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Melanocytic nevus rests in lymph nodes are a known diagnostic challenge, especially in patients with a history of melanoma. Reticulin and NM23 have been studied in this context. The pattern of reticulin staining in melanomas surrounds groups/nests of melanocytes but individual cells in benign nevi. NM23, a metastasis-suppressor gene, has an association with metastatic potential in melanomas and some carcinomas. Twenty-eight cases (14 cases of metastatic melanoma to lymph nodes and 14 cases of lymph node nevus rests, all confirmed with Melan-A staining) were stained with reticulin and NM23. The pattern of reticulin staining was reported as surrounding groups if staining was noted in approximately 5-10 melanocytes in greater than 50% of the lesion but was otherwise reported as surrounding individual melanocytes. Cytoplasmic staining was considered to represent reactivity for NM23. Reticulin staining around groups of melanocytes was identified in all 14 cases of metastatic melanoma. Regarding nodal nevus rest cases, 12 of 14 cases (86%) demonstrated staining around individual melanocytes, whereas in 2 cases, reticulin surrounded melanocytic groups. NM23 staining was equivocal in all cases. Reticulin staining reliably invests groups of melanocytes in cases of metastatic melanoma, whereas in nodal nevus rests, it predominantly surrounds individual melanocytes. NM23 demonstrated no discriminatory value in this analysis. In cases in which a collection of melanocytes is present within a lymph node, reticulin deposition around individual melanocytes supports a diagnosis of lymph nodal nevus rest.

Histochemistry has an interesting history, extending back to ancient times, in some ways. Man has long had a desire to understand the workings of the human body and the roles that various "humors" or chemicals have in those processes. This review traces the evolution of histochemistry as an investigative and diagnostic discipline, beginning with the efforts of medicinal chemists and extending through a period in which histology was increasingly paired with biochemistry. Those developments served as the underpinnings for an eventual marriage of microscopy, chemistry, immunology, and molecular biology, as realized in the current practice of anatomical pathology., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Context: Contrary to the intuitive impressions of many pathologists, several areas exist in laboratory medicine where evidence-based medicine (EBM) principles are not applied. These include aspects of both anatomic and clinical pathology. Some non-EBM practices are perpetuated by clinical "consumers" of laboratory services because of inadequate education, habit, or overreliance on empirical factors. Other faulty procedures are driven by pathologists themselves., Objectives: To consider (1) several selected problem areas representing non-EBM practices in laboratory medicine; such examples include ideas and techniques that concern metastatic malignancies, "targeted" oncologic therapy, general laboratory testing and data utilization, evaluation of selected coagulation defects, administration of blood products, and analysis of hepatic iron-overload syndromes; and (2) EBM principles as methods for remediation of deficiencies in hospital pathology, and implements for the construction of "quality" practices in our specialty., Data Sources: Current English literature relating to evidence-based principles in pathology and laboratory medicine, as well as the authors' experience., Conclusions: Evidence-based medicine holds the promise of optimizing laboratory services to produce "quality" practices in pathology. It will also be a key to restraining the overall cost of health care.

CD10 is a cell surface-related neutral endopeptidase that is involved in cleaving cytokine peptides; it may also play a role in the proliferation of tumor cells and their acquisition of invasiveness. On account of its association with other overtly epithelial neoplasms, we hypothesized that CD10 might be preferentially expressed in the sarcoma-like components of sarcomatoid carcinomas as compared with true sarcomas. Immunohistochemical labeling for CD10 was assessed in various sarcomas and sarcomatoid carcinomas. An aggregate score was generated using both the intensity and extent of staining throughout the neoplasms. Overall, CD10 was expressed more often in true sarcomas (27 of 33 cases) as contrasted with sarcomatoid carcinomas (22 of 34 cases), but with no statistically significant difference between the 2 groups. Uterine "carcinosarcomas" expressed CD10 with accentuation in periglandular tumor cells. The sarcoma-like components in squamous cell carcinoma of the respiratory tract (larynx and lung), tongue, bladder, skin, and penis also expressed CD10 consistently. In the final analysis, there was no difference in CD10 expression between sarcomatoid carcinomas and true sarcomas. This marker seems to have little, if any, differential diagnostic value in the specified histopathologic context.

Transducer-like enhancer of split 1 (TLE1) is overexpressed in synovial sarcomas. We investigated TLE1 expression by immunohistochemical analysis in a well-characterized series of synovial sarcomas and other mesenchymal tumors most commonly considered in the differential diagnosis. Whole tissue sections of 212 tumors were evaluated: 73 synovial sarcomas (23 biphasic, 28 monophasic, 22 poorly differentiated), 47 malignant peripheral nerve sheath tumors (MPNSTs), 49 solitary fibrous tumors (SFTs), 20 fibrosarcomatous variants of dermatofibrosarcoma protuberans, and 23 Ewing sarcomas/primitive neuroectodermal tumors (PNETs). All monophasic and poorly differentiated SSs and Ewing sarcoma/PNETs were previously confirmed to harbor t(X;18) and EWSR1 gene rearrangements, respectively. In total, 60 (82%) of 73 synovial sarcomas were positive for TLE1, including 18 biphasic (78%), 22 monophasic (79%), and 20 poorly differentiated (91%) tumors. Of the other tumors, only 7 MPNSTs (15%) and 4 SFTs (8%) were positive for TLE1, most of which showed only weak staining. TLE1 is a sensitive and specific marker for synovial sarcoma and can be helpful to distinguish synovial sarcoma from histologic mimics, particularly if moderate or strong staining is observed. In this study, only a small subset of MPNSTs and SFTs showed limited staining for TLE1.

Fabry disease is an X-linked recessive lysosomal storage disease caused by a deficiency of α-galactosidase A, with characteristic ultrastructural cytoplasmic myelin-like inclusions. Renal lesions are seen in male and variably in heterozygous female patients. One previous report has described Fabry disease involving a renal allograft from a deceased female donor with no history of Fabry disease. The authors describe another case, in which suspicion for Fabry disease was raised ultrastructurally. This serves as a reminder that proteinuria after renal transplantation may be due to donor-derived disease. Fabry disease is probably an underrecognized cause of graft dysfunction. This case provides further justification for ultrastructural examination of renal allograft biopsies.

Multicentric reticulohistiocytosis (MR) is a rare non-Langerhans histiocytosis that is characterized by cutaneous nodules and severe destructive arthritis. Although 25-30% of reported cases have been associated with internal malignancies, the pathophysiology of MR is unknown. Herein, we report two cases of MR that were associated with urologic neoplasms. Because the tumor suppressor gene p53 may play a role in the biology of other histiocytoses, we investigated its p53 immunoexpression in these two cases. Both cases were positive immunohistochemically, but it remains to be seen whether this finding is truly important in the pathogenesis of MR associated with underlying visceral neoplasms., (Copyright © 2010 John Wiley & Sons A/S.)

Two of the most challenging areas in dermatopathology are lymphoproliferative disorders and melanocytic lesions. We present a case of peripheral T-cell lymphoma occurring with an intradermal melanocytic proliferation. A 63-year-old Caucasian man presented with a 12-cm edematous, erythematous to violaceous, scalp ulceration that had enlarged over six months. Previous biopsies showed reactive changes which were concerning for infection. The last biopsies showed small to intermediate sized, angulated cells with clear cytoplasm within the dermis, with extension into the epidermis. These cells stained positive with markers for CD3, CD45RO and CD43, yet showed decreased expression of pan-T-cell markers CD5 and CD7, and absent expression of CD4, CD8, CD56 and CD57 and EBV. Molecular studies showed a clonal T-cell receptor gamma chain gene rearrangement. The diagnosis was peripheral T-cell lymphoma, unspecified. Another biopsy from an indurated area separate from the ulcer showed scattered, enlarged cells embedded in the same lymphocytic infiltrate. No mitotic figures were identified. These cells stained for S100 and Melan-A, in a partly nested arrangement. This was felt to represent a melanocytic nevus. This case likely represents an extraordinary coincidence of two distinctly different neoplasms., (Copyright © 2009 John Wiley & Sons A/S.)

Proximal epithelioid sarcoma is an extremely uncommon lesion of the vulva, with the potential for aggressive behavior. We report a case of this entity and discuss its relationship to the epithelial-type "malignant rhabdoid tumor" (MRT) of the soft tissue. On the basis of a review of the pertinent information on both these entities, it is concluded that they likely represent biologically different but morphologically and immunohistochemically similar neoplasms. Both proximal epithelioid sarcoma and MRT comprise epithelioid cells with densely eosinophilic cytoplasmic inclusions, and they each lack the INI1 gene product. Nevertheless, the literature suggests that other selected genetic differences between the 2 lesions, and the more rapid and aggressive course of MRT distinguish these tumor types as separate clinicopathologic entities.

Liesegang rings represent an in vivo chemical precipitation phenomenon representing a potential diagnostic pitfall for misdiagnosis as parasitic infections. These acellular patterns of lamellar concretions are rare in human tissue. The authors report a case of Liesegang rings observed within an intradermal apocrine hidrocystoma and review the literature for reports of these structures, with particular emphasis on mucocutaneous lesions.

Background: Atypical fibroxanthoma (AFX) is a pleomorphic spindle cell lesion of the skin; it is considered in the differential diagnosis with spindle cell malignant melanoma (MM) and sarcomatoid carcinoma/spindle cell squamous cell carcinoma (SCC). An optimum approach has yet to fully emerge with respect to the immunohistochemical discrimination of these lesions., Methods: Departmental archives from 1978 onwards were searched for clinicopathologically confirmed cases of AFX, MM and SCC. Immunostains for CD10, CD99 and p63 were performed in each case. Scored staining results were analyzed using Fisher's Exact Test., Results: Twenty-seven of 31 cases of AFX were positive for CD10, as compared with 3 of 22 SCCs and 0 of 20 MMs. CD10 positivity was preferentially associated with the diagnosis of AFX (p < 0.001). p63 reactivity was observed in 15/22 cases of SCCs, 5/31 AFXs and 1/20 MMs. CD99 reactivity was observed in 3/31 cases of AFX, 2/22 SCCs and 3/20 MMs., Conclusion: CD10 positivity is relatively specific in this context for the diagnosis of AFX. Its utility is enhanced when only strong, diffuse membranocytoplasmic staining is considered as a positive result. In contrast to prior reports, p63 was not found to be highly sensitive for SCC. Similarly, CD99 showed no preferential staining of any single diagnostic group of lesions.

The mucosal surfaces represent the third most common site of origin for melanoma, after the skin and ocular uveal tract. However, anorectal mucosal melanoma is a rare neoplasm, usually occurring in the sixth and seventh decades of life. It may often be confused clinically with other pathologic entities, such as prolapsed rectal polyps and hemorrhoids. The prognosis of anorectal melanoma is poor; this is at least in part attributable to the relatively large size that such tumors have frequently achieved at presentation, as well as their rich vascular network. In particular, anorectal melanoma in children and adolescents is extraordinarily uncommon. The authors herein report 2 examples of that tumor in 11-year-old and 19-year-old patients; one was alive and tumor-free after 6 years, whereas the other died with osseous and hepatic metastasis at the same time point. The authors emphasize the need for differential diagnostic inclusion of melanocytic malignancies when considering anorectal masses in pediatric individuals. Systematic collation and evaluation of pediatric melanomas of the anus and rectum are needed, to better define the biologic attributes of those neoplasms., (Copyright 2010. Published by Elsevier Inc.)

Background: In 1952, Zoon described a series of patients with dense plasma-cell infiltrates in the glans penis. Since then, similar Zoon-like lesions (ZLL) have been described on the external female genitalia and in the airways, for which over 20 designations currently exist., Methods: Twenty-eight cases of ZLL, twenty-two cases of lichen planus, eight cases of plasmacytoma and two cases of syphilis were evaluated from the surgical pathology archive at the University of Virginia. Twenty-four histologic data points were tabulated in each case, including 12 epidermal and 12 dermal features., Results: Histopathologic findings were similar in the majority of cases of ZLL, regardless of their location. They demonstrated superficial cutaneous erosions, basal vacuolar alteration and many showed lozenge-shaped keratinocytes in the epiderms. The dermis contained a dense inflammatory infiltrate composed predominantly of plasma cells, with scattered neutrophils and lymphocytes. Dense fibrosis was seen in the upper dermis., Conclusions: A uniform nomenclature for ZLL does not exist. Based on the results of this analysis, we suggest that the generic term idiopathic lymphoplasmacellular mucositis-dermatitis be considered to encompass the lymphoplasmacellular infiltrates in the skin and mucosal surfaces considered herein. This designation is morphologically descriptive and can be applied regardless of anatomic location.

Asbestosis has long been defined as a diffuse interstitial "fibrotic" process, in similarity to other chronic interstitial pulmonary diseases. To address the hypothesis (which was based on morphological nuances) that the interstitial connective tissue response in asbestosis may be fibroelastotic rather than fibrotic, a comparative characterization of the connective response in cases of asbestosis and other forms of interstitial lung disease was performed. Archival open lung biopsies or autopsy specimens of pulmonary diseases featuring interstitial connective tissue abnormalities (15 of asbestosis, 21 of organizing pneumonia, 15 usual interstitial pneumonitis/idiopathic pulmonary fibrosis [IPF], 9 organizing diffuse alveolar damage, 9 "nonspecific" interstitial pneumonitis, 4 sarcoidosis, 3 each of desquamative interstitial pneumonia and chronic amiodarone toxicity, 2 cryptogenic organizing pneumonias, and 1 each of chronic hypersensitivity pneumonitis and chronic eosinophilic pneumonitis [85 total]) were stained histochemically with hematoxylin and eosin, Perl's method, Gomori's trichrome procedure, and the Verhoeff-van Gieson technique. Representative subsets of the cases (n = 20) were also studied immunohistologically using an antibody to elastin. Fibroelastosis in each of the samples was assessed for the degree of response and its location using a 3-tiered scale. The degree of fibroelastosis in the 15 cases of asbestosis was variable, with the pattern being peribronchial and perivascular in all instances; at least 2 asbestos bodies were identified in fibroelastotic foci in each of the 15 cases as highlighted with Perl's stain. Forty-seven cases of nonasbestotic lung disease (71%) showed interstitial fibrosis with a variable (usually modest) amount of admixed elastic tissue; when present, elastic fibers were distributed in a diffuse interstitial pattern, with or without perivascular accentuation. All cases of IPF also showed areas of fibroelastosis, but those foci were confined to regions of overt "honeycomb" change. No asbestos bodies were seen in any disease except asbestosis, and a predominantly peribronchial pattern of fibroelastosis was not identified in any nonasbestotic interstitial lung disease in this study. The authors conclude that the types and patterns of pulmonary connective tissue response in interstitial lung diseases may provide additional diagnostic clues to the presence of asbestosis.

Objective: Esophageal cancer tumor biology is best assessed clinically by 2-[18F]fluoro-2-deoxy-d-glucose (FDG)-PET. Both FDG-PET maximal positron emission tomography (PET) standardized uptake values (SUVmax) and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in esophageal cancer. Interestingly, there is limited data examining the relationship between FDG-PET SUVmax and expression of these tumor markers in esophageal cancer. The purpose of this study was to determine the correlation of tumor markers with FDG-PET SUVmax in esophageal cancer., Methods: FDG-PET SUVmax was calculated in 67 patients with esophageal cancer of which 59 (88%) had adenocarcinoma. Neoadjuvant radiotherapy and/or chemotherapy were administered to 42% (28/67) of patients. Esophageal tumor tissue and surrounding normal tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for five known esophageal cancer tumor markers (GLUT-1, p53, cyclin D1, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF)). Assessment of each tumor marker was made by two independent, blinded pathologists using common grading criteria of intensity and percentage of cells stained. A p value <0.05 was considered significant., Results: There were 55 men (82%) and 12 women (18%) with a median age of 63 years (range 40-83). Pathologic staging included stage I (n=29, 43%), stage II (n=19, 28%), stage III disease (n=18, 27%), and stage IV disease (n=1, 2%). PET SUVmax correlated with T stage (p=0.001). In patients undergoing surgery without induction therapy, increasing SUVmax values correlated with increased expression of GLUT-1 transporter (p=0.01). There was no correlation between SUVmax and EGFR, cyclin D1, VEGF, or p53 expression in primary tumor., Conclusions: FDG-PET SUVmax correlates with an increased expression of GLUT-1 transporter in esophageal cancer specimens not subjected to induction therapy. No significant difference in tumor marker expression was noted between patients undergoing induction therapy or surgery alone except p53 expression decreased in primary tumors following induction therapy. Failure of SUVmax values to correlate with known prognostic esophageal cancer tumor markers suggests that FDG-PET may have limited clinical utility in assessing response to therapies targeting these markers.

Neuroendocrine carcinomas represent an important group of primary neoplasms in the lung. During the last decades, the nomenclature of these tumors has evolved and the current use of immunohistochemical and molecular biology studies have, to some extent, expanded the conventional view of these tumors. However, the primary diagnosis of most of these lesions is performed on limited biopsy specimens, which may not translate well when one is confronted with a nomenclature that is based on resected material. In addition, for some of these specific entities, some confusion and controversy apparently remain, allowing for the proliferations of different terms that, although they may be dismissed as "semantics," may have a role in interpretation, further subclassification, and, possibly, treatment. Herein we review current concepts regarding the classification of these neoplasms and the role of this classification in our daily practice and discuss how it may impact treatment.

Objective: The best current noninvasive surrogate for tumor biology is fluorodeoxyglucose positron emission tomography (FDG-PET). Both FDG-PET maximal standardized uptake values and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in non-small cell lung cancer (NSCLC). However, there are limited data correlating FDG-PET with tumor markers. The purpose of this study was to determine the correlation of tumor marker expression with FDG-PET maximal standardized uptake values in NSCLC., Methods: FDG-PET maximal standardized uptake values were calculated in patients with NSCLC (n = 149). No patient had induction chemoradiotherapy. Intraoperative NSCLC tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for 5 known NSCLC tumor markers (glucose transporter 1, p53, cyclin D1, epidermal growth factor receptor, and vascular endothelial growth factor). Each tumor marker was assessed independently by two pathologists using common grading criteria. Subgroup analysis based on histologic characteristics and regional nodal status was performed., Results: FDG-PET correlated with T classification (P < .0001), N stage (P = .002), and greatest tumor dimension (P < .0001). In addition, increasing maximal standardized uptake values correlated with increased expression of glucose transporter 1 (P < .0001) and p53 (P = .04) in adenocarcinoma. Epidermal growth factor receptor expression correlated with maximal standardized uptake values without predilection for histologic subtype (P = .004)., Conclusion: FDG-PET maximal standardized uptake values correlate with an increased expression of glucose transporter 1 and p53 in lung adenocarcinoma, but not squamous cell cancer. Future studies attempting to correlate FDG-PET with tumor biology will need to consider the effect of different tumor histologic types.

Three cases of cutaneous pseudosarcomatous polyp, a lesion recently described in the dermatopathology literature, are reported here. These benign proliferations display dramatic cytologic pleomorphism, but despite their disquieting morphological features, they have behaved in a benign fashion to date. All 3 lesions in this study were clinically innocuous, with 1 having been present for 1 year and another for 2 years. The first lesion arose on the back of a 30-year-old man, the second on the nasal columella of a 65-year-old woman, and the third on the back of a 91-year-old woman. All 3 had the typical architecture of a fibroepithelial polyp (acrochordon) with widely separated stellate cells occupying a myxoid to collagenous stroma. Markedly pleomorphic stellate cells were widely dispersed, with an increased density of atypical cells beneath the epidermis and in small foci of adipose tissue in 1 case. Multinucleated cells, some with a floret-type configuration, were also observed. One of the polyps demonstrated focal mild hyalinization of vessel walls. Only rare mitotic figures were identified in 2 cases, but 1 showed atypical forms. Immunohistochemically, the atypical cells reacted diffusely for vimentin and variably for CD34 and factor XIIIa, but they lacked smooth muscle actin and desmin. Cutaneous pseudosarcomatous polyps can be added to the list of pathologic entities with symplastic or pseudomalignant features.

CD34-positive stromal cells (CD34SC) are distributed throughout the body, including the dermis. They are thought to play a role in maturation and proliferation of adjacent mesenchymal and epithelial stem cells and in immune responses. To investigate the role of such cells in wound healing after excision of cutaneous lesions, we examined the distribution and quantity of CD34SC in scars from the sites of removal of malignant skin tumors and from reconstructive surgery, as well as in samples of normal skin. In normal skin, CD34 staining was confined to dendritic cells in the dermis, endothelial cells, perifollicular cells and eccrine glands. In cutaneous scars, the cicatricial tissue was totally devoid of CD34SC. However, the dermis adjacent to scar showed increased numbers of CD34SC as compared with normal skin [41.5 cells/mm(2) vs. 24.5 cells/mm(2) (p < 0.001)]. We conclude that CD34SC disappears from scars but are induced to proliferate in pericicatricial tissue. The cells in question may play a role in remodeling of scarred skin. One should be aware that augmented labeling for CD34SC around scars is common; it should not be interpreted as evidence for the persistence or recurrence of tumors that may also express CD34.

Olfactory neuroblastoma (ONB) is a rare neoplasm of the head and neck region that is included in the differential diagnosis of other sinonasal tract malignancies. We studied the usefulness of using p63 as an aid in the diagnosis of ONB and other tumors of the sinonasal region. The specimens were 14 ONBs; 4 nasopharyngeal carcinomas (NPCs), nonkeratinizing subtype; 2 NPCs, undifferentiated subtype; 10 sinonasal undifferentiated carcinomas (SNUCs); 7 malignant melanomas; and 2 extranodal natural killer (NK)/T-cell lymphomas. We observed p63 expression in 5 ONBs (36%), 4 nonkeratinizing NPCs (100%), 1 undifferentiated NPC (50%), 2 SNUCs (20%); 0 malignant melanomas (0%); and 1 extranodal NK/T-cell lymphoma (50%). While all cases of NPC with positive staining for p63 showed strong and diffuse immunoreactivity, the ONB, SNUC, and lymphoma cases with positive immunoreactivity showed only focal staining for p63. No p63 expression was observed in malignant melanoma. We think p63 is a useful marker to help distinguish nonkeratinizing or undifferentiated NPC subtypes from various sinonasal tract malignancies. In particular, p63 helps distinguish nonkeratinizing and undifferentiated NPC subtypes from SNUC.

The prognosis of thymic epithelial tumors depends on their separation into thymoma and thymic carcinoma, as well as the extent to which they involve adjacent tissues and organs. To formalize evaluations of the latter attribute, several staging systems have been developed over the past 30 years. These include the Masaoka, Bergh, Wilkins-Castleman, Groupe d'Etudes des Tumeurs Thymiques, and tumor-nodal-metastasis schemes. The first of those formulations is most commonly employed in clinical practice, at least in the United States. The author believes that surgical-pathologic staging is the most powerful and reliable prognosticator for thymoma, as compared with histologic subtype-related prediction of behavior for that tumor type. Those topics, as well as affiliated issues concerning tissue sampling and staging techniques, are discussed in this article.

Undifferentiated malignant neoplasms are a daunting diagnostic problem for anatomical pathologists, calling for a tour de force in morphological skill, clinicopathologic correlation, and application of adjunctive laboratory studies. The most useful approach to these lesions begins with generic classification into 1 of 4 histologic categories: small round cell; spindle cell; large polygonal cell (epithelioid); and pleomorphic neoplasms. Once that step has been accomplished, one can systemically apply corresponding groups of antibody reagents in immunohistologic studies and interpret the results in an algorithmic fashion. This review presents the tumor markers that are the most useful in this contextual approach, as well as the specific algorithmic structures that can be applied to the 4 specified tumor groups. Other selected problems in the diagnosis of morphologically ambiguous tumors are considered as well.

Pulmonary cytology has progressed over the past decades because of advancement in imaging studies and increased confidence of pathologists in cytomorphologic diagnosis. It has an overall sensitivity and specificity ranging from approximately 60 to 96%. However, even with the most conscientious laboratories, false-positive diagnoses of malignancy do occur in respiratory specimens, potentially resulting in unnecessary treatment and morbidity. Selected respiratory cytopathology cases with false-positive diagnoses are presented here, along with a review of pertinent literature and a discussion of possible steps to minimize the problem being considered.

Immunohistochemistry using a broad panel of markers is an invaluable tool for diagnosing sarcomatoid mesothelioma. Membranous podoplanin staining has been proposed as a specific and sensitive marker to distinguish epithelioid mesothelioma from adenocarcinoma. We found that cytoplasmic podoplanin staining was present in sarcomatoid mesotheliomas, and wanted to explore the reproducibility and specificity of this staining pattern. Immunohistochemistry for podoplanin, using 2 podoplanin antibodies (antipodoplanin and D2-40), was performed in 55 mesotheliomas (24 epithelioid, 18 sarcomatoid, and 13 biphasic), 80 pulmonary adenocarcinomas, 8 synovial sarcomas, and 16 sarcomatoid carcinomas. Expression of calretinin, vimentin, MOC31, and TTF-1 was also examined in all adenocarcinomas, sarcomatoid carcinomas, 7 synovial sarcomas, and 21 of the mesotheliomas. Calretinin staining performed previously on an additional 31 mesotheliomas was reviewed. Using membranous or cytoplasmic staining as indicative of positivity, we found that antipodoplanin and D2-40 each stained 84% of mesotheliomas (antipodoplanin: 46/55; D2-40: 38/44), including 72% of sarcomatoid mesotheliomas (antipodoplanin: 13/18; D2-40: 11/14). With antipodoplanin antibody, no staining was seen in the pulmonary adenocarcinomas (0/80, 0%) or the synovial sarcomas (0/8, 0%), and weak cytoplasmic staining was seen in only 1 sarcomatoid carcinoma (1/15, 7%). D2-40 showed similar results, staining 3% (2/80) of pulmonary adenocarcinomas, 13% (1/8) of synovial sarcomas, and 8% (1/13) of sarcomatoid carcinomas. Overall sensitivities and specificities were 84% and 99% for antipodoplanin, and 86% and 96% for D2-40. These findings suggest that cytoplasmic podoplanin expression may be useful in the diagnosis of sarcomatoid mesothelioma, although it should be used with caution on biopsy material.

Solitary fibrous tumor (SFT) is a relatively uncommon neoplasm that most commonly arises in the pleura. However, SFT is now known to affect various other anatomic sites as well, including rare examples in the skin, where the histologic features of this lesion may create diagnostic confusion with a variety of other spindle-cell tumors. In order to further the characterization of cutaneous SFT, all available cases of that entity were retrieved from the authors' institutional files. Immunohistochemical analysis for CD-34, CD-99, vimentin, bcl-2, factor XIIIa, S100 protein, smooth muscle actin, pankeratin, epithelial membrane antigen (EMA) and desmin was performed on those neoplasms and the corresponding clinical information was obtained whenever possible. There were eight men and two women in the study group, with a median age of 43 years. Sites of involvement included the trunk (two cases), cheek (two), scalp (one), forehead (one), lip (one), temple (one), heel (one) and toe (one). All patients were treated with local excision; only one lesion recurred locally, but it required multiple re-excisions. All of the neoplasms were composed of bland spindle cells with a variably fibrous but focally hyalinized collagenous stroma. A variety of case-specific growth patterns were observed. Mitoses were generally rare, ranging from 0 to 3 per 10 x400 microscopic fields. Immunostains showed reactivity for vimentin in all SFTs, CD-34 in 8 of 10 cases, CD-99 and bcl-2 in 4 of 10 (each) and smooth-muscle actin in 3 of 10 cases. None of the lesions was labeled for factor XIIIa, keratin, EMA, desmin or S100 protein. SFT of the skin appears to be a 'borderline' neoplasm that only uncommonly recurs. Immunoreactivity for CD-34, - especially together with bcl-2 or CD-99, or both - is helpful in identifying this tumor.

The histopathologic distinction between pigmented actinic keratosis (PAK) and atypical junctional melanocytic proliferations (AJMP) is a common problem, and it is one with meaningful clinical significance. Previous publications have suggested that Melanocyte Antigen Related to T-cells-1 (MART-1)--a melanocytic marker related to host immune response--was not useful in making this interpretative separation. To revisit that assertion, the authors selected 68 specimens that concerned the diagnosis of PAK vs. AJMP. The degree of morphologic difficulty attached to each case was rated semiquantitatively using a three-tiered scale, and interpretative problems were caused by cytologic similarity between atypical keratinocytes and aberrant melanocytes, obscuring lichenoid inflammation, subepidermal fibrosis, and an absence of clearly defined cell nests at the dermoepidermal junction. Each biopsy sample was immunostained for MART-1 (using antibody clone A103) with azure-B counterstaining; the principal criterion for a diagnosis of AJMP was that of confluent cellular positivity over at least 1 high-power (x400) microscopic field, in conjunction with nested cell growth. The specimens were then re-examined diagnostically. Immunostaining definitely improved interpretative certitude in 65 examples (96% effectiveness); the final diagnosis was that of PAK for 21 lesions and AJMP for 47. Three specimens--all of which represented AJMP--did not benefit by MART-1 staining. It is concluded that MART-1 immunostaining with azure-B counterstaining is a useful adjunct in the interpretation of problematic intra-epidermal pigmented lesions.

There are no firmly established guidelines for the use of antibodies in immunohistology as individual tests or panels. Practicing pathologists must rely on information available in individual publications, review articles, books, and internet-based databases to develop diagnostic immunohistochemical algorithms for their individual practices. In contrast, other medical specialties have crafted many evidence-based practice guidelines (EBG) that are widely used; these have helped to augment standardization and cost effectiveness. In particular, the use of several "epithelial" and "mesothelial" antibodies has been proposed to distinguish epithelioid malignant mesothelioma from metastatic pulmonary adenocarcinoma. Other authors have previously done systematic literature reviews of this subject up through 2004 and integrated the results of 88 publications into summarized test-performance values for 15 preselected immunohistochemical markers. The results suggested that 7 tests provide optimal sensitivity and specificity (MOC-31, BG8, CEA, TTF-1, CK5/6, WT-1, and HBME-1), but they provide no guidance for integration of such data into EBG. Odds ratios (ORs) were employed to compare the effectiveness of any single test, and chosen combinations thereof, in the differential diagnosis of malignant mesothelioma and metastatic pulmonary adenocarcinoma. Surprisingly, selected single immunostains or antibody pairs yielded ORs (varying from 96.34 to 1233.19) that were equal or better in efficacy when compared with more comprehensive panels. These results support the potential value of systematic reviews, meta-analysis, and OR calculations for development of EBG in diagnostic immunohistology.

Oculocutaneous oncocytic tumors (OCOTs) are uncommon neoplasms that have been reported only rarely in the dermatopathology literature and whose immunophenotypic profile has not been well characterized. The clinical, histologic, and immunophenotypic features of 2 cases seen by the authors were assessed, and relevant publications in the literature were reviewed. Both patients with OCOTs were adult women with gradually enlarging, asymptomatic lesions involving the caruncle; they were locally excised. Histologically, the tumors were well-circumscribed nodules comprised of large oxyphilic cells arranged in confluent sheets and forming glandular spaces with secretory material. Microcystic areas and sparse intermingled goblet-cells were also apparent. Nuclear atypia and infiltrative growth were absent. Mitotic activity was absent in one case; a single mitotic figure was identified in the other. Immunostains demonstrated uniform expression of pankeratin and mitochondrial antigens. Both neoplasms were also labeled for markers associated with cutaneous adnexal, lacrimal, and minor salivary glandular tissue, including alpha-1-antitrypsin, gross cystic disease fluid protein-15, carcinoembryonic antigen, lysozyme and MUC1; each case expressed 4 of the 5 substances. Some cells expressed cytokeratins 5/6 and p63 consistent with the presence of basal-type differentiation in a subset of cells. No definite evidence of myoepithelial differentiation was demonstrated, as stains for smooth muscle actin, muscle-specific actin, and S100 protein were negative. Estrogen and progesterone receptor proteins were absent; strong cytoplasmic immunoreactivity for androgen receptor protein was evident, but nuclear staining was absent. The authors conclude that OCOTs show glandular differentiation. A review of the literature disclosed that none of these lesions arising in the caruncle behaved aggressively, in contrast to occasional tumors in other oculocutaneous sites.

Malpractice actions against surgical pathologists are still relatively uncommon, but they have increased in frequency over time and are associated with sizable indemnity figures. This discussion categorizes areas of liability in surgical pathology into three groups: those that represent health system flaws (problems with specimen identification, or transportation, or both; lack of clinical information or erroneous information; sampling effects and defects; and poorly reproducible or poorly defined diagnostic or prognostic criteria), others that exist at the interface between the system and individuals (allowing clinicians to bypass pathologic review of referred specimens; acceding to clinical demands for inadvisable procedures; and working in a disruptive environment), and truly individual errors by pathologists (lapses in reasoning; deficiencies concerning continuity in the laboratory; invalid assumptions regarding recipients of surgical pathology reports; over-reliance on the results of "special" tests; and problems with peer consultation). Finally, two important topic areas are discussed that commonly enter into lawsuits filed against surgical pathologists; namely, "delay in diagnosis" of malignant neoplasms and "failure to provide adequate prognostic information." Based on a review of the pertinent literature, we conclude that the clinical courses of most common malignancies are not affected in a significant manner by delays in diagnosis. Moreover, the practice of using "personalized external validity" for supposedly prognostic tests is examined, with the resulting opinion that prognostication of tumor behavior in individual patients is not reliable using anything but anatomic staging systems.

One of the major goals of residency training is to prepare pathologists to communicate effectively in a variety of clinical settings. Well-educated pathologists are able to explain medical facts and offer cogent opinions to audiences that vary from other physicians to laypersons. As would be expected, there is an overlap between the skill-set required for medical communication and the skill-set necessary to participate effectively in malpractice litigation. However, residency curricula do not specifically prepare pathologists for the unique challenges posed by legal proceedings. The resulting lack of preparation may leave pathologists poorly prepared to be confronted by the "black-and-white" world in which attorneys try to live and work, but avoidance of that world is not always possible. Lawsuits against physicians are common, and even if the unpleasant experience of being sued is avoided, there is a high probability that one will, at least, be required to serve as a "fact witness" to provide sworn testimony if a suit has been filed against a physician colleague. In addition, some pathologists voluntarily provide the professional testimony required by the tort system, when it attempts to integrate science and Law. This paper is directed at pathologists who have had little or no prior experience with the legal system. The authors hope that the information provided therein will lessen physician vulnerability in and out of the courtroom, vis-à-vis malpractice litigation.

Medical malpractice suits are intensely anxiety-provoking for physicians, in part because of the foreignness of legal terminology and procedure that accompanies them. Consultations with attorneys in such matters may be confusing, and the sequence of necessary legal steps, after the filing of a complaint against the physician, can appear to be arcane and laborious. This brief discussion outlines the legal terminology and procedure that are part of any tort action--including malpractice--with the goal of reducing unfamiliarity with those elements on the part of physicians.

Physicians who become ensnarled in malpractice litigation often feel that the tort system has treated them unfairly. This negative perception has fueled physician efforts to enact "reforms" intended to mitigate the damage that allegations of medical negligence currently have on both individual physicians and on the practice of medicine itself. Although physicians are generally enthusiastic about "reform," there is currently no definition that allows tort "reform" to be separated from related initiatives. Some physicians largely restrict the term to defendant-friendly changes in the rules and procedures governing the workings of the tort system, whereas others take a somewhat broader view. In the present paper, we have favored the broader approach to the topic, leading to a discussion of 30 measures that have been presented in the context of tort "reform." Although most of these measures involve changes in the complex rules governing the malpractice tort system itself (eg, capping jury awarded damages), our broader view of "reform" also includes attempts to exert influence on the tort system from the outside (eg, peer review of expert testimony) and measures designed to keep patient dissatisfaction out of the tort system (eg, apology for error). Some would argue for an even broader view of tort "reform" that would including measures for reducing the pool of dissatisfied patients. For example, trial lawyers have claimed that physicians have put far too much effort into "reforms" that reduce the legal consequences of committing medical errors, and not enough effort into "reforms" that would reduce the errors themselves. The latter point may or may not have some validity, but there is a natural demarcation between measures designed to align medical outcomes with patient expectations (eg, error reduction, better diagnostic technology) and others designed to improve the processes that resolve patient dissatisfaction. Only the latter meet our definition of tort "reform."

An inevitable outcome of modern Medicine in any country is that some patients will experience adverse events, some of which would have been preventable. Different nations have developed various approaches to such cases; their legal efficacies are probably dissimilar and dependent on a number of disparate variables. An international "snapshot" of the results of the interacting forces can be obtained by asking physicians in several countries how they view selected subjective facets of their tort systems. In the U.S., many physicians view the structure of malpractice torts as unfair, and that belief is shared by at least some pathologists. The American Medical Association has declared that a multiregional malpractice "crisis" exists which raises medical costs and threatens access to care. Furthermore, malpractice tort decisions are often flawed scientifically because lay jurors and judges cannot properly evaluate the quality of "expert" testimony given by adversarial witnesses. Despite these factors, there has been little effort to investigate the views of pathologists on malpractice actions outside the U.S. In this paper, the authors have collected the responses of an international group of pathologists to a questionnaire on that topic. The respondents practice in academic centers in 15 countries outside the U.S. As expected, a range of views was represented, with some pathologists reporting that malpractice litigation was uncommon and others noting a worrisome trend toward its growth. Interestingly, so-called "defensive medicine" was found to be relatively common in pathology in many countries.

Context: Selected cutaneous neoplasms share features with benign counterparts or have subtle morphologic features that could be overlooked by the pathologist., Objective: To present clues to the diagnosis of potentially deceptive malignancies, including desmoplastic malignant melanoma, nevoid malignant melanoma, subcutaneous lymphoma, metastatic breast carcinoma, and epithelioid sarcoma., Data Sources: Published literature and personal experience., Conclusions: Knowledge of commonly misdiagnosed cutaneous neoplasms will help the general surgical pathologist avoid these potential pitfalls in neoplastic dermatopathology.

The specific parameters of nonoccupational asbestos exposures (NOAE) that can distinguish an idiopathic from an asbestos-caused malignant mesothelioma (MM) are controversial. A systematic literature review yielded 1028 cases with this putative association. Only 287 of those reports had a defined single exposure to a household, building occupant, or neighborhood/community asbestos source. The available "evidence" was used to develop semiarbitrary evidence-based causation guideline rules for the assessment of putative associations between MM and NOAE. The rules are classified into class A (tissue burden analysis shows asbestos body counts or fiber counts in lung tissues comparable to MM caused by occupational exposure to asbestos) and classes B to D based on whether certain combinations of NOAE features and MM (evidence) have been described in over 15% (class B), 5% to 15% (class C), and less than 5% (class D) of the patients reviewed. The proposed 4 classes of evidence-based causation guidelines provide a semiarbitrary framework to evaluate the causation of individual MM patients by NOAE based on decreasing levels of currently available evidence. The neoplasms in classes A to C patients are probably caused by NOAE, with decreasing weight of evidence in the 3 groups. There is minimal evidence to support the causation of MM by NOAE in class D patients. There is no evidence or only anecdotal evidence to support a causal association between MM and NOAE in individuals who cannot be classified into any of the 4 classes. Future studies are needed to provide more comprehensive data regarding the association between MM and NOAE.

Background: There is renewed interest in adjuvant chemotherapy after complete resection of nonsmall cell lung cancer, including stage IB (T2N0) cancers. Given the heterogeneity of the T2 classification, we hypothesize that there are survival differences in patients with stage IB NSCLC based on specific histopathologic tumor characteristics., Methods: A retrospective evaluation of 119 consecutive patients from 1999 to 2004 with a pathologic diagnosis of T2N0 nonsmall cell lung cancer was performed. Patient follow-up was 97%. Overall survival and disease-free survival rates were calculated by the Kaplan-Meier method. Univariate analysis was performed using the log rank test and multivariate analysis by Cox's proportional hazard model. Data were significant if p < 0.05., Results: The 4-year overall survival and disease-free survival rates were 62% and 60%, respectively. The local and distant recurrence rates were 5% and 18%, respectively. Tumor size (p = 0.001), histologic grade (p = 0.002), the Eastern Cooperative Oncology Group performance status (p = 0.002), angioinvasion (p = 0.03), and visceral pleural involvement (p = 0.02) were predictors of overall survival by univariate analysis. Multivariate analysis demonstrated increasing tumor size (1.26 [95% confidence intervals 1.12, 1.64]) and histologic grade (4.05 [95% confidence intervals 1.38, 11.90]) to be significant independent predictors of a worse overall survival. The 4-year survival of patients without any of these variables was 89% compared with 56% if one or more of these factors were present (p = 0.03)., Conclusions: There is significant heterogeneity in the T2N0 class of nonsmall cell lung cancer. Risk stratification using specific histopathologic variables may help determine which patients will benefit most from adjuvant therapy.