Gerald Langman

WT1 expression in salivary gland pleomorphic adenomas: a reliable marker of the neoplastic myoepithelium

Pleomorphic adenoma is a benign salivary gland neoplasm with a diverse morphology. This is considered to be a function of the neoplastic myoepithelium, which shows histological and immunophenotypical variability. Wilms’ tumor 1 gene (WT1) protein, involved in bidirectional mesenchymal–epithelial transition, has been detected by reverse transcription PCR in salivary gland tumors showing myoepithelial–epithelial differentiation. The aim of this study was to investigate the immunoreactivity of WT1 in pleomorphic adenomas and to compare the pattern of staining with p63 and calponin, two reliable markers of myoepithelial cells. A total of 31 cases of pleomorphic adenoma were selected. The myoepithelium was classified as myoepithelial-like (juxtatubular and spindled), modified myoepithelium (myxoid, chondroid and plasmacytoid) and transformed myoepithelium (solid epithelioid, squamous and basaloid cribriform). Immunohistochemistry for WT1, p63 and calponin was assessed in each myoepithelial component, as well as in nonneoplastic myoepithelial cells and inner tubular epithelial cells. There was no immunostaining of tubular epithelial cells by any of the markers. In contrast to p63 and calponin, WT1 did not react with normal myoepithelial cells. Cytoplasmic WT1 staining was present in all pleomorphic adenomas, and in 29 cases (94%), >50% of neoplastic myoepithelial cells were highlighted. p63 and calponin stained the myoepithelium in 30 tumors. In comparison, 50% of cells were positive in 21 (68%) and 9 (29%) cases of p63 and calponin, respectively. Staining with WT1 showed less variability across the spectrum of myoepithelial differentiation with the difference most marked in the transformed myoepithelium. WT1 is a sensitive marker of the neoplastic myoepithelial cell in pleomorphic adenomas. The role of this protein in influencing the mesenchymal–epithelial state of cells suggests that WT1 and the myoepithelial cell have an important role in the histogenesis of pleomorphic adenomas.

Circulating DBP level and prognosis in operated lung cancer: an exploration of pathophysiology

Vitamin D stimulates transcription of antiangiogenic and apoptotic factors that may suppress tumours, while vitamin D binding protein (DBP) may be a biomarker in murine lung cancer models. We sought to ascertain whether the vitamin D axis is altered in lung cancer or influences prognosis. 148 lung cancer patients, 68 other intrathoracic cancer patients and 33 noncancer controls were studied for up to 5 yrs. Circulating DBP and vitamin D levels were compared between groups and their effect on survival assessed by Cox regression analysis. Expression of DBP and vitamin D receptor (VDR) was examined in lung cancer cell lines and in normal and tumour lung tissue by Western blot and immunohistochemistry. Low serum DBP levels predicted lung cancer-specific death (p=0.04), and DBP was poorly expressed in lung cancer cells on Western blot and immunohistochemistry. Vitamin D did not predict cancer survival and VDR expression was variable in tumours. Preservation of serum DBP is a significant independent factor associated with better cancer outcome in operated lung cancer patients. Given the established role of DBP in macrophage activation and clearance of abnormal cells, further study on its involvement in lung cancer is merited.

An intracapsular carcinoma ex pleomorphic adenoma with lung metastases composed exclusively of benign elements: histological evidence of a continuum between metastasizing pleomorphic adenoma and carcinoma ex pleomorphic adenoma.

Malignant mixed tumors of the salivary glands, encompassing carcinoma ex pleomorphic adenoma (ca ex PA), carcinosarcoma and metastasizing pleomorphic adenoma (mPA), are rare neoplasms. Ca ex PA arises in a pre-existing pleomorphic adenoma (PA). When the malignant component does not breach the capsule of the parent PA, the lesion is termed intracapsular ca ex PA, a neoplasm which is thought to have no metastatic potential. Metastatic deposits of ca ex PA are composed exclusively of malignant elements or mixed benign and malignant components. We describe the case of a 62-year-old female with an intracapsular ca ex PA of the buccal mucosa with subsequent metastases to the lung. The metastatic deposits resembled benign PA with no histological evidence of malignancy. This pattern of spread is described with mPA, an entity that caused controversy in the past regarding its exact classification as a benign or malignant tumor. The possibility that ca ex PA originates from a mPA, with intracapsular ca ex PA representing an intermediate lesion in a histological continuum, is discussed.

IRP2 as a potential modulator of cell proliferation, apoptosis and prognosis in nonsmall cell lung cancer

IREB2 is a gene that produces iron regulatory protein 2 (IRP2), which is critical to intracellular iron homeostasis and which relates to the rate of cellular proliferation. IREB2 lies in a lung cancer susceptibility locus. The aims were to assess 1) the relationship between iron loading, cell proliferation and IRP2 expression in lung cancer; 2) the potential of iron related pathways as therapeutic targets; and 3) the relevance of IRP2 in operated lung cancer patients. Cells of two nonsmall cell cancer (NSCLC) lines and primary bronchial epithelial cells (PBECs) were cultured with and without iron; and proliferation, apoptosis and migration were assessed. Reverse transcriptase PCR and Western blot were used to assess expression of iron homeostasis genes/proteins. Iron chelation and knockdown of IREB2 were used in vitro to explore therapeutics. A cohort of operated NSCLC patients was studied for markers of systemic iron status, tumour IRP2 staining and survival. Iron loading caused cell proliferation in cancer cell lines, which were less able to regulate IREB2 expression than PBECs. Iron chelation resulted in a return of proliferation rates to baseline levels; knockdown of IREB2 had a similar effect. IRP2-positive tumours were larger (p=0.045) and higher percentage staining related to poorer survival (p=0.079). Loss of iron regulation represents a poor prognostic marker in lung cancer. Iron loading causes cell proliferation in lung cancer. Iron chelation can return proliferation rates to baseline http://ow.ly/zkes3093yYF

A solitary painful papule on the ear.

An 80-year-old woman presented with a slowly enlarging, intermittently painful lesion on the upper part of her right ear. It had been present for 2 years. On examination, there was a discrete, firm, translucent papule, 7 · 4 mm in size, on the posterior aspect of the upper crus of the antihelix of the right ear. A single prominent blood vessel was visible on the surface of the lesion and it was tender to palpation (Fig. 1).

Acute interstitial nephritis secondary to long-term use of cetirizine for the treatment of urticaria pigmentosa.

may be functional; the change of C to G may increase the stability between miR-146a and its complementary strand, resulting in increased expression of the miRNA. Recent studies have indicated an association between vascular abnormalities with miR-146a, but not with rs2910164. Our study had some limitations. The number of patients included in this study is rather low for an SNP study, thus larger studies are needed to confirm our result. However, our results suggest that rs2910164 may be involved in the mechanisms of vascular involvement of SSc, and patients with the CC genotype might have a higher risk of vascular involvement. Genotyping of rs2910164 in patients with SSc may contribute to our understanding of the mechanism of the disease.

Thymoma: a clinicopathological correlation of 1470 cases

We present 1470 surgical resections for thymoma identified in the pathology files of 14 institutions from 11 countries with the purpose of determining and correlating a simplified histological classification of thymoma and pathological staging with clinical outcome. The study population was composed of 720 men and 750 women between the ages of 12 and 86 years (average, 54.8 years). Clinically, 137 patients (17%) had a history of myasthenia gravis, 31 patients (3.8%) of other autoimmune disease, and 55 (6.8%) patients of another neoplastic process. Surgical resection was performed in all patients. Histologically, 1284 (87.13%) cases were thymomas (World Health Organization types A, B1, and B2, and mixed histologies), and 186 (12.7%) were atypical thymomas (World Health Organization type B3). Of the entire group, 630 (42.9%) were encapsulated thymomas, and 840 (57.9%) were invasive thymomas in different stages. Follow-up information was obtained in 1339 (91%) patients, who subsequently were analyzed by univariate and multivariate statistical analysis. Follow-up ranging from 1 to 384 months was obtained (mean, 69.2 months) showing tumor recurrence in 136 patients (10.1%), whereas 227 died: 64 (28.2%) due to tumor and 163 (71.8%) due to other causes. Statistical analysis shows that separation of these tumors into thymoma and atypical thymoma is statistically significant (P = .001), whereas tumor staging into categories of encapsulated, minimally invasive, and invasion into adjacent organs offers a meaningful clinical assessment with a P = .038. Our findings suggest that our simplified histological schema and pathological staging system are excellent predictors of clinical outcome.

A cutaneous presentation of a common condition

A 25 year old woman was reviewed on the ward by the dermatology team for persistent, painful intertriginous skin erosions beneath both breasts and in both groins. She had been admitted over a month ago with cellulitis around the erosions, which initially responded to intravenous antibiotics but needed several repeat courses owing to recurrence. Crohn’s disease had necessitated a total colectomy at age 18 years. She also had severe learning difficulties and behavioural problems. She could not tolerate topical treatments. The only regular drugs at admission were mesalazine 1500 mg daily and clozapine. High dose oral corticosteroids before colectomy caused a marked transient psychosis and she had not received further systemic corticosteroids since. She was obese with deep sloughy linear erosions demonstrating the “knife-cut” sign beneath the abdominal apron, in the inguinal creases, and under both breasts (fig 1⇓). She also had an eroded ulcer in her right labium majus. Fig 1 Knife-cut ulcer in the right submammary fold Multiple skin swabs were negative for bacterial, candidal, and herpes simplex virus (HSV) infections. Initial skin biopsy showed only non-specific scarring in the dermis, but a deeper one showed non-caseating granulomatous inflammation. ### 1. Which differential diagnoses must be excluded in this patient? #### Short answer Linear erosive HSV infection, cutaneous Crohn’s disease, bacterial and fungal infections. #### Discussion The term “knife-cut” sign was originally used to refer to the linear fissures commonly seen on colonoscopy in patients with Crohn’s disease. It was later used to describe the cutaneous linear erosive lesions seen in some patients with Crohn’s disease affecting the skin (termed metastatic Crohn’s disease).1 However, other disorders may also produce linear erosive fissures with a similar appearance. …

A blue nodule on the forehead.

A healthy 74-year-old woman presented with a mass on her forehead just below the hairline. This had been present since childhood and had changed from skin colour to blue–black over the past year. On examination, there was a blue–black dermal nodule 10 mm in diameter on the mid-forehead. It had a smooth surface, was firm to palpation and had a slightly translucent quality (Fig. 1). The lesion was excised with narrow margins.

Misdiagnosing Whipple's disease in the young.

Whipples disease is considered an infection of middle-aged white men of European ancestry. Cases are rare and disproportionately associated with occupational exposure to soil or animals. We report the case of a man aged 22 years with no risk factors, erroneously diagnosed with, and treated for, toxoplasmosis on the basis of consistent lymph node histology. The correct diagnosis was delayed by the dramatic symptomatic improvement resulting from this therapy. Whipples disease should be considered in cases of granulomatous lymphadenopathy of unknown cause, even if the age of the patient does not fit the classic presentation of the disease.