Richard N. Eisen

Thyroid transcription factor-1: a review.

Thyroid transcription factor-1 (TTF-1) is a 38-kd homeodomain containing DNA-binding protein originally identified in follicular cells of the thyroid and subsequently in pneumocytes. This review focuses on the utility of antisera in TTF-1 immunohistochemical staining in the diagnosis of neoplastic conditions. Based on published studies to date, anti-TTF-1 is a very useful reagent in distinguishing pulmonary adenocarcinoma from other primary carcinomas, identifying differentiated thyroid neoplasms, distinguishing mesothelioma from pulmonary adenocarcinoma, and distinguishing small cell carcinoma of the lung from Merkel cell carcinoma. It may also be useful in distinguishing neuroendocrine (NE) tumors of the lung from well-differentiated NE tumors from other sites, such as the intestine.

Consensus recommendations on estrogen receptor testing in breast cancer by immunohistochemistry.

Estrogen receptor (ER) status in breast cancer is currently the most important predictive biomarker that determines breast cancer prognosis after treatment with endocrine therapy. Although immunohistochemistry has been widely viewed as the gold standard methodology for ER testing in breast cancer, lack of standardized procedures, and lack of regulatory adherence to testing guidelines has resulted in high rates of “false-negative” results worldwide. Standardized testing is only possible after all aspects of ER testing—preanalytical, analytical, and postanalytical, have been closely controlled. A meeting of the “ad-hoc committee” of expert pathologists, technologists, and scientists, representing academic centers, reference laboratories, and various agencies, issued standardization testing recommendations, aimed at optimization of clinical ER testing environment, as a step toward improved standardized testing.

Immunohistochemical comparison of cutaneous lymphadenoma, trichoblastoma, and basal cell carcinoma: support for classification of lymphadenoma as a variant of trichoblastoma.

Cutaneous lymphadenoma is an uncommon basaloid epithelial tumor of uncertain histogenesis, most recently classified as a variant of trichoblastoma. Because characteristic immunohistochemical findings have been reported in trichoblastomas, we evaluated the staining patterns of five cutaneous lymphadenomas and compared the results to those of ten trichoblastomas and ten nodular basal cell carcinomas (BCCs), using antibodies to cytokeratin 20 (CK20), bcl‐2, and CD34. In addition, because lymphadenomas contain intraepithelial S100‐positive putative Langerhans cells, we compared staining of all tumor groups for S100 protein and CD1a. We also attempted to corroborate recent reports of CD30‐positive activated lymphocytes in lymphadenomas. We identified GK20‐positive Merkel cells in 3/5 lymphadenomas, 7/10 trichoblastomas, and none of the BCCs. Staining for bcl‐2 accentuated the peripheral epithelial layer in all lymphadenomas and in 3/10 trichoblastomas, while the remaining trichoblastomas and all BCCs stained diffusely. There was stromal staining with CD34 in two lymphadenoma, 4 trichoblastomas, and 3 BCCs. All lymphadenomas featured numerous intraepithelial S100‐positive cells which were also positive for CD1a in three cases tested. In addition, 8/10 trichoblastomas and 2/10 BCCs contained modest numbers of cells labelling for S100 and CD1a. Two of three lymphadenomas contained rare single cells resembling histiocytes faintly positive For CD30, and similar cells labelled for CD68. We conclude that the similar staining patterns of lymphadenomas and trichoblastomas support the classification of lymphadenoma as a variant of trichoblastoma. Staining with CD34 does not reliably distinguish between these tumors and BCCs. Lymphadenomas, trichoblastomas, and BCCs may all contain Langerhans’cells. The relationship between these cells and the striking lymphoid infiltrates seen in lymphadenomas is not clear. In our cases, the CD30‐positive cells in lymphadenomas appear to represent histiocytes rather than activated lymphocytes.

Bile-Induced Laryngitis: Is There a Basis in Evidence?

Most agree that bile reflux occurs with regularity in an otherwise healthy population and that biliary and acid reflux may play a synergistic role in damaging esophageal mucosa. But to what extent is laryngeal mucosa at risk? We constructed a saline-controlled rat model (n = 40) in which active component solutions of bile — taurocholic acid and chenodeoxycholic acid — were applied to intact laryngeal mucosa at various pH levels. Histologic sampling of the laryngeal mucosa allowed inflammation scores to be generated by a pathologist blinded to the solutions used. Both taurocholic acid at acid pH and chenodeoxycholic acid at basic pH preferentially induced statistically greater inflammation scores than did the saline control, approaching or exceeding inflammation scores attributed to hydrochloric acid at pH 1.2. These observations may clarify reasons for failure to uniformly control laryngeal injury by adequate suppression of gastric acid alone and may further justify alternative methods of laryngeal protection in patients refractory to adequate acid control.

Immunohistochemistry validation procedures and practices: a College of American Pathologists survey of 727 laboratories.

CONTEXT The immunohistochemistry (IHC) laboratory represents a dynamic area of surgical pathology with limited practice guidelines. Studies have shown significant interlaboratory variability in results. OBJECTIVE To establish baseline parameters for IHC validation procedures and practice, and to assess their feasibility of implementation. DESIGN In September 2010, a questionnaire was distributed by the College of American Pathologists. It was composed of 32 questions relating to nonpredictive assays as well as non-US Food and Drug Administration (non-FDA)-approved, predictive IHC assays other than human epidermal growth factor 2 (HER2/neu). RESULTS For non-FDA approved, nonpredictive IHC assays, 68% of laboratories had a written validation procedure. Eighty-six percent of laboratories validated the most recently introduced nonpredictive antibody. Seventy-five percent used 21 or fewer total cases for the validation and 40% used weakly or focally positive cases. Forty-six percent of respondents had a written procedure for validation procedures for non-FDA approved, predictive marker IHC assays other than HER2/neu. Seventy-five percent of laboratories validated the most recently introduced predictive antibody other than HER2/neu. Fewer than half used 25 or more cases for the validation, and 47% used weakly or focally positive cases. CONCLUSION Some laboratories have written validation procedures that appear to build upon HER2/neu testing guidelines. Some laboratories also manage to validate new antibodies according to those standards; however, many do not. There appears to be a need for further validation guideline development for nonpredictive and non-FDA approved predictive antibody IHC assays.

Renal Failure and Severe Hypokalemia Associated With Acute Myelomonocytic Leukemia

The leukemias have long been associated, albeit rarely, with the development of renal failure and several metabolic perturbations. While renal insufficiency may result from a variety of mechanisms in the setting of leukemia, severe leukostasis with microvascular insufficiency and renal parenchymal infiltration by blast cells are rare and infrequently described etiologies. In addition, hypokalemia can occur from lysozyme-induced renal tubular injury with inappropriate kaliuresis. We present a case of acute myelomonocytic leukemia that was complicated by renal failure and severe hypokalemia and discuss the probable mechanisms.

Infantile Hemangioendothelioma of the Pelvis Associated with Kasabach-merritt Syndrome

A case of infantile hemangioendothelioma of the pelvis in a newborn male infant is described. Shortly after delivery, a large abdominal mass was found by external examination. CT scan revealed a hypervascular retroperitoneal pelvic mass invading the lumbar spinal column. Exploratory laparotomy was performed and biopsy revealed infantile hemangioendothelioma. The tumor was associated with profound thrombocytopenia, intratumoral hemorrhage, and right hydroureteronephrosis. After treatment with high dose steroids, Cytoxan, and external beam radiation for 2 months, the patient was discharged with persistent thrombocytopenia requiring platelet transfusions. The hydroureteronephrosis has also not improved. The literature on this subject is reviewed.

Immunohistochemistry cocktails are here to stay: Center for Medicare and Medicaid Services should revise its new reimbursement policy

On January 1st, 2012, the Center for Medicare and Medicaid Services (CMS) implemented a policy in conjunction with the National Correct Coding Initiative (NCCI) to pay pathologists and laboratories for immunohistochemistry (IHC) cocktail stains as a single unit of Current Procedural Terminology (CPT) code 88342, regardless of how many individually interpretable antibodies are included in the cocktail. Medicare has, in the past, paid for IHC cocktail stains based on the American Medical Association’s prescription: 1 unit of CPT code 88342 was payable for each separately interpreted and reported antibody (eg, via unique color expression compared with other markers in the cocktail). Knowledgeable sources indicate that this new policy is a reaction by CMS to a dramatic increase in the number of IHC charges on physician and laboratory claims during the past 2 or 3 years. This period roughly corresponds to the observed proliferation of in-office and other histology laboratory arrangements entered into, particularly but not exclusively, by urologists and gastrointestinal practitioners. Overutilization of IHC stains—the application of diagnostic markers in medically suspect situations (eg, staining all of a patient’s biopsy specimens instead of just 1 or 2 tumor-rich samples, applying a stain to rule out a condition not suggested by the H&E slides)—by these physicians, and perhaps by a minority of overly aggressive pathologists as well, is a natural cause for alarm among government payers and private medical insurers alike. As taxpayers and as ethical practitioners of the medical arts, we are highly sympathetic to the goal of CMS and other parties to eliminate waste and abuse in the laboratory industry. Notwithstanding, it is the strong opinion of leaders in the field of IHC testing that the …

Uniform Labeling of Blocks and Slides in Surgical Pathology: Guideline From the College of American Pathologists Pathology and Laboratory Quality Center and the National Society for Histotechnology

CONTEXT The labeling of paraffin blocks and microscopic glass slides in the practice of surgical pathology varies from institution to institution and introduces potential risk of preanalytic error. Currently there are no evidence-based guidelines regarding the uniform labeling of these materials. OBJECTIVE To develop recommendations that will address the need for adequate patient identification and provide a consistent method of identifying slides originating from a particular block. DESIGN - The College of American Pathologists Pathology and Laboratory Quality Center and the National Society for Histotechnology convened a panel of pathologists and histotechnologists with expertise in histology laboratory quality practices to develop labeling recommendations. A systematic evidence review was conducted to address 6 main key questions. Recommendations were derived from strength of evidence, open comment feedback, and expert panel consensus. RESULTS Twelve guideline statements were established to assist pathology laboratories in developing standardized block and slide labeling practices. These guidelines call for the use of 2 patient identifiers, 1 of which includes the accession number and case type, on all paraffin blocks and slides. Recommendations were also developed to address the order and format in which identifying elements should appear. CONCLUSIONS Uniform labeling of paraffin blocks and slides derived from patient specimens will provide an important enhancement to patient safety by assuring that all preparations derived from a patients tissue can be uniquely and unambiguously linked to that patient. Adoption of standardized practices additionally will improve patient care by facilitating interpretation of histologic sections when they are referred in consultation to a second institution.

Fixation time does not affect expression of HER2/neu.

To the Editor We read with interest the article by Ibarra and colleagues1 reporting their findings on the effects of varying fixation times on HER2/neu immunohistochemical analysis. In this study, the authors studied 10 breast carcinoma excisional biopsy specimens with corresponding preexcision core biopsy specimens that showed HER2/neu overexpression (3+). The results showed a high level of HER2/neu expression at all fixation times studied (3, 48, 72, 96, and 120 hours). While the authors correctly identify this study as a pilot study, these experiments have at least 3 significant shortcomings that should be noted. First, the authors concluded that “formalin fixation time over wide intervals has little or no impact on the expression of routine prognostic markers.” It is not possible to reach this conclusion based on the presented data because cases with intermediate and low levels of expression (HER2/neu 1+ and 2+ cases) were not studied, as the authors subsequently note. In addition, confirmation of the immunohistochemical results by fluorescence in situ hybridization (FISH) would be …