A critical examination of the immunophenotype of pulmonary sclerosing hemangioma

The authors studied a series of 21 cases of pulmonary sclerosing hemangioma (SH) to address conflicting and unconfirmed reports of immunohistologic evidence of differentiation that have been made in the literature. They found the lesional cells of SH to be epithelial membrane antigen (EMA) positive (21 of 21 cases), to be keratin positive only infrequently and focally (six of 21), and to be nonreactive for carcinoembryonic antigen, S-100, smooth muscle actin, and CD34. Faint nuclear staining was seen for estrogen receptors, whereas progesterone receptors were expressed strongly in 17 cases. Neuroendocrine markers (chromogranin A, adrenocorticotrophic hormone, human growth hormone, and calcitonin) were negative uniformly on the lesional cells except for one case in which rare chromogranin-positive cells were present and another case in which rare human growth hormone-positive cells were seen. In contrast to the general EMA-positive, keratin-negative phenotype of the lesional cells, the cells lining the papillae or air spaces within the SH were typically positive for both markers. The following other lesions were identified in the cases studied: carcinoid tumorlets (n = 2), a neuroendocrine body (n = 1), and multiple meningothelial-like nodules (n = 1). All were clearly separable from the SH on morphologic grounds. The authors interpreted these to be chance occurrences of unrelated lesions. Recognition of the phenotype of SH as EMA positive, keratin weak to negative, and negative for S-100, smooth muscle actin, and neuroendocrine markers is notable in its differential diagnosis from other lesions. This phenotype does not suggest a precise lineage or type of differentiation for SH.     

Paranuclear dot-like immunostaining for CD99: a unique staining pattern for diagnosing solid-pseudopapillary neoplasm of the pancreas

Solid-pseudopapillary neoplasm of the pancreas is a rare tumor of uncertain histogenesis that is characterized by a cystic and solid growth pattern with pseudopapillary structures. The differentiation of solid-pseudopapillary neoplasm from other pancreatic tumors is of great importance. However, it is sometimes difficult because of similarities in morphologic features and immunophenotype. CD99 is a diagnostically useful marker for Ewing sarcoma/primitive neuroectodermal tumor. The aim of this study was to investigate the diagnostic value of CD99 in solid-pseudopapillary neoplasm. We investigated immunohistochemical staining for CD99 in tissue microarray blocks from 55 cases of pancreatic solid-pseudopapillary neoplasm, 51 cases of pancreatic neuroendocrine tumor, and 54 cases of pancreatic adenocarcinoma. Biopsy specimens from 7 solid-pseudopapillary neoplasms, 6 acinar cell carcinomas, and 1 pancreatoblastoma were also investigated. All the solid-pseudopapillary neoplasm cells exhibited paranuclear dot-like immunoreactivity for CD99 regardless of the clinicopathologic or morphologic features. Forty of the 51 pancreatic neuroendocrine tumors were positive for CD99. Staining here was membranous, or membranous and cytoplasmic. Four of the 54 pancreatic adenocarcinomas and 1 pancreatoblastoma showed faint membranous staining. None of the acinar cell carcinomas was reactive for CD99. Our study has identified for the first time that pancreatic solid-pseudopapillary neoplasm exhibits a unique dot-like staining pattern for CD99. This could prove to be the most useful aspect of its immunoprofile for the definitive diagnosis of solid-pseudopapillary neoplasm and differentiation from other pancreatic tumors.     

Clear cell tumor of the lung. A clinicopathologic, immunohistochemical, and ultrastructural study of eight cases.

We studied eight clear cell tumors of the lung (CCTL) to better define their clinical, immunohistochemical, and ultrastructural features, and to clarify their distinction from other neoplasms, particularly metastatic renal cell carcinoma. Patients ranged in age from 31 to 67 years (mean, 51 years). Seven patients had clinically benign, asymptomatic lesions measuring less than 2 cm in diameter that were devoid of necrosis. The eighth patient had a symptomatic, partially necrotic CCTL 4.5 cm in diameter that metastasized to the liver and peritoneum; the patient died of tumor 17 years after diagnosis. Ultrastructural study of seven CCTL showed interdigitating cell processes (all cases), primitive cell junctions (five of seven cases), intracytoplasmic glycogen (all cases), and rare dense core granules (two of seven cases). Immunohistochemically, paraffin-embedded sections from all eight CCTL were negative for cytokeratin (CK), epithelial membrane antigen (EMA), chromogranin, and vimentin. Focal staining was seen for S-100 protein (three of eight cases), neuron-specific enolase (three cases), synaptophysin (one case), and Leu 7 (one case). Although these findings suggest that at least some CCTL exhibit neuroendocrine differentiation, the tumor's histogenesis remains uncertain. Of more practical importance, the combined absence of CK, EMA, and vimentin in formalin-fixed, paraffin-embedded CCTL virtually precludes confusion with renal cell carcinoma. Although traditionally considered benign, CCTL larger than 2 cm that are symptomatic, and focally necrotic should be regarded as potentially malignant neoplasms.     

Intraabdominal desmoplastic small-cell tumors with divergent differentiation. Observations on three cases of childhood

We studied three intraabdominal tumors that manifested in childhood and were attached to peritoneum, and in which the histologic pattern suggested metastatic tumor of epithelial nature but gave no evidence of a primary neoplasm in the major abdominal organs. Follow-up observation lasted from 1 to 6 years but never disclosed a primary site. Histologic, immunohistochemical, and electronmicroscopic observations indicated a primitive malignant neoplasm of uncertain histogenesis capable of simultaneously expressing epithelial, mesenchymal, and, less consistently, neural phenotypes. In childhood, the possibility of embryonic neoplasm, such as nephroblastoma occurring in atypical sites, is difficult to exclude. Despite the prevailing uncertainty about histogenesis, combined therapy achieved an apparent cure in one of our cases.     

Small-cell neuroendocrine carcinoma of the ampullary region. A clinicopathologic, immunohistochemical, and ultrastructural study of three cases.

We report the clinicopathologic, immunohistochemical, and ultrastructural features of three small-cell neuroendocrine carcinomas of the ampullary region of the duodenum. All patients were men; their ages were 51, 62, and 66 years. The therapy consisted of pancreatoduodenectomy. All patients died of the disease; median survival was 10 months from the diagnosis. The histological appearance was identical to pulmonary and extrapulmonary small-cell carcinoma. The neuroendocrine differentiation was demonstrated ultrastructurally by the presence of dense-core granules, and by the positive immunoreaction for neuron-specific enolase and Leu-7 in each case. One case expressed a focal positivity for chromogranin A (PHE-5) and argyrophilic granules. The same case showed the presence of neurofilaments on frozen material. Neurofilament proteins could not be demonstrated in any case in paraffin sections. Neoplastic cells exhibited cytoplasmic immunostaining for cytokeratins (CAM 5.2) in all cases. In one case, a large number of neoplastic cells (60-70%) exhibited nuclear Ki-67 positivity. We postulate that the disease's histogenesis was from epithelial stem cell expressing both epithelial and neuroendocrine characteristics. The clinical behavior of small-cell neuroendocrine carcinomas of the ampullary region appears to be extremely aggressive, with early metastases and fatal outcome.     

Small cell carcinoma of the prostate: an immunohistochemical study

Small cell carcinoma of the prostate (SCPC) is morphologically similar to small cell carcinoma of the lung (SCLC) and maybe misinterpreted as Gleason pattern 5b prostate adenocarcinoma (HGPC). Recognition of SCPC is important because of its different clinical behavior. This study aims to characterize the immunophenotype of histologically classic SCPC using a comprehensive panel of markers, to better understand its histogenesis, aid in its classification, and evaluate potential therapeutic targets. Using the World Health Organization morphologic criteria for SCLC, 18 SCPC cases were identified; and studied for the following tumor marker groups: prostate specific/related, neuroendocrine, sex steroid hormone receptors, and prognostic/treatment target-related. Ten cases of UPC were used as controls. PSA was positive in 17% of SCPC and neuroendocrine markers were expressed in HGPC. PSA, TTF-1 and CD56 were the most helpful markers in differentiating between SCPC and HGPC (P<0.01), whereas bombesin/GRP, c-kit, bcl-2, and EGFR expression was more frequent in SCPC. SCPC is best diagnosed by following the World Health Organization diagnostic criteria for SCLC. Immunohistochemical markers can help separate SCPC from HGPC and may be useful in histologically borderline cases. Potential therapeutic targets are identified immunohistochemically in SCPC (Bombesin/GRP, c-kit, bcl-2, and EGFR).     

Papillary cystic tumor of the pancreas. An analysis of cellular differentiation by electron microscopy and immunohistochemistry

Three cases of clinically benign pancreatic papillary cystic tumors in young female patients were studied by immunohistochemistry and electron microscopy in order to define the cellular nature of this type of neoplasm. Two of the tumors showed focal cytokeratin- and desmoplakin-positivity as evidence of focal epithelial differentiation, while the tumor cells were in all cases positive for vimentin--the intermediate filament protein typical of (but not specific for) mesenchymal cells. Electron microscopy showed some cell-cell junctions, but there was no evidence of acinar or islet cell differentiation. The tumors were at least focally positive for neuron-specific enolase, and small clusters of polypeptide hormone immunoreactive cells were present in all cases (glucagon 3/3, somatostatin 2/3, insulin 2/3). However, the tumors were negative for synaptophysin and neurofilament proteins, unlike most islet cell tumors. Trypsin and chymotrypsin immunoreactivity was found in all tumors, but because many nonpancreatic carcinomas were also positive, we doubt whether these two enzyme proteins can act as specific markers for pancreatic acinar cell differentiation. Two of the tumors that were studied immunohistochemically for the presence of nuclear estrogen receptors, were negative. Therefore no proof of the suggested hormone dependence of this tumor could be obtained. We conclude that papillary cystic tumor is a neoplasm of primitive pancreatic epithelial cells, that may exhibit focal endocrine cell differentiation.     

Immunohistochemical distribution of epithelial membrane antigen in bladder carcinomas as detected with a monoclonal antibody

Summary Expression of epithelial membrane antigen (EMA) was investigated immunohistochemically in 27 cases of bladder carcinoma using a monoclonal antibody. Normal urothelial epithelium showed EMA staining restricted to the upper layer of the surface epithelium. G-I transitional cell carcinomas demonstrated positive EMA staining which could be divided into the following 3 types; type 1, in which highly stained cells occurred in the upper layer of the neoplastic epithelium; type 2, in which the whole tumour focus was slightly stained; and type 3, in which cells strongly positive for EMA were scattered throughout the tumour focus. G-III (undifferentiated) transitional cell lesions exhibited irregular expression of EMA whereas squamous cell demonstrated specific intense EMA staining within keratinized tumour cells.     

Biphasic Low-Grade Nasopharyngeal Papillary Adenocarcinoma with a Prominent Spindle Cell Component: Report of a Case Localized to the Posterior Nasal Septum

A case (female, 39 years of) of thyroid-like nasopharyngeal low-grade papillary adenocarcinoma with a significant spindle cell component is presented. The tumor was located on the posterior nasal septum. The spindle cells displayed nuclear features very much similar to the epithelial component and the two cell types merged imperceptibly. Immunohistochemically, the neoplastic cells (including the spindle cell component) were strongly and diffusely positive for TTF-1, cytokeratins (AE1-3), cytokeratin 19 and vimentin. C-kit immunohistochemistry showed diffuse mild to moderate membranous positivity with focal areas displaying moderate to strong immunoreactivity. EMA was strongly positive in the epithelial component with membranous and cytoplasmic reactivity whereas the spindle cell component was weakly although diffusely positive. Carcinoembryonic antigen, calcitonin, chromogranin A, S100-protein, thyroglobulin, cdx2 and p63 were negative. The proliferative activity (Mib-1/Ki-67) was low; 3–4%. In the molecular genetic study we found no mutations at position 1799 (exon 15) in the BRAF-gene, (BRAFV600E) or in exons 9 and 11 of the KIT-gene.     

Neuroendocrine carcinoma of the colon and rectum. A clinicopathologic, ultrastructural, and immunohistochemical study of 24 cases

To further characterize the clinicopathologic spectrum of colorectal neuroendocrine neoplasia, 24 carcinomas with neuroendocrine differentiation were subtyped as either small cell neuroendocrine, oat cell variant (six cases), small cell neuroendocrine, intermediate variant (16 cases), or moderately differentiated neuroendocrine carcinoma (two cases). Five oat cell variants, 14 intermediate variants, and two moderately differentiated tumors were studied with antibodies to cytokeratin, vimentin, epithelial membrane antigen (EMA), neuron-specific enolase (NSE), chromogranin (CRG), synaptophysin (SYN), neurofilament, S-100 protein, carcinoembryonic antigen (CEA), and Leu-7. All tumors were immunoreactive for cytokeratin and the majority were also positive for EMA and NSE. Positivity for specific neuroendocrine markers was uncommon, with SYN reactivity noted in one oat cell variant and four intermediate variants, and CRG positivity observed in four intermediate variants and one moderately differentiated tumor. Ultrastructural analysis of four oat cell, eight intermediate, and one moderately differentiated tumor revealed neurosecretory-type, dense-core granules in all lesions, except two oat cell variants studied from paraffin-retrieved material. Hepatic and regional lymph node metastases were noted in five of six oat cell, eight of 16 intermediate, and two of two moderately differentiated tumors. Of 17 patients with follow-up (four oat cell, 11 intermediate, and two moderately differentiated tumors), only two individuals were alive after 1 year. There were no detectable differences in survival or response to treatment between morphologic subtypes. The prognosis of colorectal neuroendocrine carcinoma appears worse than for adenocarcinoma of comparable stage. Their distinction is thus warranted, especially in regard to the intermediate variant and moderately differentiated tumors, which may be potentially misinterpreted as forms of adenocarcinoma.     

Lobular carcinoma of the breast with hybrid myoepithelial and secretory ("myosecretory") cell differentiation

Three cases of lobular carcinoma of the breast showing a complex morphology that included myoepithelial cell differentiation are reported. One case was a pure in situ acinar lesion, while the other 2 cases were in situ and invasive carcinomas. Three different cell types were seen in these tumors: one was the phenotype commonly seen in the garden variety of in situ lobular carcinoma (LCIS) constituted by noncohesive round to ovoid cells with round nuclei and positivity for epithelial membrane antigen (EMA), estrogen receptor (ER), and progesteron receptor (PR). E-cadherin was negative in these cells. The second type was represented by cohesive elements with irregular nuclei. These cells were immunoreactive for smooth muscle actin, calponin, keratin 14, p63, and e-cadherin. EMA, ER, and PR were consistently negative. The third type, seen in a minority of cell population of case nos. 2 and 3, consisted of cells showing at the same time EMA and smooth muscle actin in their cytoplasm. This type was defined as "hybrid myosecretory cell" to highlight contractile and secretory properties present at the same time. Cells with hybrid features probably indicate that myoepithelial and secretory cells are strictly related and the existence of a stem cell, at least for these cases, is not necessary.     

Neuroendocrine (Merkel cell) carcinoma of the skin. Its natural history, diagnosis, and treatment.

Over 400 cases of neuroendocrine (Merkel cell) carcinoma of the skin (NCS) have been reported. This tumor continues to pose problems in diagnosis and effective treatment for physicians unfamiliar with its biological characteristics. Reported here are five additional cases of NCS and the literature for this rare neoplasm is comprehensively reviewed. An early and accurate diagnosis is made possible by combining clinical presentation with results of histologic study, immunoperoxidase staining for neuron-specific enolase (NSE), epithelial membrane antigen (EMA), cytokeratins, and electron microscopy. NCS is an aggressive tumor. Depending on the length of follow-up, up to 40% of tumors locally recur, 55% develop regional nodal metastases, and 36% undergo distant metastasis. Survival is sex, but not age, dependent, with an overall 2-year survival rate of 72% (males 58% vs. females 79%). No standard procedure for initial and/or follow-up treatment for NCS exists. The authors recommend that NCS be treated, whenever possible, using the same rationale as applied for the treatment of squamous cell carcinoma of the skin.     

Desmoplastic small round cell tumor

Desmoplastic small round cell tumour (DSRCT) is a unique, highly aggressive neoplasm that chiefly affects adolescent male and young adults and most frequently presents as a large abdominal mass with widespread peritoneal involvement at the time of diagnosis. Histologically, it is composed of nests of small, undifferentiated round or oval hyperchromatic cells embedded in abundant desmoplastic stroma. Co-expression of epithelial, mesenchymal, and neural antigens in the same cell provides evidence of origin from a primitive pluripotent stem cell with multiphenotypic differentiation. A multidisciplinary treatment including high-dose chemotherapy, aggressive debulking surgery, radiation and myeloablative chemotherapy with stem cell rescue might be the proper approach to treat this rare malignancy and may improve progression-free survival.     

成人肾恶性横纹肌样瘤15例临床病理及免疫表型分析

目的：探讨成人肾恶性横纹肌样瘤（MRTK）的病理组织学,分子免疫表型的特点及临床意义.方法：对我院1983～2009年收治15例肾脏恶性横纹肌样瘤的石蜡组织切片运用SP法进行免疫组化染色,检测Vi-mentin、Myoglobin、Desmin、α-SMA、EMA、NSE、S-100的表达,并结合临床病理特征进行分析.结果：组织学上瘤细胞胞界清楚.胞浆丰富具有嗜酸性颗粒、常见大的嗜酸性包涵体,呈圆形或椭圆形,将细胞核挤向一侧.核膜明显而核仁突出,核分裂多见.经SP染色后,Vimentin均警阳性或强阳性表达,EMA、NSE和S-100均有不同程度的阳性表达,α-SMA有2例呈阳性表达,而Myoglobin、Desmin均呈阴性表达.结论：成人MRTK是一种表达多种免疫抗原,独立的可多向分化的肾恶性肿瘤,Vimentin和Myoglobin、Desmin、α-SMA有助于MRTK的诊断和鉴别诊断.     

Polymorphous low-grade adenocarcinoma of minor salivary gland. An immunohistochemical and clinicopathologic study

Polymorphous low-grade adenocarcinoma (PLGA) is a minor salivary gland carcinoma usually arising intraorally, primarily in the palate. It is characterized by cytologic uniformity, histologic blandness, and a variable, infiltrating growth pattern. To date, 117 tumors have been reported but the immunohistochemical features of this neoplasm have not been adequately described. This report describes the immunohistochemical distribution of epithelial membrane antigen (EMA), carcinoembryonic antigen (CEA), high-molecular-weight keratin, muscle-specific actin (MSA), and S-100 protein in four palatal polymorphous low-grade adenocarcinomas arising in two men and two women. Three patients were treated with a combination of radiation and surgery, and one was treated with just surgery; none of the tumors recurred or metastasized. More than 90% of tumor cells in all four tumors stained with S-100 and EMA, while 75 to 95% stained with keratin. MSA staining intensity was variable; it ranged from less than 10% to 67% of tumor cells staining positively. CEA staining also was markedly variable; it ranged from very focal luminal positivity to 75% of tumor cells staining positive. The diffuse staining pattern of EMA and S-100 and the difference in staining patterns of EMA and CEA in PLGA is distinct from that found in adenoid cystic carcinoma. In the latter neoplasm, EMA and CEA staining patterns are similar and they are localized to ductal lumina; S-100 stains much less diffusely. These differences are useful in the differential diagnosis between these two tumors.     

肾囊性病变临床病理分析（附3例报告）

目的 探讨肾囊性病变的临床病理学特点、免疫表型和鉴别诊断。方法 采用常规HE和免疫组织化学染色,观察3例肾囊性病变组织学形态,并复习有关文献。结果 3个病例临床症状均为腰痛或血尿,最后经病理确诊为囊性肾瘤2例和多房性囊性肾癌1例。囊性肾瘤为多房囊腔组织,囊壁薄,内衬单层上皮。免疫表型：上皮细胞角蛋白（CK）、上皮细胞膜抗原(EMA)均呈阳性表达;间质成分波形蛋白阳性。多房性囊性肾癌囊壁被覆单层或多层胞浆透明的细胞,间隔内含聚集的透明细胞巢。免疫表型：透明细胞CK和EMA阳性,CD68阴性。结论 囊性肾瘤和多房性囊性肾癌均是少见的肾脏肿瘤。两种病变临床症状和影像学改变极为相似,确诊需依赖病理检查。两种病变均预后良好。     

Brain surface clear cell ependymoma: case report]

We report a case of brain surface clear cell ependymoma. A 13-year-old boy presented with complaints of right hypesthesia. Computed tomography and magnetic resonance image showed a left fronto-parietal cystic, calcified mass lesion. He underwent total resection of the tumor including cyst wall. The tumor located on the surface of the parietal lobe was sharply demarcated from the surrounding brain tissue and there was no continuity with the ventricular wall. Histological examination of the surgical specimens showed oligodendroglioma-like cells that had round unclei, clear cytoplasm which formed perivascular pseudorosettes, and immunoreactivity for glial fibrillary acidic protein (GFAP). Electromicroscopically, microvilli were seen. The findings were compatible with clear cell ependymoma. The cyst wall was lined with a layer of single cuboidal cells and, immunohistochemically, had no basal membrane. The inner surface of the cyst was positive for EMA, and the cuboidal cells were positive for GFAP. We discuss possible mechanisms for tumor growth in our case and the histogenesis of its cyst.