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Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose.- To provide updated, practical guidelines for the pathologic diagnosis of MM.- Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks.- There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.

GATA3 is a transcription factor that is involved in the embryonic development of the parathyroid glands and in adult parathyroid cell proliferation. The aim of this study is to investigate the expression of GATA3 in parathyroid tumors and to determine whether it could be used as an immunohistochemical marker for parathyroid differentiation in tumors. Immunoreactivity for GATA3 was nuclear and was demonstrated in all 10 hyperplastic parathyroid glands, 22 parathyroid adenomas, and 6 parathyroid carcinomas; whereas, all thyroid tumors, renal cell carcinomas, thymic epithelial tumors, and carcinoid tumors investigated for comparison purposes were negative for this marker. It is concluded that GATA3 is a very sensitive and relatively specific immunohistochemical marker for parathyroid differentiation that can assist in the differential diagnosis of parathyroid tumors.

Calretinin is a member of the EF-hand family of calcium-binding proteins. Because its expression is highly restricted to mesotheliomas, calretinin is, at present, the most commonly used positive mesothelioma marker that is most often recommended to be included in the various immunohistochemical panels used to assist in the differential diagnosis of these tumors. Calretinin expression has also been reported to be commonly expressed in a wide variety of other neoplasms, including sex cord-stromal tumors, adrenal cortical neoplasms, olfactory neuroblastomas, Schwann cell tumors, cardiac myxomas, and ameloblastomas. This article reviews the information that is currently available on calretinin expression in tumors and on its application as an immunohistochemical marker in diagnostic pathology.

Podoplanin is a type I integral membrane glycoprotein that, because it is expressed in lymphatic endothelium, but not in vascular blood vessel endothelial cells, is commonly used in the identification of lymphatic endothelial differentiation in vascular endothelial neoplasms and lymphatic invasion by tumor. Because podoplanin is also expressed in mesothelial cells and fetal gonocytes, it has proved to be a useful marker for assisting in the differential diagnosis of mesotheliomas and germ cell tumors, particularly seminomas/dysgerminomas. Podoplanin expression has also been reported in a wide variety of other neoplasms, including hemangioblastomas, meningiomas, cartilaginous tumors, and follicular dendritic cell neoplasms. This article reviews the information that is currently available on the application of podoplanin immunostaining in diagnostic pathology.

Background Primary laryngeal adenocarcinomas are uncommon and typically of salivary or seromucinous glands origin. Similarly, metastatic adenocarcinoma, including intestinal origin to the larynx, is a rare occurrence. Methods We present a case of a 63-year-old woman with odynophagia and an epiglottic mass of 2 months' duration. Physical examination revealed a large mass involving the entire epiglottis with extension to the preepiglottic space anteriorly and to the right lateral wall of the oropharyngeal/hypopharyngeal junction. Results Induction chemotherapy was initiated, and, after 4 cycles with no noticeable response, the patient underwent total laryngectomy and bilateral levels II to IV neck dissection. The final pathology diagnosis was primary intestinal-type adenocarcinoma of the larynx. Conclusion We present a primary high-stage intestinal-type adenocarcinoma of the larynx and discuss its putative origin and the clinicopathologic characteristics. © 2013 Wiley Periodicals, Inc. Head Neck 36: E44–E47, 2014

GATA3 is a member of a group of zinc-finger transcription factors that is involved in cell development and differentiation. Recent studies have shown that, among tumors, GATA3 is commonly expressed in both urothelial tumors and breast epithelial neoplasms. With the exception of salivary gland and parathyroid tumors, GATA3 has been reported to be either absent or only rarely expressed in other epithelial tumors. Owing to its restricted expression in urothelial and breast carcinomas, GATA3 has proved to be a useful immunohistochemical marker for assisting in distinguishing these 2 groups of neoplasms from other malignancies with which they may be confused.

SOX10 is a transcription factor that is essential for the generation of neural crest cells, their survival, and maintenance of pluripotency. Recent studies have shown that, among tumors, SOX10 is commonly expressed in melanomas, including desmoplastic melanomas, tumors with Schwann cell differentiation, and some salivary gland neoplasms, particularly those with myoepithelial differentiation. Because of its restricted expression, SOX10 has proved to be a useful immunohistochemical marker with a wide range of diagnostic applications in surgical pathology, some of which are briefly reviewed.

A large number of immunohistochemical markers that can assist in the differential diagnosis of epithelioid mesotheliomas are currently available. Because these markers are expressed differently in the various types of carcinomas that can metastasize to the serosal membranes and can potentially be confused with epithelioid mesothelioma, their selection for inclusion in a diagnostic panel largely depends on the differential diagnosis, as well as on which ones work the best in a given laboratory. Traditionally, the panels used in the differential diagnosis of epithelioid mesothelioma have consisted of a combination of positive mesothelioma markers and broad-spectrum carcinoma markers. At present, a wide variety of organ-associated carcinoma markers such as thyroid transcription factor-1 and napsin A for the lung, PAX 8 and PAX 2 for the kidney, and Müllerian-derived tumors; gross cystic disease fluid protein-15 and mammaglobin for the breast; and CDX2 for intestinal differentiation are available, which can assist in establishing the site of origin of an adenocarcinoma when included in a diagnostic panel. This article provides updated information on the composition of the panels of markers recommended in the various differential diagnoses.

PAX2 is a member of the PAX family of transcription factors that, together with PAX8, is involved in the regulation of the organogenesis of the kidney and the Müllerian system. Recent investigations have demonstrated that, among tumors, PAX2 is commonly expressed in epithelial tumors of the kidney and female genital tract. Although PAX2 expression has also been reported in B-cell lymphomas and rhabdomyosarcomas, especially alveolar rhabdomyosarcomas, it has been suggested that the positivity in these tumors was most probably due to a cross-reactivity of the anti-PAX2 antibody used in those investigations with other members of the PAX protein family. An analysis of published studies indicates that PAX2 sensitivity for epithelial renal neoplasms and epithelial tumors of the female genital tract is lower than that of PAX8. In contrast to the latter marker, however, PAX2 does not appear to be expressed in epithelial tumors of the thyroid gland or thymus. Because of its restricted expression, PAX2 has proved to be a useful immunohistochemical marker with a wide range of diagnostic applications in surgical pathology, some of which will be briefly reviewed.

Thyroid transcription factor-1 (TTF-1) is a tissue-specific transcription factor that plays a critical role in the normal development of embryonic epithelial cells of the thyroid and lung. Because TTF-1 expression is highly restricted to epithelial tumors arising in these organs, it is, at present, one of the immunohistochemical markers most commonly used to assist in the differential diagnosis of carcinomas of the lung and thyroid. Recent studies, however, have reported that TTF-1 is not as specific for lung and thyroid carcinomas as was previously thought as it can be found to be expressed, although much less frequently, in some carcinomas arising in other organs, such as the ovaries, endometrium, colon, and breast, as well as in some tumors of the central nervous system. Even though this unexpected TTF-1 positivity has been reported more frequently with the recently available SPT24 anti-TTF-1 monoclonal antibody, it has also been shown to occur with the commonly used 8G7G3/1 clone, albeit in a lower percentage of cases. Despite these findings, TTF-1 remains a very useful immunohistochemical marker in diagnostic pathology.

A case of a collision lymph node metastasis of a mesothelioma and a carcinoid tumor in a 73-year-old man with a history of asbestos exposure is reported. An interesting finding in this case was that both the mesothelioma and its lymph node metastases exhibited a wide variety of histologic patterns, including one characterized by a solid growth of large cells with abundant, clear, and foamy cytoplasm and another exhibiting deciduoid features. Pathologists should be aware that mesotheliomas can present very unusual morphologic features, such as those seen in the present case, and therefore, should be included in the differential diagnosis of those tumors that can display similar morphology and can metastasize to the serosal membranes. Reexamination of the pneumonectomy specimen in the current case identified a primary peripheral carcinoid tumor. The recognition of a nonasbestos-related tumor in a patient with mesothelioma is important since its presence may have an impact on the patient's life expectancy and, therefore, may affect any compensation settlement.

Mesotheliomas with small cell morphology are rare and only one study of such cases has been published. As a result of their rare occurrence, some investigators have cast doubt on the existence of such a histologic variant of mesothelioma. This investigator reports a series of eight cases of epithelioid mesothelioma with small cell features, all of which originated in the pleura. Seven of the patients were men and one was a woman. Four patients had a history of asbestos exposure. Histologically, four of the mesotheliomas were epithelioid and four biphasic. The proportion of small cells seen in these cases constituted 80 to 100% of the tumor included in the biopsy material and 15 to 20% of the tumor present in the pneumonectomy specimens. Immunoreactivity for calretinin, keratin 5/6, keratin 7, pan-keratin, WT1, podoplanin, and mesothelin was seen in all cases tested for these markers. All of the cases were negative for MOC-31, Ber-EP4, CEA, CD15, TAG-72, TTF-1, chromogranin A, synaptophysin, CD99, and desmin. The mean survival of the six patients for whom this information was available was 8.2 months. It is important for pathologists to be aware that mesotheliomas can present small cell features and, because of this, they can be confused with other malignancies that can exhibit similar morphology. The value of immunohistochemistry in the differential diagnosis of these tumors is discussed.

Napsin A is a novel peripheral airway epithelial marker that, because it is commonly expressed in lung adenocarcinomas but absent in squamous cell carcinomas, is considered to be useful in distinguishing between these 2 types of tumors. Recent immunohistochemical studies, however, have reported napsin A expression in up to 26% of squamous cell carcinomas of the lung, a finding that indicates that this marker may not be as specific for lung adenocarcinomas as is generally believed. To determine the causes of the discrepancies between some recent immunohistochemical studies and previous reports on napsin A expression in squamous cell carcinomas of the lung, 90 pulmonary and 64 nonpulmonary squamous cell carcinomas (20 skin, 10 esophagus, 7 uterine cervix, and 27 from the head and neck region) were investigated by immunohistochemistry for this marker. None of the 90 squamous cell carcinomas of the lung exhibited napsin A positivity in the neoplastic cells; however, because strong napsin A reactivity was observed in hyperplastic type II pneumocytes and in intra-alveolar macrophages, both of which were sometimes seen entrapped within the tumor, it has been concluded that the presence of these entrapped cells was the most likely cause of the discrepancies. Pathologists should be aware of this potential pitfall in the interpretation of the immunostaining for napsin A, especially when small lung biopsy specimens, tissue microarrays, or cytology specimens are being evaluated.

Napsin A is an aspartic protease present in the epithelial cells of the lung and kidney. Recent studies have shown that, in lung tumors, napsin A expression is restricted to lung adenocarcinomas, whereas among renal tumors, it is frequently expressed in renal cell carcinomas, especially the papillary and clear cell subtypes. Owing to its restricted expression, napsin A is a useful marker that can assist in the diagnosis of both lung adenocarcinomas and renal cell carcinomas.

We report 9 patients with pleural biopsies referred because of concern about infiltration of what appeared to be chest wall fat by pan-keratin-positive spindled cells, a finding that led to a consideration of desmoplastic mesothelioma. All patients showed pleural effusions/pleural thickening on computed tomographic scan. Pleural biopsy showed a greatly thickened and fibrotic paucicellular pleura with circular fat-like spaces and, sometimes, adjacent oblate spaces mostly deep in the fibrotic area. Indistinct, keratin-positive, spindle cells arranged parallel to the pleural surface coursed between these fat-like spaces. S-100 stains were negative around the fat-like spaces. Vimentin stains showed that the spaces did not have a cellular lining of any kind. Sometimes the spaces contained faintly hematoxyphilic material that was Alcian blue positive, and similar material was seen in the fibrotic stroma. Follow-up with periods ranging from 6 to 30 months revealed that 8 cases had stable disease on chest imaging or by clinical findings. One case had slowly progressive pleural thickening. These observations suggest that spaces resembling fat may be encountered in fibrotic pleurae and that horizontally oriented keratin-positive spindled cells between the fat-like spaces deep in the fibrotic portion of a thickened pleura represent a benign finding seen in some cases of organizing pleuritis/fibrothorax. The spaces themselves are probably artifacts derived from the biopsy procedure and/or cutting artifacts. In contrast, in true desmoplastic mesotheliomas there is downward, rather than horizontal, growth of keratin-positive spindled cells running between clearly definable fat cells.

Context.—Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose.Objective.—To develop practical guidelines for the pathologic diagnosis of MM.Data Sources.—A pathology panel was convened at the International Mesothelioma Interest Group biennial meeting (October 2006). Pathologists with an interest in the field also contributed after the meeting.Conclusions.—There was consensus opinion regarding (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the differential diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. The International Mesothelioma Interest Group recommends that markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist.

Background. Simultaneous malignancies in the field of radiation for Hodgkin's disease is an extremely rare event. A unique case of concurrent thyroid and neck mass in the postirradiation field of a young patient with Hodgkin's disease is presented. Methods and Results. Thyroidectomy and excision biopsy of the neck mass were performed. A 1.5-cm papillary thyroid carcinoma was identified in thyroidectomy and an initial diagnosis of undifferentiated malignant neoplasm was rendered on the neck mass biopsy. Subsequent surgical excision of the neck mass and immunohistochemical analysis revealed malignant peripheral nerve sheath tumor. Conclusion. Concurrent malignancies in the field of treatment of Hodgkin's disease may occur. Rare malignancies including malignant peripheral nerve sheath tumor may be encountered along with the more common papillary thyroid carcinoma. © 2007 Wiley Periodicals, Inc. Head Neck, 2008

Epithelioid hemangioendothelioma is an uncommon vascular tumor of soft tissue and bone that may rarely occur in the liver, lung and the head and neck. We present five new cases of epithelioid hemangioendothelioma of the head and neck region diagnosed and managed in one institution in order to define the phenotypic characteristics, podoplanin immunohistochemical staining and the biological outcome. Podoplanin is a transmembrane mucoprotein selectively expressed in lymphatic endothelium and recently in some vascular neoplasms. The patients were comprised of two male and three female patients ranging in age from 4 to 71 years. The lesions were found in the gingiva, submandibular region soft tissue, nasal cavity and tongue, and ranged in size from 0.7 to 2.5 cm. All tumors manifested infiltrative cords and nests of epithelioid cells with occasional spindle morphology in a myxoid stroma. Immunohistochemical analysis of vascular and epithelial markers showed strong and uniform cytoplasmic reactivity for podoplanin and variable intensity and staining of CD31 and lack of cytokeratin staining in tumor cells. Surgical treatment included simple and wide local excisions. Of the three patients with follow-up, one developed lymph node metastasis and one had no evidence of disease 10 months after surgery. The patient with multiple recurrences and LN metastases was additionally treated with chemotherapy and is under consideration for radiation therapy. Hemangioendothelioma of the head and neck is: (1) a low-grade malignancy with a tendency for local recurrence and regional lymph node metastasis, (2) complete excision with negative margins is the treatment of choice for localized disease and (3) podoplanin may be useful in differentiating epithelioid hemangioendothelioma from non-vascular tumors.

Malignant pleural mesothelioma (MPM) is a deadly disease with few systemic treatment options. One potential therapeutic target, the non–receptor tyrosine kinase c-Src, causes changes in proliferation, motility, invasion, survival, and angiogenesis in cancer cells and may be a valid therapeutic target in MPM. To test this hypothesis, we determined the effects of c-Src inhibition in MPM cell lines and examined c-Src expression and activation in tissue samples. We analyzed four MPM cell lines and found that all expressed total and activated c-Src. Three of the four cell lines were sensitive by in vitro cytotoxicity assays to the c-Src inhibitor dasatinib, which led to cell cycle arrest and increased apoptosis. Dasatinib also inhibited migration and invasion independent of the cytotoxic effects, and led to the rapid and durable inhibition of c-Src and its downstream pathways. We used immunohistochemical analysis to determine the levels of c-Src expression and activation in 46 archived MPM tumor specimens. The Src protein was highly expressed in tumor cells, but expression did not correlate with survival. However, expression of activated Src (p-Src Y419) on the tumor cell membrane was higher in patients with advanced-stage disease; the presence of metastasis correlated with higher membrane (P = 0.03) and cytoplasmic (P = 0.04) expression of p-Src Y419. Lower levels of membrane expression of inactive c-Src (p-Src Y530) correlated with advanced N stage (P = 0.02). Activated c-Src may play a role in survival, metastasis, and invasion of MPM, and targeting c-Src may be an important therapeutic strategy. [Mol Cancer Ther 2007;6(7):1962–72]

Mucinous tubular and spindle cell carcinoma is a rare and newly described type of renal cell carcinoma (RCC) with a relatively indolent behavior. However, its histogenetic origin or line of differentiation remains unclear. Twelve cases of mucinous tubular and spindle cell carcinoma were identified and retrieved from the files of 3 institutions. Detailed morphological features, as well as their immunohistochemical profile established with markers of proximal renal tubules (RCC marker antigen, CD15, and α -methylacyl-CoA racemase) and of distal renal tubules (kidney-specific cadherin and cytokeratin 7), were studied. The age range of the patients was 35 to 73 years with a median of 56 years. The male to female ratio was 1:3. All of the patients were alive with follow-up between 4 and 38 months. All the tumors were confined to the kidney with a mean tumor size of 6.9 cm (range, 1.8-17 cm). The tumors were composed of variable proportions of tubular and spindle cell areas with focal to prominent mucinous or myxoid stroma. Foamy macrophages were seen in 10 cases and were prominent in 4 cases. A focal compressed tubulopapillary growth pattern was seen in 10 cases. The tumor cells were uniformly cuboidal with ovoid to round nuclei and inconspicuous nucleoli (Furhman nuclear grade 3 in 6 cases). Focal necrosis was seen in 3 cases. Immunostains showed that tumors were positive for RCC marker antigen (11/12), α -methylacyl-CoA racemase (11/12), CD15 (8/12), CD10 (2/12), kidney-specific cadherin (1/12), and cytokeratin 7 (11/12). Its morphological features as well as a strong preferential expression of proximal tubule markers suggest that this tumor is a type of RCC with proximal tubular differentiation, which appears closely related to or represents a morphological variant of papillary RCC.

Numerous immunohistochemical markers that can assist in the diagnosis of epithelioid mesotheliomas, some of which have only recently been recognized, are currently available. Because the various types of carcinomas express these markers differently, their selection for inclusion in a diagnostic panel can vary according to the differential diagnosis. This article provides a critical review of all of the information that is presently available on those markers that are believed to have the greatest potential for assisting in distinguishing between epithelioid mesotheliomas and those carcinomas with which they are most likely to be confused. Information is also provided regarding the panels of immunohistochemical markers that are, at present, recommended in these differential diagnoses.

As both mesotheliomas and squamous carcinomas can present a wide variety of morphological patterns, they can on occasion be confused. Recently, some groups of investigators have called attention to the difficulties that sometimes exist in distinguishing between these malignancies and the need to define a panel of markers that can assist in reaching the correct diagnosis. The aim of the present study is to compare the value of the various immunohistochemical markers currently available for the diagnosis of mesothelioma and squamous carcinoma of the lung. A total of 30 epithelioid pleural mesotheliomas exhibiting a solid or predominantly solid pattern, and 30 nonkeratinizing squamous carcinomas of the lung were investigated for the expression of the following markers: podoplanin, calretinin, mesothelin, WT1, keratin 5/6, keratin 7, p63, carcinoembryonic antigen (CEA), MOC-31, Ber-EP4, B72.3, BG-8 (Lewis(y)), leu-M1 (CD15), and thyroid transcription factor-1 (TTF-1). All 30 (100%) of the mesotheliomas reacted for calretinin, mesothelin and keratin 7, 93% each for podoplanin, WT1 and keratin 5/6, 13% for Ber-EP4, 7% each for p63, MOC-31 and BG-8, and 0% for B72.3, CEA, leu-M1 and TTF-1. All 30 (100%) of the squamous carcinomas were positive for p63 and keratin 5/6, 97% for MOC-31, 87% for Ber-EP4, 80% for BG-8, 77% for CEA, 57% for keratin 7, 40% for calretinin and B72.3, 30% for leu-M1, 27% for mesothelin, 15% for podoplanin, and 0% for WT 1 and TTF-1. After analyzing the results, it is concluded that from a practical point-of-view, a combination of two positive mesothelioma markers (WT1 and calretinin or mesothelin) with two negative mesothelioma markers (p63 and MOC-31) would allow the differential diagnosis to be established between epithelioid mesotheliomas and squamous carcinomas of the lung in nearly all instances.

BACKGROUND Recently, several case reports have described a rare but distinct subtype of renal tumor, referred to as a "low grade renal epithelial neoplasm," that appears to have a better prognosis than conventional renal cell carcinoma does. This report describes the cytologic features of this tumor as determined by fine needle aspiration (FNA) biopsy. CASE A 53-year-old woman with a history of lymphoma had a renal mass incidentally discovered on an abdominal computed tomographic scan performed for lymphoma restaging. Results of an FNA biopsy showed relatively uniform, medium-sized tumor cells with moderate amounts of finely vacuolated or wispy cytoplasm and indistinct cell borders. The nuclei were primarily round with coarse chromatin and had prominent nucleoli. In the cell block preparation, the tumor cells showed a tubular architecture and an abundant myxoid matrix. The patient underwent a partial nephrectomy. The tumor was classified as a low grade myxoid renal epithelial tumor. CONCLUSION This unusual kidney tumor appears to have distinctive cytomorphologic features, including a uniform population of epithelial cells with round nuclei, an abundant myxoid matrix and tubular architecture.

BACKGROUND Well-differentiated papillary mesothelioma (WDPM) is an uncommon subtype of mesothelioma that typically occurs in the peritoneum of women without a history of asbestos exposure and usually follows an indolent clinical course. Fine needle aspiration (FNA) of this type of tumor has rarely been reported. CASE A 64-year-old woman with 11-year history of colon cancer and an adrenal nodule was found, on abdominal computed tomography, to have a mass in the right lobe of the liver. Aspirates of the mass were composed of abundant, tight, papillary groups, monolayered, pavementlike sheets; and scattered single cells with minimal atypia. The cell block showed a predominantly papillary growth pattern and a single layer of bland, cuboidal to flattened covering cells with stout, fibrovascular cores containing clusters of foamy histiocytes. Tumor cells in the focal tubulopapillary and solid areas were mingled with inflammatory cells and showed slightly more atypia than did the cells covering the papillae. The differential diagnoses were intrahepatic papillary neoplasm, including well-differentiated mesothelioma and metastatic low grade papillary serous carcinoma. At surgery the tumor was found to be a pedunculated peritoneal mass that arose from the posterior surface of the right lobe of the liver. The mesothelial origin of the tumor was confirmed by both immunoperoxidase study and electron microscopic examination, which demonstrated long, slender, branching microvilli. CONCLUSION Familiarity with the cytomorphologic features and clinical presentation of WDPM, knowledge of the exact anatomic location and consideration of the appropriate differential diagnosis combined with ancillary studies are the keys to an accurate diagnosis.

Lung tumors with rhabdoid features, included as variants of large cell carcinoma in the 1999 World Health Organization classification of lung tumors, are rare and have an aggressive clinical course. We report 11 patients with primary lung tumors with rhabdoid features and review the literature on this uncommon tumor. We examined samples from 7 primary (6 resections, 1 biopsy) and 4 metastatic tumor samples. All specimens were stained with immunohistochemical stains for pancytokeratin (CK), cytokeratin 7 (CK7), cytokeratin (CK20), thyroid transcription factor-1 (TTF-1), and vimentin. The patients were 7 men and 4 women whose ages ranged from 35 to 70 years. Nine patients presented with respiratory symptoms, and 9 patients had a history of heavy smoking. One patient had TNM stage I tumor, 3 had stage III tumors, and 6 had stage IV tumors at presentation; tumor stage could not be determined in 1 patient. Histological examination of these tumors showed typical rhabdoid cells: large cells with abundant cytoplasm, a large eccentric nucleus with a central macronucleolus, and a rounded eosinophilic cytoplasmic inclusion that sometimes caused nuclear indentation. These cells constituted 10% to 90% of the tumor. The "parent" neoplasm was sarcomatoid carcinoma and adenocarcinoma in 4 cases each and was large cell undifferentiated carcinoma in 3 cases. Cytoplasmic staining in the rhabdoid cells was seen in 9 of 11 cases for CK, in 4 of 10 cases for CK7, and in all 11 cases for vimentin. Nuclear staining for TTF-1 in the rhabdoid cells was absent in all 11 cases, and cytoplasmic staining for CK20 was negative in the rhabdoid cells in all 10 cases studied. Of the 9 patients with available follow-up information, 8 died of disease, and 1 is alive with no evidence of disease 20 months after the initial diagnosis. We conclude that rhabdoid features can occur in a variety of lung tumors, including sarcomatoid carcinoma. Recognizing these lesions is important because of their possibly aggressive clinical course.

Mesothelin is a differentiation antigen that was first described as the antigenic target of the monoclonal antibody K1. Using this antibody, it was demonstrated that mesothelin is strongly expressed in normal mesothelial cells, mesotheliomas, nonmucinous ovarian carcinomas, and some other malignancies. Immunostaining with the K1 antibody was suggested to be useful in the diagnosis of mesothelioma in the early 1990s. This, however, could not be further explored until recently because of the lack of commercially available anti-mesothelin antibodies. In a recent investigation by this author, all epithelioid mesotheliomas and about 40% of the lung adenocarcinomas reacted with the 5B2 anti-mesothelin antibody, which has only recently become commercially available. It was concluded that immunostaining with this antibody has limited value in discriminating between these conditions. The aim of the current study was to further investigate the potential application of the 5B2 antibody in tumor diagnosis. Mesothelin expression was evaluated in formalin-fixed, paraffin-embedded samples of normal tissues and in 471 tumors of various origins. The carcinomas that most frequently exhibited strong mesothelin reactivity were nonmucinous carcinomas of the ovary (14 of 14 serous, 3 of 3 endometrioid, 6 of 8 clear cell, and 4 of 4 transitional cell carcinoma), and adenocarcinomas of the pancreas (12 of 14), the ampulla of Vater (3 of 3), endometrium (7 of 11), lung (14 of 34), and liver (7 of 19 cholangiocarcinomas). The carcinomas that did not express mesothelin included renal cell carcinomas, hepatomas, carcinomas of the thyroid, adrenal cortical carcinomas, prostatic adenocarcinomas, and carcinoid tumors. All germ cell tumors, with the exception of teratomas, were consistently negative for mesothelin. Because of the strong mesothelin expression in nonmucinous carcinomas of the ovary, but not in a variety of tumors with which these lesions may be confused (eg, clear cell carcinoma of the ovary versus endodermal sinus tumor or renal cell carcinoma, clear cell type; transitional cell carcinoma of the ovary versus TCC of the urinary tract), immunostaining for this marker could be useful in establishing the differential diagnosis. The strong mesothelin expression in the large majority of pancreatic ductal adenocarcinomas (12 of 14), but not in normal pancreas, confirms that this marker may have some diagnostic utility in discriminating between neoplastic and nonneoplastic pancreatic ductal epithelium. The mesothelin expression in about one-third of the cholangiocarcinomas, but not in hepatomas, suggests that this marker may have some utility in distinguishing between these two malignancies when they are poorly differentiated. In the group of small round blue cell tumors, only desmoplastic small round cell tumors exhibited mesothelin positivity (7 of 12). Of the soft tissue tumors, only the epithelial component of biphasic synovial sarcomas (9 of 9) expressed mesothelin. These findings indicate that, in some instances, mesothelin immunostaining can assist in the diagnosis of these tumors. Finally, the strong mesothelin reactivity seen in the adenomatoid tumors (3 of 3) provides further support for a mesothelial derivation for this lesion.

Distinguishing between epithelioid mesothelioma and pulmonary adenocarcinoma involving the pleura can be difficult on routine histological preparations. This differential diagnosis can be greatly facilitated by using immunohistochemical markers. E-cadherin and N-cadherin are among the newly described markers that have been proposed as potentially useful in the diagnosis of mesothelioma. E-cadherin and N-cadherin are members of the cadherin family of calcium-dependent cell adhesion molecules that play an important role in the embryogenic development and maintenance of normal tissue. Although several investigations have indicated that immunostaining for these markers can be useful in discriminating between mesotheliomas and adenocarcinomas, others have not confirmed this observation. In an attempt to resolve this controversy, the present study investigated 31 epithelioid mesotheliomas and 29 pulmonary adenocarcinomas for E-cadherin and N-cadherin expression using the 5H9, HECD-1, and clone 36 anti-E-cadherin antibodies, and the 3B9 and clone 32 anti-N-cadherin antibodies. Among the mesotheliomas, 68% reacted with the clone 36, 52% reacted with the HECD-1, and 19% reacted with the 5H9 anti-E-cadherin antibodies, and 74% reacted with the 3B9 and 71% reacted with the clone 32 anti-N-cadherin antibodies. Of the adenocarcinomas, 93% stained with the clone 36, 90% reacted with the HECD-1, and 90% reacted with the 5H9 anti-E-cadherin antibodies, 45% reacted with the clone 32 and 34% reacted with the 3B9 anti-N-cadherin antibodies. Based on the frequent strong reactivity with adenocarcinomas but not with mesotheliomas, it is concluded that only the 5H9 anti-E-cadherin antibody may have some utility in discriminating between epithelioid pleural mesotheliomas and pulmonary adenocarcinomas. The causes of the disparate results reported in the literature on the value of E-cadherin and N-cadherin immunostaining in distinguishing between mesotheliomas and pulmonary adenocarcinomas are unclear, but a significant factor appears to be differences in the reactivity of the antibodies used.

Uterine tumors resembling ovarian sex-cord tumors (UTROSCTs) are unusual neoplasms with histologic features that resemble those within ovarian Sertoli and granulosa cell tumors. We report the case of a 24-year-old woman with a UTROSCT presenting as a cervical mass, which on initial evaluation was thought to represent cervical adenocarcinoma. The patient's cervical biopsy specimen contained epithelioid cells arranged in tubules and anastomosing cords, without significant cellular atypia or mitotic activity. Because this morphology elicited a broad differential diagnosis, immunohistochemical studies were performed. The tumor was found to be diffusely positive for cytokeratin cocktail, calretinin, and desmin, focally positive for CK7 and SMA, and negative for EMA, CEA, inhibin, CD10, CK20, chromogranin, and synaptophysin. Ultrastructural examination revealed occasional gland-like lumens with cells joined by desmosomes and a continuous basal lamina. UTROSCTs have features that may cause them to be confused with more common tumors, especially in limited biopsy samples, and should be included in the differential diagnosis when a gland-forming neoplasm with an unusual appearance is identified in a cervical or endometrial biopsy specimen.

BACKGROUND Hurthle cell neoplasms, often considered a variant of follicular thyroid neoplasms, represent 3% of thyroid carcinomas. Only a handful of publications have focused on the biologic behavior, prognostic factors, and treatment outcomes of Hurthle cell carcinoma. The objective of the current study was to identify the clinical and pathologic features of Hurthle cell carcinomas that predict disease progression or death. METHODS The authors reviewed medical records of patients who were treated for Hurthle cell carcinoma (HCC) and Hurthle cell adenoma (HCA) at The University of Texas M. D. Anderson Cancer Center from March 1944 to February 1995, including follow-up information. The pathologic diagnosis was confirmed by one of the authors. RESULTS The authors identified 127 patients with Hurthle cell neoplasms, 89 patients with HCC and 38 patients with HCA. Seven patients with HCC had foci of anaplastic thyroid carcinoma. Survival for this subgroup was worse compared with the overall group and was analyzed separately. The HCC group was significantly older (age 51.8 years vs. age 43.1. years) and had larger tumors (4.3 cm vs. 2.9 cm) compared with the HCA group. No differences were seen in gender or previous radiation exposure. Forty percent of patients in the HCC group died of thyroid carcinoma, whereas no patients in the HCA group died of the disease. There has been no improvement in all-cause and disease specific mortality in the past 5 decades for patients with these neoplasms. Conventional staging systems predicted mortality with minor differences. Of the patients with known metastasis, 38% showed radioiodine uptake. Univariate analysis identified older age, higher disease stage, tumor size, extraglandular invasion, multifocality, lymph node disease, distant metastasis, extensive surgery, external beam radiation therapy, and chemotherapy as factors that were associated with decreased survival. Tumor encapsulation was associated with improved survival. Although radioactive iodine treatment had no overall effect on survival, subgroup analysis showed that patients who received radioactive iodine for adjuvant ablation therapy had better outcomes compared either with patients who did not receive radioactive iodine or with patients who received radioactive iodine as treatment for residual disease. Multivariate analysis indicated that older age and larger tumor size predicted worse survival through an association with worse behaving tumors (multifocal, less encapsulated, and with extraglandular invasion). The decreased survival in patients with lymph node metastases may be explained by its association with distant metastases. The association of extensive surgery, external beam radiation therapy, and chemotherapy with worse survival also disappeared once those factors were analyzed together with other prognostic factors, such as distant metastases. CONCLUSIONS Several clinical and pathologic prognostic factors were identified in patients with HCC and HCA. Older age and larger tumor size predicted reduced survival. Radioactive iodine therapy may confer a survival benefit when it is used for adjuvant ablation therapy, but not when residual disease is present. The authors could not demonstrate a survival benefit for the use of extensive surgery, external beam radiation therapy, or chemotherapy. Cancer 2003;97:1186–94. © 2003 American Cancer Society. DOI 10.1002/cncr.11176

Foam cells with abundant vacuolated cytoplasm are prominent in most samples of spontaneous nipple discharge, nipple aspirate fluid, and ductal lavage. Although several investigators have attempted to characterize these cells, there is no consensus about whether these cells are derived entirely from macrophages or from both ductal epithelial cells and macrophages. Using immunocytochemical methods, we studied 20 paired specimens of nipple aspirate fluid containing abundant foam cells obtained from the involved breast of women with in situ or invasive carcinoma and from the contralateral normal breast. We used a cocktail of anticytokeratin antibodies including AE1, AE3, and CAM5.2 and the macrophage marker KP1 (CD68). In addition, we examined samples by electron microscopy. The foam cells were consistently negative for cytokeratin and positive for CD68. In every case electron microscopy of these cells revealed irregular outlines with short cytoplasmic processes. The cytoplasm was abundant and contained numerous lysosomes, a small Golgi complex, lipid droplets, mitochondria, and short profiles of rough endoplasmic reticulum. There was no evidence, however, of cell junctions or tonofilaments. The immunocytochemical and electron microscopic findings of our study together clearly support a macrophage derivation for foam cells in nipple aspirate fluid.

Numerous new immunohistochemical markers that can be used in the diagnosis of mesothelioma have recently become available. As a result, new panels of antibodies that could be useful for distinguishing between epithelioid mesotheliomas and adenocarcinomas have been proposed. However, great differences of opinion exist regarding the individual value of some of these markers, especially when compared with those whose value has already been established. This article provides a critical review of the currently available information on those markers that could be useful in the diagnosis of epithelioid mesotheliomas or whose utility remains controversial. A practical approach to the diagnosis of these tumors is also provided.

Micropapillary carcinoma or a micropapillary carcinoma component has been reported in the ovary, breast, and urinary bladder and is generally thought to have prognostic significance. However, little has been written on micropapillary differentiation in lung carcinoma. We studied 35 cases of primary lung adenocarcinoma with a micropapillary component seen at the M.D. Anderson Cancer Center. The micropapillary component in these tumors ranged from focal to prominent and was seen at both primary and metastatic sites. This component was not associated with any particular histologic subtype of lung adenocarcinoma. Of the 15 cases with available material, 14 (93%) stained positive for cytokeratin 7, whereas only two of the 15 cases (13%) stained positive for cytokeratin 20. Thyroid transcription factor-1 immunostaining of tumor nuclei was seen in 12 of the 15 cases (80%). Immunostaining was seen in areas both with and without micropapillary differentiation. Thirty-three of 35 patients (94%) developed metastases, which occurred most commonly in the lymph nodes (n = 26), and also in the lung (n = 17), brain (n = 9 cases), bone (n = 9 cases), and other sites. Most metastases had a prominent micropapillary component, irrespective of the extent of the micropapillary carcinoma component in the primary lung tumor. Adequate clinical follow-up information was available for 29 patients. The mean follow-up was 25 months. At their last follow-up, 16 of 29 patients (55%) were still alive with disease, 5 (17%) were dead of disease, and 8 (28%) were alive with no evidence of disease. We believe that a micropapillary component occurring in lung adenocarcinoma should be reported, as this component may be more likely to metastasize. The presence of this component should alert the clinician to search more carefully for metastases and have a closer follow-up on these patients. It is also important to recognize this component in evaluating a metastasis from an unknown primary site, as it should alert the pathologist to a possible primary in the lung in addition to breast, urinary bladder, and ovary.

Arginase-1 is an enzyme that catalyzes the hydrolysis of arginine to ornithine and urea in the urea cycle. In normal tissues, arginase-1 is primarily expressed in hepatocytes. Recent investigations have reported that the vast majority of hepatocellular carcinomas express this marker, but it is found only rarely in nonhepatocellular tumors. Owing to its restricted expression in hepatocellular carcinomas, arginase-1 has proved to be a useful immunohistochemical marker for assisting in distinguishing between these tumors and other neoplasms with which they may be confused.

Cadherin 17 is a member of a multigene family of calcium-dependent, transmembrane proteins that mediates cell-cell adhesion, plays important roles during embryogenesis, and is crucial for tissue morphogenesis and maintenance. Cadherin 17 is exclusively expressed in the epithelial cells of embryonic and adult small intestine and colon, and pancreatic ducts. It has also been reported to be frequently expressed in adenocarcinomas arising in the gastrointestinal tract and pancreas. Owing to its restricted expression in these groups of tumors, cadherin 17 has proven to be a useful immunohistochemical marker for assisting in distinguishing these neoplasms from other malignancies with which they may be confused.

Epithelioid mesotheliomas and breast carcinomas can present a variety of morphologic patterns. Because of this, breast carcinomas that metastasize to the pleura and lung may be confused with mesotheliomas. The aim of the present study is to compare the immunohistochemical markers currently available for the diagnosis of these 2 malignancies and to determine the best panel of markers that can be used to assist in discriminating between them. Sixty epithelioid mesotheliomas and 80 breast carcinomas (40 triple negative and 40 estrogen receptor positive) were investigated for expression of the positive mesothelioma markers calretinin, keratin 5/6, mesothelin, podoplanin, thrombomodulin, and WT1; the positive carcinoma marker claudin 4; and the breast-associated markers gross cystic disease fluid protein 15 (GCDFP-15), mammaglobin, and GATA3. All of the epithelioid mesotheliomas reacted for calretinin and keratin 5/6, 93% for WT1; 88% for podoplanin; 77% for thrombomodulin; 23% for GATA3; and 0% for claudin 4, GCDFP-15, and mammaglobin, respectively. Of the triple-negative breast carcinomas, 100% expressed claudin 4; 5%, keratin 5/6; 30%, GATA3; 18%, mammaglobin; 15%, GCDFP-15; 56%, mesothelin; 38%, calretinin; 18%, thrombomodulin; 5%, WT1; and 3%, podoplanin. Among the estrogen receptor-positive breast carcinomas, 100% were claudin 4 and GATA3 positive; 70% expressed GCDFP-15; 63%, mammaglobin; 13%, calretinin; 13%, thrombomodulin; 8%, WT1; 5%, keratin 5/6; 3%, mesothelin; and 0%, podoplanin. It is concluded that podoplanin and WT1 are the best positive mesothelioma markers for differentiating epithelioid mesotheliomas from breast carcinomas. An accurate differential diagnosis can be reached with the use of these two markers in combination with the breast-associated markers GCDFP-15, mammaglobin, and GATA3.

We report a case of clinically aggressive reticulum cell sarcoma with mixed follicular dendritic cell (FDC) and fibroblastic reticular cell (FRC) features. Histologically, the tumor was confined to lymph nodes occurring as a multifocal epithelioid and spindle cell proliferation with appreciable mitotic rate and numerous admixed non-neoplastic B-cells. Ultrastructural examination revealed elongated cells with prominent nucleoli, interdigitating cell processes and frequent desmosomes. These features are typical of FDC sarcoma. However, immunohistochemical stains showed no expression of antigens characteristic of FDCs, including CD21, CD23 and CD35. Cytogenetic characterization of this tumor, by conventional G-banding and multicolor spectral karyotyping, revealed multiple clonal chromosomal aberrations, including del(X)(p11.4) and add (21)(p11.2). Gene expression analysis by cDNA microarray of RNA obtained from short-term tumor cultures revealed high-level expression of a set of genes (including PDGF receptor-alpha and -beta, certain metalloproteinases, and CD105) that were also highly expressed in cultures of nodal FRC cultured from non-neoplastic lymph nodes. We propose that this tumor represents a nodal sarcoma with intermediate differentiation between FDCs and FRCs. This case adds to the diversity of tumors that may arise from lymph node stroma and supports a possible relationship between the FDC and FRC lineages.

Spindle cell carcinoma of the breast, a variant of metaplastic carcinoma, includes a wide spectrum of lesions with histomorphologic and nuclear features ranging from overtly malignant to mildly atypical. Spindle cell carcinomas with mildly atypical features may resemble fasciitis, fibromatosis, or myofibroblastic tumors and therefore are often misinterpreted as such. A recent study has suggested that spindle cell carcinomas with a dominant fibromatosis-like phenotype, unlike spindle cell carcinomas in general, have no propensity for distant metastasis and should be termed "tumors" rather than "carcinomas." To investigate the question of fibromatosis-like spindle cell breast carcinoma (FLSpCCs) metastatic potential, we studied cases of FLSpCC seen at the University of Texas M.D. Anderson Cancer Center between 1987 and 2000. Clinical, pathologic, and immunophenotypic features were reviewed, with emphasis on biologic behavior and predictors of clinical outcome. Our series included 24 women who ranged in age from 55 to 85 years (mean 66 years). Tumor size ranged from 1.0 to 5 cm (mean 2.8 cm). Most tumors were grossly well defined but had microscopic infiltrative borders. Tumors showed a dominant fibromatosis-like or myofibroblastic-like growth pattern with prominent collagenization. Inflammatory infiltrate was noted in the majority of tumors. Cytokeratin-positive cells were seen in all cases and usually appeared as cords or sheets of polygonal cells; isolated cytokeratin-positive cells were rare. In most tumors immunoreactivity for smooth muscle actin (SMA) was confined to the cytokeratin-negative cells. In five cases intense co-expression of cytokeratin and SMA was noted. None of the tumors showed immunoreactivity for smooth muscle heavy chain myosin, estrogen receptors, progesterone receptors, or HER-2/neu. Ki-67 expression was noted in fewer than 5% of tumor cells. Treatment consisted of local excision (seven cases) or modified radical mastectomy (13 cases). Treatment was unknown in four cases. In patients who underwent axillary nodal dissection, no lymph node metastases were found. Two of the six patients who underwent local excision developed local recurrence. Two patients who underwent modified radical mastectomy developed lung metastases within 2 years after the initial diagnosis. The metastatic tumors were histologically similar to the primary tumors. Our findings indicate that FLSpCCs have the potential for local recurrence and distant metastasis and should be treated accordingly. Because FLSpCCs may be underdiagnosed as benign, the use of immunohistochemical studies, especially for cytokeratins and SMA, is essential in the evaluation of any spindle cell proliferations of the breast.

Acinar cell carcinomas (ACCs) are rare neoplasms that represent less than 2% of all exocrine tumors of the pancreas. Although they occur more often in adults between the 5th and 7th decades of life, a few cases have been reported in children. Histologically, ACCs can resemble islet cell tumors, but they differ in their ultrastructural and immunohistochemical features. Although ACCs present a bland histology, they are highly malignant and the survival of patients with these tumors, even though better than that of those with ductal cell carcinomas, is generally poor.

A large number of patients are diagnosed every year with non–small-cell lung cancer, and their prognosis and response to treatment are inversely correlated to tumor stage at initial diagnosis. Despite the surgical removal of all apparent malignancy from patients with early disease, many will relapse, presumably as a result of disease that was undetected at initial evaluation. In an effort to identify those patients who have early lymph node involvement by metastatic disease, several groups of investigators have searched for the presence of micrometastases in hematoxylin-eosin–negative lymph nodes using immunohistochemical or molecular methods. Four of six groups of investigators using immunohistochemistry have found a significant incidence of lymph node micrometastases and a direct correlation between the absence of micrometastases and disease-free survival; these are encouraging results that require confirmatory studies. Molecular methods may potentially offer increased sensitivity; however, their high cost and the requirement to process large numbers of samples limits their use to research settings at present.

The distinction between small cell lung carcinoma (SCLC) and small cell carcinomas of other sites is difficult by routine histology. Thyroid transcription factor-1 (TTF-1) is a homeodomain-containing transcription factor that is selectively expressed in thyroid and pulmonary epithelial cells. TTF-1 expression has also been demonstrated in adenocarcinomas of the thyroid and lung, and SCLC. However, the value of TTF-1 immunostaining in discriminating between SCLC and nonpulmonary small cell carcinomas has not been investigated. In the present study using an immunoperoxidase staining procedure on paraffin sections, we investigated the expression of TTF-1 and cytokeratin 20 (CK20), a marker that has previously been demonstrated in small cell carcinomas of the skin (Merkel cell carcinomas), in 82 small cell carcinomas from a wide variety of sites (28 lung, 18 skin, 12 gastrointestinal tract, 8 sinonasal, 5 bladder, 3 prostate, 3 uterine cervix, 2 thyroid, 2 salivary gland, and 1 pancreas). Twenty-seven (96%) of the 28 SCLCs were positive for TTF-1. Among the nonpulmonary small cell carcinomas, two tumors of the gastrointestinal tract, one of the bladder, and one of the uterine cervix exhibited TTF-1 positivity. Sixteen (89%) of the 18 Merkel cell carcinomas and one SCLC were CK20-positive. All other small cell carcinomas were negative for this marker. These results indicate that although TTF-1 is not a specific marker for SCLC, it may assist in distinguishing SCLC from some nonpulmonary small cell carcinomas, particularly Merkel cell carcinoma, especially when it is used in conjunction with CK20.

We compared the detection of HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) with detection of HER-2/neu protein overexpression by immunohistochemistry using 2 antibodies on 100 archival invasive breast carcinomas. Protein overexpression for each marker was scored independently by 4 pathologists using standardized criteria, and consensus was compared with results obtained from gene amplification. The concordance rate between FISH and immunohistochemistry was 76% for e2-4001 and 91% for the HercepTest. Of the 37 cases positive by e2-4001, 21 demonstrated no gene amplification; 7 of 24 cases positive by the HercepTest demonstrated no gene amplification. However, 1 of 61 cases negative by e2-4001 showed gene amplification; none of the cases negative by the HercepTest showed amplification. The predictive values of gene amplification based on 0-1+, 2+, and 3+ immunohistochemical staining were best for cases scored as 3+ (75% for e2-4001 and 89% for the HercepTest). Complete agreement among observers for immunohistochemical scoring of e2-4001 and the HercepTest was achieved in 75 and 85 cases, respectively. The pairwise kappa agreement values were substantial for e2-4001 and substantial to almost perfect for the HercepTest. Immunohistochemical staining may be considered a useful screening test. While negative staining almost always correlated with a lack of gene amplification, positive membranous staining, especially 2+, did not predict gene amplification. The low interobserver reproducibility in separating 2+ from 3+ cases necessitates further confirmation by FISH before treatment decisions are made.

Two cases of extraosseous Ewing's sarcoma/peripheral neuroectodermal tumor arising in unusual, superficial sites are reported. One tumor involved the vaginal wall of a 35-year-old woman, and the other neoplasm arose in the dermis of the vulva in a 28-year-old woman. The tumors showed characteristic microscopic features of Ewing's sarcoma/peripheral neuroectodermal tumor with nodular monotonous proliferations of undifferentiated, small, round, hyperchromatic cells with a low mitotic index. Rare rosette-like formations were apparent only in the vulvar neoplasm. The tumors displayed intense immunoreactivity in a membranous pattern for CD99, the cell surface glycoprotein encoded by the MIC2 gene. Genetically, the tumors expressed the EWS/FLI-1 chimeric transcript, derived from the t(11;22)(q24;q12) chromosomal translocation. Both patients had localized disease treated with wide local excision; one received postoperative chemotherapy, and the other received chemotherapy and radiotherapy. To date, 18 and 19 months after diagnosis, neither patient has had clinical evidence of local recurrence or metastasis. To our knowledge, these are the first reported cases of vaginal and vulvar Ewing's sarcoma/peripheral neuroectodermal tumor, confirmed with molecular genetic analysis, in the English literature.

We have used severe combined immunodeficiency (SCID) (c.b.-17, ICR/SCID) mice to develop xenotransplantation (XT) models for human intermediate-and-low-grade non-Hodgkin's lymphomas (NHL). In the past, SCID mice have provided a variety of useful XT models for human hematopoietic neoplasms that primarily involve the acute leukemias and some nonhematopoietic tumors, but only rare reports exist on use of the SCID mouse model in the study of primary tumor cells from NHL. Intermediate-grade and low-grade NHL are the most common lymphomas seen in adults. There is no effective therapy for those types of NHL, and they have not been established in an animal model to date. The lack of an animal model has hampered studies that can evaluate the disease process in vivo as well as the definition of therapeutic parameters involved in treatment. We report in this study that primary patient samples of NHL ( intermediate grade and low grade) have been successfully established in SCID mice after XT. NHL include intermediate-grade (mantle cell lymphoma) and low-grade (eg, small lymphocytic lymphoma/chronic lymphocytic lymphoma and marginal zone lymphoma) forms. Studies have been directed toward creating appropriate conditions for the optimal grafting of these NHL in SCID mice so that the disease process in humans could be accurately simulated. These studies indicate that development of XT-human lymphoma cells in SCID mice appear to be linked to their biologic and/or clinical behavior, transplanted lymphoma cell number, and age, as well as to the natural killer cell status of the SCID mouse recipients. Evidence has also shown that NHL cells can exhibit homing or trafficking patterns in SCID recipients that resemble those observed in patients with gastrointestinal lymphomatous involvement (particularly that of mantle cell lymphoma). Our studies also indicate that artefactual influences, such as the outgrowth of Epstein-Barr virus-associated lymphoblastoid lesions, are rare occurrences in the human NHL/SCID models that we have established.

Malignant fibrous histiocytoma is a frequent diagnosis, but the relationship of the tumors to histologically similar soft tissue neoplasms is controversial. In this study, 157 examples representing the 4 main subtypes were reviewed by light microscopy and each tumor was studied with the electron microscope. Immunohistochemical stains were performed on 77 tumors. Electron micrographs on 100 fibrosarcomas were reviewed for comparison. Malignant fibrous histiocytomas often closely resemble fibrosarcomas at the ultrastructural level and differences between the two are generally of degree only. Evidence for true histiocytic differentiation was not found. The immunohistochemical results did not contradict the authors' impression from electron microscopy that malignant fibrous histiocytoma forms part of the histologic spectrum of tumors of fibroblasts.

BACKGROUND: Osmotic nephrosis is a form of renal tubular injury that has been found in patients treated with intravenous immunoglobulin (IVIG). CASE: A 46-year-old male who had two courses of chemotherapy for acute myelogenous leukemia was found to have refractory thrombocytopenia. After IVIG (Sandoglobulin 12%, Novartis) administration (1 g/kg) for five consecutive days, the patient became oliguric and eventually an uric on the fifth dose. Hemodialysis was initiated, and urine production was noted on day 2 of hospitalization. Routine cytologic examination of fresh, voided urine showed numerous macrophagelike, bland epithelial cells with abundant, multivacuolated cytoplasm. Cytokeratin immunostain revealed positivity, thus confirming the epithelial origin of these cells. CONCLUSION: To our knowledge, this is the first such case reported in the English-language cytology literature. Awareness of a patient's clinical history may be helpful in avoiding an incorrect diagnosis. Urine cytology may be useful in obtaining an early diagnosis of osmotic nephrosis in patients receiving high-dose IVIG therapy that may eliminate the need for a renal biopsy.

Natural Killer (NK) cell lymphomas, which include the nasal and the "nasal type" varieties, are defined as angiocentric lymphomas in the revised European American Lymphoma (R.E.A.L.) classification. This group of diseases is rare in the United States and Europe but is more common in Asia and Central America. It is associated with the Epstein-Barr virus (EBV) and its response to treatment and prognosis are usually very poor. The aim of this study was to describe our experience with 13 patients with angiocentric lymphomas seen at The University of Texas M. D. Anderson Cancer Center (UTMDACC) over the last 14 years. Thirteen patients with a diagnosis of nasal NK cell lymphoma were treated at UTMDACC from 1987 to 1999. Eleven patients were treated initially with doxorubicin based chemotherapy with or without radiotherapy. One patient received interferon (IFN)-alpha and vitamin A and another methotrexate, vincristine, L-Asparaginase, and radiotherapy. The median age was 44 years (range 15-76); there were four women and nine men. All patients presented with local disease involving the sinonasal region. Typical immunophenotypes expressing CD2+, CD3- and CD56+ surface markers as well as non rearrangement of T-receptors were present in all patients. Eight patients (62%) responded to therapy; six (46%) with complete response (CR) and two (16%) with partial response (PR). Five patients (38%) were alive, four with no evidence of disease (NED) at 1, 2, 3, and 9 years after treatment, and one patient was alive with disease (AWD) at the time of publication. One patient died while in CR from complications from allogeneic bone marrow transplant. Six patients had disease progression to extranodal sites including: testis (2), central nervous system (2), lung (1), bone marrow (2), liver (2), peripheral blood (2), and skin (2). In conclusion, the response to doxorubicin-containing regimens is inferior to that of patients with other non-Hodgkin's lymphomas and similar prognostic factors. Because the disease is associated with EBV virus in 90%-100% of the cases and the prognosis is poor, innovative therapies should be tried including immunotherapy that targets the expression of EBV by the tumor with or without myeloablative procedures.

A pigmented skin lesion on a breast removed for carcinoma resembled melanoma by routine light microscopy, but correlation with immunohistochemistry and electron microscopy established that carcinoma cells within the upper dermis were intermingled with a proliferation of non-neoplastic melanocytic cells. Ultrastructurally, the tumor cells possessed desmosomes and intracytoplasmic lumina and mature melanosomes were present in their cytoplasm. The melanocytic cells were identified as melanocytes or melanophages, and it was concluded that the tumor in the skin was a passively pigmented carcinoma and not a melanoma or metaplastic breast carcinoma.

A 49-year-old woman presented with a 2-year history of back pain. An abdominal computed tomography revealed a 15.0 × 12.0 cm hypodense lesion in the posterior right lobe of her liver. A right hepatic lobectomy was performed, which revealed a well-demarcated lipomatous tumor that microscopically proved to be a myelolipoma. Our case together with 10 other well-documented cases showed the median age of the patients as 55 years (range, 40-69), a predilection for the female gender, and the right lobe of the liver as the most commonly involved site.

Myoepithelioma, a rare benign salivary gland neoplasm, is a tumor composed entirely of myoepithelial cells. Unlike pleomorphic adenoma, these tumors lack any ductal epithelial differentiation, and manifest a minor stromal element. Previous cytogenetic and molecular genetic studies have mainly investigated pleomorphic adenomas and reported recurring specific chromosomal alterations at 8q12 and 12q13 ∼ q15 regions. The cell origin of these alterations, however, remains speculative. We report the cytogenetic analysis of a parotid myoepithelioma and discuss the putative origin for the cells with cytogenetic alterations. Our analysis shows 12q12 involved in a translocation with a previously unreported partner (1q), and nonrandom del(9)(q22.1q22.3) and del(13)(q12q22). Our results indicate that the myoepithelial cell is the source of those cells with chromosomal alterations, and that myoepithelioma shares 12q alterations reported in a subset of pleomorphic adenomas.