Peter A. Drew

Pirfenidone Inhibits Lung Allograft Fibrosis through L-Arginine-Arginase Pathway

Transplant‐related lung fibrosis is characterized by excessive fibro‐collagenous deposition. Induction of arginase, an enzyme that metabolizes L‐arginine to urea and L‐ornithine, is vital for collagen synthesis. Pirfenidone is an investigational anti‐fibrotic agent shown to be effective in blocking pulmonary fibrosis. The purpose of this study was to determine if pirfenidone was protective against the development of fibro‐collagenous injury in rat lung orthotopic transplants through altering L‐arginine–arginase metabolic pathways. Lung transplants were performed using Lewis donors and Sprague‐Dawley recipients (allografts) or the same strain (isografts). Recipients were given pirfenidone (0.5% chow) 1–21‐day post‐transplantation. A significantly increased peak airway pressure (PawP) with excessive collagen deposition was found in untreated lung allografts. Pirfenidone treatment decreased PawP and collagen content in lung allografts. The beneficial effects were associated with downregulation of arginase protein expression and activity. In addition, pirfenidone decreased endogenous transforming growth factor (TGF)‐β level in lung allografts, and TGF‐β stimulated arginase activity in a dose‐dependent manner in both lung tissue and fibroblasts. These results suggest that pirfenidone inhibits local arginase activity possibly through suppression of endogenous TGF‐β, hence, limiting the development of fibrosis in lung allografts.

Do Qualifiers of ASCUS Distinguish Between Low- and High-Risk Patients?

OBJECTIVE To evaluate the qualification of a Pap smear classified as atypical squamous cells of undetermined significance (ASCUS) favor reactive or neoplasia as recommended by the Bethesda System. STUDY DESIGN The smears from 105 concurrent patients with a cytologic diagnosis of ASCUS not otherwise qualified were reviewed and subclassified as ASCUS favor reactive, low grade squamous intraepithelial lesion (LSIL) or high grade squamous intraepithelial lesion (HSIL) based on the Bethesda System criteria. The cervical biopsy diagnoses were correlated. RESULTS Of the 105 cases classified as ASCUS, 37 were subclassified as favor reactive, 51 as favor LSIL and 17 as favor HSIL on cytologic review. In the ASCUS favor reactive group, 19 (51%) had reactive changes on biopsy, 17 (46%) had cervical intraepithelial neoplasia (CIN) 1, and 1 (2%) had CIN 3. A total of 48% patients had CIN. In the favor LSIL group, there was CIN 1 in 28 cases (55%), CIN 2 or 3 in 12 (23%) and benign changes in 11 (22%) on biopsy. Seventy-eight percent had CIN. In the 17 cases classified as ASCUS favor HSIL group, all had CIN. CONCLUSION Of the total 105 cases of ASCUS, 71% had CIN, 29% had reactive changes on follow-up biopsies, and 48% of patients in the ASCUS favor reactive group had CIN. Qualifiers of ASCUS have questionable utility in patient management.

Clear cell adenocarcinoma of the bladder and urethra: cases diffusely mimicking nephrogenic adenoma

Although clear cell adenocarcinoma have been described focally mimicking nephrogenic adenoma, we have identified a subset of clear cell adenocarcinoma that diffusely resembles nephrogenic adenoma (nephrogenic adenoma-like clear cell adenocarcinoma). Twelve classic clear cell adenocarcinomas of the bladder and urethra and 7 nephrogenic adenoma-like clear cell adenocarcinomas were compared to 10 nephrogenic adenomas. Classic clear cell adenocarcinomas and nephrogenic adenoma-like clear cell adenocarcinomas comprised 4 men and 15 women. The following features were seen in classic clear cell adenocarcinomas: nephrogenic adenoma-like clear cell adenocarcinomas: predominantly solid pattern (7/12:0/7), marked nuclear pleomorphism (7/12:1/7), prominent nucleoli (5/12:1/7), clear cytoplasm in 50% or greater of tumor (7/12:0/7), and necrosis (8/12:3/7), although the necrosis in nephrogenic adenoma-like clear cell adenocarcinomas was often focal and intraluminal. Both patterns of clear cell adenocarcinomas showed prominent hobnail features, although more pronounced in nephrogenic adenoma-like clear cell adenocarcinomas. Muscularis propria invasion was seen in 5 of 9 classic clear cell adenocarcinomas and 6 of 6 nephrogenic adenoma-like clear cell adenocarcinomas, where evaluable. Classic clear cell adenocarcinoma was associated with urothelial carcinoma (n = 2) and endometriosis (n = 1). The Ki-67 rate in clear cell adenocarcinomas ranged from 10% to 80% compared with 0% to 5% in nephrogenic adenoma. The following antibodies were not helpful in distinguishing nephrogenic adenoma-like clear cell adenocarcinoma from nephrogenic adenoma: CD10, estrogen receptor, p63, high-molecular-weight cytokeratin, and alpha-methylacyl coenzyme-A racemase. PAX2 expression was more frequent in nephrogenic adenoma (89%) compared to both patterns of clear cell adenocarcinoma (29%-32%). The key features discriminating between nephrogenic adenoma-like clear cell adenocarcinoma and nephrogenic adenoma include occasional clear cells, more prominent pleomorphism especially hyperchromatic enlarged nuclei, and extensive muscular invasion. Presence of mitoses and a high rate of Ki-67 expression in lesions resembling nephrogenic adenoma require clinical correlation, close follow-up, and repeat biopsy with more extensive sampling.

Ki-67 expression in vulvar carcinoma

The proliferative activity of invasive squamous cell carcinoma of the vulva was examined using a Ki-67 equivalent monoclonal antibody (MIB1), which gives a strong immunoreaction in paraffin-embedded tissue. Quantitation of Ki-67 immunostaining was accomplished by image analysis. Ki-67 immunostaining revealed two general patterns of reactivity in vulvar tumors: (a) a diffuse distribution of Ki-67 positive nuclei within the tumor mass and (b) a localized distribution of Ki-67 positive nuclei staining predominantly basilar components of tumor aggregates. The distribution of localized and diffuse patterns did not differ significantly between various clinicopathologic categories (age, histologic type and grade, FIGO stage, and lymph node status). However, the survival times for patients with a diffuse Ki-67 labelling pattern tended to be shorter than those for patients with a localized pattern. Survival curves based on the median positive nuclear area (PNA) calculated by image analysis did not differ significantly. Thus, the pattern of Ki-67 immunostaining, rather than the percentage of PNA, may have prognostic significance in vulvar squamous cell carcinoma.

Smoothelin immunohistochemistry is a useful adjunct for assessing muscularis propria invasion in bladder carcinoma

Bovio I M, Al‐Quran S Z, Rosser C J, Algood C B, Drew P A & Allan R W
(2010) Histopathology 56, 951–956 
Smoothelin immunohistochemistry is a useful adjunct for assessing muscularis propria invasion in bladder carcinoma

Labial salivary gland biopsies in Sjögren's syndrome: still the gold standard?

OBJECTIVES The accuracy and diagnostic benefits of the labial salivary gland (LSG) biopsy for Sjögrens syndrome (SS) have received mixed reviews. This study was conducted to assess (1) the inter-rater agreement among 5 pathologists, and (2) the relationship between biopsy findings and clinical disease parameters. STUDY DESIGN Three oral pathologists (OP) and two surgical pathologists (SP) provided independent diagnoses, focus scores, and plasma cell characterizations for 37 LSG biopsies. Inter-rater reliability was assessed using percentage of overall agreement and intraclass correlation coefficients. Relationships between diagnoses and clinical parameters were assessed by nonparametric correlations. RESULTS Overall agreement among the pathologists was poor, although the intra-specialty agreement was good. The ratings of OP were most highly correlated with serological measures, while those of SP were correlated with salivary flow rate and disease damage. CONCLUSION Since the LSG biopsy can be the determining factor in SS diagnoses, these demonstrated inconsistencies merit further consideration.

Benign cellular changes in Pap smears. Causes and significance.

Objective We reviewed consecutive cases classified as benign cellular changes (BCC) over a four-month period. Study design Cases classified as BCC were retrieved from the cytology files. A search was carried out to identify the previous Pap smears and concomitant cervical biopsies. Results One thousand one hundred three cases (23% of our gynecologic smears) were classified as BCC. Ninety-two patients (8.3%) underwent concurrent cervical biopsies. Specific infections accounted for 8% of BCC cases; reactive changes accounted for 92%. Of the biopsy specimens, 8.3% had no significant pathologic change. The most common biopsy diagnoses were cervicitis (31.5%), immature squamous metaplasia (16.3%) and reserve cell hyperplasia (10.8%). Miscellaneous benign diagnoses accounted for 21.7%. Cervical intraepithelial neoplasia (CIN) 1/human papillomavirus (HPV) was present in 14% of cases. All patients with biopsy diagnoses of CIN 1 had at least two previous abnormal Pap smears. Previous biopsy reports were available for review in 127 (12%) of the 1,103 patients. Of these 127 cases, 53.5% had a previous diagnosis of CIN/HPV; 9.4% had invasive carcinoma. A benign diagnosis was reported in 36.5%. Conclusion The majority of BCC cases are due to reactive and inflammatory processes. In patients with a previous history of CIN, BCC may be of some significance. In patients with no significant prior cervical abnormalities, a Pap smear classified as BCC represents a reactive process.

Pulmonary cryptococcosis and pituitary Cushing's disease

Pulmonary cryptococcosis was diagnosed by examining smears obtained by fine‐needle aspiration (FNA) in a patient with pituitary Cushings disease. FNA allowed for rapid diagnosis and prompt treatment of a potentially serious infection. The patient fully recovered from her pulmonary disease.

Characterization of papillary squamotransitional cell carcinoma of the cervix.

Objective Does papillary squamotransitional cell carcinoma (PSTCC) behave differently from conventional squamous cell carcinoma of the cervix and does PSTCC have true transitional cell differentiation? Materials and Methods Twenty cases of PSTCC were identified from archival files. Clinical data were compiled. Immunoperoxidase stains for uroplakin III, p63 and p16INK4a were performed on available tissue blocks. Results Patients ranged in age from 27 to 85 years. Twelve patients were FIGO Stage I, 4 were Stage II, and 2 were Stage III. Thirteen patients had clinical follow-up ranging from 5 to 132 months. Three patients subsequently had more extensive disease than initial clinical staging indicated. Nine patients had no tumor progression, three had local recurrence and one had metastatic disease. Eight cases were strongly immunoreactive for p63 and p16INK4a and 14 were negative for uroplakin III. Conclusions PSTCC lacks true transitional cell differentiation and probably shares similar clinicopathologic features with conventional cervical squamous cell carcinoma.

Squamous intraepithelial lesions of the cervix in a high-risk population.

Objectives We set out to examine our use of the squamous intraepithelial lesion (SIL) category, compare our SIL rate to rates reported by others, and determine the corre-lation between SIL and histologically proven cervical intraepithelial neoplasia (CIN) in our population. Materials and Methods Reports from all Papanicolaou smears and associated histological specimens interpreted by the University of Florida Department of Pathology between 1992 and 1996 were reviewed. Results Of 39,484 Papanicolaou smears, 2,101 (5.3%) were classified as low-grade squamous intraepithelial lesion (LGSIL) and 1,366 (3.5%) were classified as high-grade (HGSIL). Of the LGSIL cases, 972 (46.3%) underwent timely biopsy: Findings were benign in 29.9%; 41.7% had CIN1,20.9% had CIN2, and 7.5% had CIN3. Of the HGSIL cases, 932 (68.2%) underwent timely biopsy: Findings were benign in 12.3%; 17.1% had CIN1, 26.7% had CIN2, 42.2% had CIN3, and 1.6% showed squamous cell carcinoma. Condusions. Our LGSIL rate is similar to reported rates, but our HGSIL rate of 3.5% is higher. We found good correlation between SIL on Papanicolaou smear and CIN on biopsy (70.1% for LGSIL and 86% for HGSIL).