CONCLUSION: To our knowledge, this is the first study demonstrate fetal cervical HPV infection due to intrauterine exposure. These findings have important implications in understanding the pathogenesis of cervical neoplasia and its management.

Immune reconstitution cryptococcosis after initiation of successful highly active antiretroviral therapy.

Five of 10 patients who commenced successful highly active antiretroviral therapy (HAART) for infection with human immunodeficiency virus type 1 (HIV-1) concurrent with or soon after a diagnosis of cryptococcal infection experienced clinical events characterized by sterile inflammation. Two patients developed aseptic meningitis with elevated intracranial pressure, 1 developed intrathoracic lyphadenopathy with hypercalcemia, 1 developed cavitary pneumonia at the site of a cryptococcal nodule, and 1 developed a supraclavicular abscess. These events occurred 2-11 months after initiation of HAART. For 3 patients, biopsy demonstrated findings atypical for acquired immunodeficiency syndrome-associated cryptococcosis. Results of fungal cultures were negative for all 5 patients, and cryptococcal antigen levels had declined markedly in 4 patients. The timing and clinical features of and biopsy findings for these cases of cryptococcosis suggest the existence of a paradoxical reaction to Cryptococcus infection that occurs in the context of HIV immune restoration.

Fine needle aspiration cytology of dermatofibrosarcoma protuberans presenting as a breast mass. A case report.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous soft tissue neoplasm with a tendency to recur but rarely metastasize. It occurs at almost any site but usually in the trunk and extremities. DFSP mimicking a primary breast lesion has not been reported before. CASE: A 30-year-old female presented with an eight-month history of a breast mass that was aspirated, revealing a spindle cell neoplasm. The diagnosis of DFSP was made on excisional biopsy. CONCLUSION: The diagnosis of DFSP may be problematic, especially when it presents clinically as a primary breast lesion.

Regression of cervical intraepithelial neoplasia and loss of human papillomavirus (HPV) infection is associated with cell-mediated immune responses to an HPV type 16 E7 peptide.

Most human papillomavirus (HPV)-associated cervical intraepithelial neoplasia(CIN) lesions in normal women regress spontaneously, but a small number persist and may progress to invasive cancer. To evaluate the role of immunity to HPV and the outcome of CIN and associated HPV infection, we examined cell-mediated immune (CMI) responses to HPV 16 E6 and E7 peptides. One hundred thirty-six women with biopsy-confirmed CIN I or CIN II were followed for 1 year at 3 month intervals. Study subjects were 58% Hispanic, 36% African American, and 6% of other ethnicity, and were attending a municipal hospital colposcopy clinic. At each visit, cervical cytology and cervicovaginal lavage for HPV detection and typing was done, and blood was obtained for immunological studies. Lymphoproliferative CMI responses to HPV 16 E6 and E7 peptides were tested. An end point biopsy was done after the 1-year follow-up. The association between CMI responses to specific peptides and the outcome of disease was evaluated. CMI responses to E7 peptide (37-54) correlated significantly with regression of disease and with resolution of viral infection within 12 months. The protective effects of CMI to this peptide were not HPV type-specific. CMI responses to several other peptides also showed an association with regression, although not significant at present sample size. E7 peptide 37-54 contains one or more human T-cell epitopes. Identification and mapping of "protective" epitopes in the HPV E6 and E7 proteins could lead to the development of immunological assays to determine the risk of CIN and the development of immunotherapeutic protocols for the management of premalignant and malignant HPV-associated neoplasia and, ultimately, for the prevention of cancer.