Pamela C. Gibson

CD117 (KIT): a diverse protein with selective applications in surgical pathology.

CD 117 (KIT) is a transmembrane, tyrosine kinase growth factor receptor which is expressed on numerous diverse fetal and adult cells including hematopoietic cells, mast cells, melanocytes, germ cells, and the interstitial cells of Cajal. Its expression in tumors is also diverse, but with selective use and attention to specific staining patterns, this marker is useful in the identification of gastrointestinal stromal tumors, mast cell tumors, and seminomatous germ cell tumors.

HER-2/neu detection in fine-needle aspirates of breast cancer: fluorescence in situ hybridization and immunocytochemical analysis.

We evaluated HER-2 receptor status by immunocytochemical and immunohistochemical analyses and fluorescence in situ hybridization (FISH) in 51 fine-needle aspiration (FNA) specimens together with the corresponding formalin-fixed, paraffin-embedded (FFPE) tissue samples obtained from surgically resected breast cancers. Three fixation methods were compared: ethanol, formalin, and CytoLyt-ThinPrep (Cytyc, Boxborough, MA). HER-2 was overexpressed and amplified in 8 (16%) of 51 FFPE specimens. Of the 8 cases, gene amplification was observed in 8 FNA specimens (100%) and overexpression in 2 (25%) ethanol-, 4 (50%) CytoLyt-, and 5 (63%) formalin-fixed FNA specimens. Strong pairwise kappa association between FISH results performed on FNA specimens and FFPE tissue samples (ethanol fixation, kappa = 0.848; ThinPrep, kappa = 0.918) and moderate (ThinPrep, kappa = 0.692; formalin fixation, kappa = 0.667) to poor (ethanol, kappa = 0.300) pairwise kappa agreement between tissue immunohistochemical and FNA immunocytochemical results was demonstrated. We conclude that HER-2 protein expression on cytologic preparations was insufficiently reliable for clinical use, whereas HER-2 gene amplification determined by FISH demonstrated strong and consistent correlation with HER-2 status of FFPE tissue samples.

HER-2/neu Detection in Fine-Needle Aspirates of Breast Cancer

We evaluated HER-2 receptor status by immunocytochemical and immunohistochemical analyses and fluorescence in situ hybridization (FISH) in 51 fine-needle aspiration (FNA) specimens together with the corresponding formalin-fixed, paraffin-embedded (FFPE) tissue samples obtained from surgically resected breast cancers. Three fixation methods were compared: ethanol, formalin, and CytoLyt-ThinPrep (Cytyc, Boxborough, MA). HER-2 was overexpressed and amplified in 8 (16%) of 51 FFPE specimens. Of the 8 cases, gene amplification was observed in 8 FNA specimens (100%) and overexpression in 2 (25%) ethanol-, 4 (50%) CytoLyt-, and 5 (63%) formalin-fixed FNA specimens. Strong pairwise κ association between FISH results performed on FNA specimens and FFPE tissue samples (ethanol fixation, κ = 0.848; ThinPrep, κ = 0.918) and moderate (ThinPrep, κ = 0.692; formalin fixation, κ = 0.667) to poor (ethanol, κ = 0.300) pairwise κ agreement between tissue immunohistochemical and FNA immunocytochemical results was demonstrated. We conclude that HER-2 protein expression on cytologic preparations was insufficiently reliable for clinical use, whereas HER-2 gene amplification determined by FISH demonstrated strong and consistent correlation with HER-2 status of FFPE tissue samples.

Digital imaging guidelines for pathology: a proposal for general and academic use.

Digital imaging is an inexpensive and widely available tool that is used by most pathologists in patient reports, education, publication, diagnosis, and data archival. Its popularity is due, in part, to the ease of modifying, storing, enhancing, and annotating images. Since digital manipulation is essentially undetectable in the final product, it poses the potential risk for fraudulent manipulation and heightens the possibility of unintentional misrepresentation. In an attempt to ensure a high degree of uniformity and quality, and to create a professional standardization amongst pathologists, digital imaging guidelines are proposed for use in general and academic practice.

GLUT1 antibody staining in thin-layer specimens of benign and malignant body cavity effusions.

OBJECTIVE To determine whether GLUT1 antibody could replace one or more of the currently used antiepithelial antibodies and to assess whether ThinPrep methodology is suited to immunocytochemical (ICC) evaluation. STUDY DESIGN In a prospective study of 10 fluids containing malignant cells from cases of proven adenocarcinoma and 10 cytologically benign effusions, multiple slides were prepared by ThinPrep technology for staining with four commercially available antibodies and appropriate isotype-matched negative controls. The antibodies used were GLUT1, CEA, B72.3 and Leu-M1 (CD 15). Tissue sections and ThinPrep slides were used as positive controls. Specimens were batched to ensure similar conditions for all antibody reactions. RESULTS Of the 11 cases ultimately proven to be carcinoma, GLUT1 and B72.3 stained 7 each (63.6%), and CEA and Leu-M1 6 each (54.5%). No false positive staining was encountered, but one case chosen as a benign control was shown to contain immunopositive cells by three of the four epithelial markers used; this case was therefore an occult true positive rather than a false positive. CONCLUSION In this small but controlled prospective analysis, GLUT1 demonstrated strong positive staining, with sensitivity similar to that of currently used epithelial markers. Using GLUT1 in conjunction with B72.3, no cases of carcinoma were missed. GLUT1 could be used in a panel of antibodies designed to confirm the presence of adenocarcinoma. ThinPrep methodology, which enables multiple slides to be prepared after routine microscopy determines the need for ICC, appears suited to this adjuvant investigation.

What Is a Picture Worth?: Digital Imaging Applications in Autopsy Reports

CONTEXT An image-enhanced report (IER) containing color digital images can serve as an educational tool and document important gross and microscopic findings in anatomic pathology. OBJECTIVE To determine the clinical impression of IERs on an academic autopsy service. DESIGN Autopsy IERs were initiated at this institution in December 2001. From January 2002 to July 2003, 261 hospital-service autopsies were performed; color images were produced for 39 (15%) of these autopsies. Of these IERs, 29 were distributed to 74 hospital-employed physicians. Each hospital physician recipient was sent a 6-question e-mail survey to evaluate his or her impression of image quality and added value. RESULTS Of the 74 hospital-employed physicians sent an IER, 41 responded to the survey (response rate, 55%). Twenty-one respondents recalled receiving a report with color images. Image quality was uniformly rated as good or excellent. Ninety-five percent thought the images increased their understanding of the report, and 76% thought that the images increased the utility of the report. All respondents stated they would (or did) use the images for educational purposes. Twenty-one percent of all respondents thought the presence of color images would increase their likelihood of requesting a future autopsy. CONCLUSIONS Color digital images are perceived as a valuable addition to the autopsy report. Although clinicians did not consider color images a strong motivator to request a future autopsy, most thought that the images enhanced their understanding and the utility of the report. All respondents stated they would use the images to educate themselves, medical students, residents, and/or the patients family.

Primary Vaginal Mucinous Adenocarcinoma of Intestinal Type, Associated With Intestinal Metaplasia of Skene Ducts in a Diethylstilbestrol-Exposed Woman

OBJECTIVES Primary mucinous vaginal adenocarcinoma of intestinal type is an extremely rare malignancy of uncertain histogenesis, which makes for a diagnostic challenge. We report a case and describe the histopathologic features and the unusual immunoprofile of this rare entity. METHODS We report a case of vaginal mucinous adenocarcinoma of intestinal type in a diethylstilbestrol-exposed woman in which intestinal metaplasia of the Skene duct was found at the time of recurrence. RESULTS As the histogenesis of primary vaginal intestinaltype adenocarcinomas remains uncertain, the finding of Skene duct metaplasia in association with invasive adenocarcinoma lends support to the origin of vaginal mucinous adenocarcinomas of intestinal type to be metaplasia, at least in some cases. Such an origin accounts for the unusual immunohistochemical profile, which raises concern for a metastatic adenocarcinoma of gastrointestinal origin. CONCLUSIONS Recognition of this rare entity is important, particularly to avoid the pitfall of misdiagnosing metastatic disease.

Microscopic uterine lymphangioleiomyomatosis perivascular epithelioid cell neoplasm: a case report with the earliest manifestation of this enigmatic neoplasm.

Lymphangioleiomyomatosis (LAM) is part of a family of lesions collectively known as perivascular epithelioid cell neoplasms (PEComas). Though these lesions are comprised of histologically and immunohistochemically distinctive perivascular epithelioid cells, their diagnosis is controversial and some investigators question their existence entirely. We present a unique case of perhaps the earliest microscopic example of a LAM PEComa in the uterine myometrium, and contrast its features to that of intravascular adenomyosis, intravascular endometrial stromal sarcoma, and intravascular leiomyoma.

Reversal of Gastric Bypass Resolves Hyperoxaluria and Improves Oxalate Nephropathy Secondary to Roux-en-Y Gastric Bypass

Hyperoxaluria after Roux-en-Y gastric bypass (RYGB) increases the risk for kidney injury. Medical therapies for hyperoxaluria have limited efficacy. A 65-year-old female was evaluated for acute kidney injury [AKI, serum creatinine (Cr) 2.1 mg/dl, baseline Cr 1.0 mg/dl]. She did not have any urinary or gastrointestinal symptoms or exposure to nephrotoxic agents. Sixteen months prior to this evaluation, she underwent RYGB for morbid obesity. Her examination was unremarkable for hypertension or edema and there was no protein or blood on urine dipstick. Kidney biopsy revealed acute tubulointerstitial nephritis with oxalate crystals in tubules. The concurrent finding of severe hyperoxaluria (urine oxalate 150 mg/day) confirmed the diagnosis of oxalate nephropathy. Despite medical management of hyperoxaluria, her AKI worsened. Laparoscopic reversal of RYGB was performed and within 1 month, her hyperoxaluria resolved (urine oxalate 20 mg/day) and AKI improved (Cr 1.7 mg/dl). Surgical reversal of RYGB may be considered in patients with oxalate nephropathy at high risk of progression who fail medical therapy. Physicians need to be aware of the possibility of oxalate nephropathy after RYGB and promptly treat the hyperoxaluria to halt further kidney damage.

Alendronate-associated focal segmental glomerulosclerosis

Sir, Alendronate sodium, a bisphosphonate and commonly used pharmacologic agent for postmenopausal osteoporosis, has been rarely linked to renal toxicity [1] but not in association with focal segmental glomerulosclerosis (FSGS). A 55-year-old Caucasian woman developed proteinuria and hypertension. Nine years earlier, she had been diagnosed with breast cancer treated with lumpectomy, radiotherapy and chemotherapy without evidence of recurrence. Two years later, she was diagnosed with osteoporosis and started on alendronate sodium 10 mg once daily for 3 years followed by 70 mg once weekly for 4 years and calcium plus vitamin D supplements. Other medications were multivitamins, primrose oil and venlafaxine for hot flushes. She had no other significant past medical history. Blood pressure was 160/90 mmHg, with ankle oedema present. Serum creatinine was 106 mmol/dl with proteinuria of 10 g/day. HIV infection and viral hepatitis were ruled out. Computed tomography of the head, chest, abdomen and pelvis was negative for malignancy or metastatic disease. A renal biopsy contained 36 glomeruli present, none of which were globally sclerotic. Few glomeruli demonstrated mesangial hypercellularity with segmental areas of sclerosis with hyperplasia of visceral epithelial cells (podocytes) (Figure ​(Figure1).1). A background of chronic interstitial inflammation and interstitial fibrosis was present. IgA, IgM, C3 and C1q were demonstrated on immunofluorescence in a globular segmental distribution. Electron microscopy supported this impression of FSGS with diffuse podocyte foot process effacement without immune-complex-type deposits (Figure ​(Figure2).2). Alendronate was discontinued, and prednisone 1 mg/kg/day and lisinopril were started. Six weeks later, she went into partial remission (proteinuria 1.1 g/day). Fig. 1 PAS stain (400× magnification)—glomerulus with focal segmental sclerosis in the upper-left aspect of the glomerulus associated with visceral epithelial cell hyperplasia. Fig. 2 Electron photomicrograph (2000×)—diffuse foot process effacement with villous transformation of epithelial cell cytoplasm. Alendronate has an estimated terminal half-life in bone of >10 years, and only ∼50% of a systemic dose is excreted unchanged in the urine within 3 days. Long-term drug excretion may cause renal toxicity through disruption of the podocyte cytoskeleton, a mechanism similar to that described in osteoclasts [2]. This beneficial effect of bisphosphonates on bone resorption has led to extensive use in several bone diseases. Pamidronate that is structurally almost identical to alendronate has been linked to FSGS. Studies in primary and recurrent FSGS implicate podocyte injury [3] and increased production of T-cell-derived lymphokines or ‘permeability factors’ [4] in the pathogenesis of segmental glomerular scarring. Drug dose and duration of treatment may influence the patient susceptibility to injury [5]. Our patient was on the recommended dose of alendronate but for an extensive period of time (∼7 years). This case suggests that alendronate, like pamidronate, may as well cause FSGS. While ‘primary’ or ‘idiopathic’ FSGS can obviously not be excluded, this entity is more commonly seen in young adults, males and Afro-American individuals. We recommend frequent monitoring of urine protein excretion and renal function for early detection of renal injury. Conflict of interest statement. None declared.