False-positive staining of thyroglobulin distinguished from mixed medullary and follicular thyroid carcinoma by duplex in situ hybridization.

Medullary thyroid carcinoma (MTC) may mimic mixed medullary and follicular thyroid carcinoma (MMFTC). MTC originates from para-follicular cells, while MMFTC is an uncommon tumor characterized by coexistence of follicular and para-follicular cell-derived tumor populations. A 35-year-old woman was diagnosed with MTC but showed a hot nodule in thyroid scintigraphy. The tumor included diffusely-spread follicular lesions within it, which were immunostained with thyroglobulin and calcitonin. Immunofluorescence showed the presence of several tumor cells that were double-stained with thyroglobulin and calcitonin. To clarify whether or not the tumor was MMFTC, we used duplex in situ hybridization (ISH). Thyroglobulin and calcitonin-related polypeptide alpha mRNA were not expressed together in a single cell, so we suspected false-positive staining of tumor cells with thyroglobulin. To make comparisons with other follicular lesions in MTC, we searched our hospital database. Five cases within a ten-year period had been pathologically diagnosed as MTC. All had follicular lesions in the tumor, but unlike the other case, they were peripherally localized. Dual differentiation into follicular or para-follicular tumor cells was not indicated by either immunofluorescence or duplex ISH. Compared with the case suspected to be MMFTC, there was only mild invasion of tumor cells into the follicular epithelium. The extent of follicular lesions and invasiveness of tumor cells may be associated with pseudo-staining of thyroglobulin in MTC. Duplex ISH can distinguish MTC that are stained with thyroglobulin from MMFTC.

SOX-10 expression in cutaneous myoepitheliomas and mixed tumors.

BACKGROUND: SOX-10 expression can be demonstrated by immunohistochemistry in salivary gland myoepitheliomas, but its expression in cutaneous myoepitheliomas and in cutaneous mixed tumors with prominent myoepithelial cells has not been studied. METHODS: We assessed the staining pattern of SOX-10 in five cutaneous myoepitheliomas and six cutaneous mixed tumors with a prominent myoepithelial component among both the myoepithelial cells and cells lining lumens. In addition, we examined the staining of S100, microphthalmia-associated transcription factor (MiTF), keratin cocktail, HMK903, smooth muscle actin (SMA) and epithelial membrane antigen (EMA). RESULTS: SOX-10 positivity was seen in three of five (60%) cutaneous myoepitheliomas and in the myoepithelial cells of all cutaneous mixed tumors. SOX-10 expression on the cells lining the glandular structures in mixed tumors was variable. All myoepitheliomas and mixed tumors stained positively with S100 and negatively with MiTF. Pan-keratin, HMK903, SMA and EMA showed variable expression. CONCLUSIONS: SOX-10 is a relatively reliable marker for staining cutaneous myoepitheliomas. Cutaneous myoepitheliomas are notoriously difficult to diagnose, and the addition of SOX-10 to the repertoire of stains that can label this tumor is of practical utility. These results further support that cutaneous myoepitheliomas and cutaneous mixed tumors exist on a morphologic and immunophenotypic spectrum.

Mixed neuroendocrine tumor of the common bile duct.

CONTEXT: Mixed adenoendocrine tumors of the extrahepatic bile ducts are exceedingly rare and most of those who are rarely diagnosed are adenocarcinomas. Neuroendorine tumors accounts for only 0.2-2%. CASE REPORT: We report a case of mixed adenoneuroendo-carcinoma of the common bile duct in an 82-year-old male. CONCLUSION: Clinical experience suggests that the neuroendocrine component of mixed tumors behave more aggressively than the regular biliary adenocarcinoma component. This clinical behavior may have an important role in the management of this clinical entity.

[Clinicopathologic features of combined hepatic carcinoma].

OBJECTIVE: To investigate clinicopathological features of combined hepatocellular-cholangiocarcinoma (C-HCC-CC) with neuroendocrine carcinoma (NEC) differentiation and to review the literature. METHODS: The clinical data, histological manifestations and immunohistochemical staining results of two cases of C-HCC-CC were analyzed along with a review of the current literature. RESULTS: Both patients were male with an average age of 57.5 years. Both patients were positive for hepatitis B virus antigen. The tumors of both cases demonstrated the following 3 unequivocal mixed elements: (1) polygonal epithelial tumor cells growing in nests or trabeculae with positive staining for Hepatocyte and AFP, diagnostic of hepatocellular carcinoma (HCC). Cytoplasmic bile production was present in the tumor cells in one case; (2) elliptic or short spindle-shape small blue tumor cells growing in nests or organoid pattern with Syn/CgA/CD56 positivity confirming the presence of neuroendocrine carcinoma (NEC) component; (3) oval tumor cells growing in nests or glandular forms with positivity of CK19 and CK7 confirming differentiation of cholangiocarcinoma (CC). In both cases, the tumors contained at least 20% of each of HCC, NEC and CC components. CONCLUSION: C-HCC-CC with NEC is a rare form of primary malignancy of the liver with a poor prognosis.

The prognoses of metaplastic breast cancer patients compared to those of triple-negative breast cancer patients.

Metaplastic breast carcinoma (MBC) is a rare, heterogeneous breast cancer characterized by admixture of adenocarcinoma with metaplastic elements, low hormone receptor expression, and poor outcomes. The authors retrospectively reviewed the medical records of 47 MBC patients and 1,346 invasive ductal carcinoma (IDC) patients. Two hundred eighteen of the IDC patients were triple-negative (TN-IDC) for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (ER-/PR-/HER2-). Patients were surgically treated at the Samsung Medical Center between 2005 and 2009. The MBC patients presented with a larger tumor size, lower lymph node involvement, higher histological and nuclear grades, higher triple negativity (ER-/PR-/HER2-) and higher p53, CK5/6, and EGFR expressions compared with those of the IDC group. However, there were no significant differences in clinicopathological characteristics between MBC and TN-IDC. During the follow-up period (median duration of 30.3 months, range 2.6-56.3 months), seven (14.9%) MBC patients, and 98 (7.1%) IDC patients had disease recurrence. The three-year disease-free survival (DFS) rate was 78.1% in the MBC group and 91.1% in IDC group (P < 0.001). The three-year DFS rate was not significantly different between the MBC and TN-IDC groups (78.1 vs. 84.9%, P = 0.114). However, in patients with lymph node metastasis who underwent adjuvant chemotherapy, the three-year DFS rate was 44.4% in the MBC group and 72.5% in the TN-IDC group (P = 0.025). The authors found that MBC had a poorer clinical outcome than did IDC. In breast cancer patients with nodal metastasis, MBC had a poorer prognosis than did TN-IDC, despite adjuvant chemotherapy.

Cutaneous mixed tumor, eccrine variant: a clinicopathologic and immunohistochemical study of 50 cases, with emphasis on unusual histopathologic features.

Mixed tumor, eccrine type, is a rare cutaneous adnexal neoplasm, mostly reported as isolated case reports. A systematic analysis of its histopathologic and immunohistochemical features has not previously been performed on a large series. The purpose of our investigation was to study a large number of cutaneous eccrine mixed tumors so as to fully characterize the entire spectrum of changes in the epithelial and stromal components, with an emphasis on unusual histopathologic features that may represent a diagnostic pitfall. This article reports a light microscopic and immunohistochemical study of 50 cases of eccrine mixed tumor, complemented by a literature review. Our study identified some unusual histopathologic features, thus extending the morphologic spectrum of this neoplasm. These included prominent cribriform areas, clear cell change, pseudorosette structures, prominent osseous metaplasia, and physaliphorous-like cells. Most of these features have not been previously recorded in eccrine mixed tumors and may represent a potential diagnostic pitfall.

Primary malignant mixed müllerian tumor of the peritoneum a case report with review of the literature.

Malignant mixed Müllerian tumor is a rare malignancy of the genital tract and extremely uncommon in extragenital sites. This report describes a case of malignant mixed Müllerian tumor arising in the lower peritoneum of a 72-year-old female patient. The patient presented with ascites, lower abdominal mass and pleural effusion. The serum level of CA125 was elevated. At operation a diffuse carcinosis associated with tumor mass measuring 20 × 15 × 10 cm in the vesicouterine and Duglas' pouch were found. The uterus and the adnexa were unremarkable. Histopathology revealed a typical malignant mixed Müllerian tumor, heterologous type. The epithelial component was positive for cytokeratin 7 and vimentin whereas the mesenchymal component was positive for Vimentin, S100 and focally for CK7. The histogenesis of this tumor arising from the peritoneum is still speculative. Based on the previous reports and the immunohistochemical analysis of our case, we believe that this is a monoclonal tumor with carcinoma being the "precursor" element. Nevertheless, further molecular and genetic evidence is needed to support such a conclusion.

A case of mixed ductal-endocrine carcinoma of the pancreas.

A 66-year-old male patient underwent a stomach-preserving pancreatoduodenectomy procedure because of a tumor located around the lower bile duct under the diagnosis of carcinoma of the lower bile duct. The tumor (3.5 × 2.5 cm) was found at the head of the pancreas and had invaded the papillae of Vater at the duodenum. Histology findings indicated both ductal adenocarcinoma and endocrine tumor. The ductal adenocarcinoma component expressed carcinoembryonic antigen, cytokeratin (CK)-19, CK-20, carbohydrate 19-9, and amylase, whereas the endocrine component, which occupied about one-third of the tumor, expressed glucagon, neuron-specific enolase, and chromogranin A. The Ki-67 labeling indices of the two components were 49.7% and 5.3%, respectively. Herein, we present this case of mixed ductal-endocrine carcinoma of the pancreas. Our findings indicate that its aggressive mass may be ascribable to the adenocarcinoma component with a high proliferative potential.

Carcinosarcoma (adenocarcinoma, neuroendocrine carcinoma, undifferentiated carcinoma and chondrosarcoma) of the gallbladder.

We present an extremely rare case of carcinosarcoma with 4 different tumor components in an 88-year-old female. After a diagnosis of acute cholecystitis, we performed percutaneous transhepatic gallbladder drainage in the patient without success, followed by a cholecystectomy and choledocholithotomy. The mass was a 60 × 25 mm polypoid lesion of the gallbladder identified histologically as a carcinosarcoma with adenocarcinoma, neuroendocrine carcinoma, undifferentiated carcinoma and chondrosarcoma components. The biliary-type adenocarcinoma portion exhibited acinar growth patterns with columnar cells having large and markedly hyperchromatic nuclei. These tumor cells were immunohistochemically positive for MUC1 and CDX2. The neuroendocrine carcinoma, small cell type, cells were densely packed and small, with scant cytoplasm, finely granular nuclear chromatin and absence of nucleoli. The mitotic index was high. These tumor cells were immunohistochemically positive for synaptophysin, Ki-67 (index 40%), MUC1, CDX2 and c-Kit. The undifferentiated carcinoma consisted exclusively of spindle cells containing large, markedly hyperchromatic nuclei with a high mitotic index. These tumor cells were immunohistochemically positive for AE1/AE3. The chondrosarcoma was composed of blue-gray chondroid matrix and atypical chondrocytes containing large, hyperchromatic nuclei. These tumor cells were immunohistochemically positive for S100. Its attributes might be suggestive of a greater malignant potential and pathogenesis of carcinosarcoma.

Apocrine mixed tumor of the skin with a prominent pilomatricomal component.

Pilomatrical differentiation within an apocrine mixed tumor (AMT) when present is only focal and has not been reported to be extensive. We herein report an AMT with prominent pilomatrical differentiation. A 47-year-old male presented with a 0.7 cm lesion on the right eyebrow. Histologic sections revealed, underneath a neurofibroma, a well-circumscribed tumor composed of nodules of branching epithelial elements and occasional keratinous cysts within a myxoid and lipomatous stroma. The ductal structures appeared to be composed of two layers of basophilic cuboidal cells and exhibited decapitation secretion. In approximately 50% of the tumor, eosinophilic ghost/shadow cells associated with a foreign body giant cell reaction formed a nodule resembling a pilomatricoma. Focally, columns of matrical cells were seen giving rise to shadow cells. Cytokeratin (CK) 5/6 and CK14 labeled the epithelial component. CK7, CK19 and Ber-EP4 labeled the ductal structures. Carcinoembryonic antigen and epithelial membrane antigen highlighted the luminal surface. S100 stained the stromal cells within the myxoid matrix, adipocytes and spindle cells within the overlying neurofibroma. CK10 highlighted the corneocytes within the keratinous cysts. CK17 labeled the epithelial lining of the keratinous cyst. The presence of follicular and apocrine differentiation within our tumor reinforces the common embryologic derivation of these elements.

An unusual mixed tumor of the pancreas: sonographic and MDCT features.

CONTEXT: Mixed tumors of the pancreas are exceedingly rare. CASE REPORT: We herein report on a 54-year-old female who presented with an enlarging cystic lesion in the head of the pancreas. Right upper quadrant ultrasound and multidetector-row CT scan showed a well-defined unilocular cystic tumor located in the head of the pancreas and surrounded, in part, by a hypervascular solid mass. CONCLUSION: Although mixed exocrine/endocrine pancreatic tumors have been described previously, to the best of our knowledge, this is the first case of a pancreatic mixed intraductal papillary mucinous neoplasm/endocrine tumor with illustration of its ultrasound and CT features. Moreover, the importance of preoperative analysis of imaging features in the assessment of pancreatic neoplasms is discussed.

Do clinical and immunohistochemical findings of pure mucinous breast carcinoma differ from mixed mucinous breast carcinoma?

Mucinous carcinoma of the breast is a relatively rare histologic type with two subtypes: pure and mixed. It has a favourable prognosis with a low risk of axillary metastases. The prognosis for pure mucinous carcinoma (PMC) was much better than for the mixed mucinous carcinoma (MMC). The aim of the study is to determine suitable candidates for breast or axillary conservation in mucinous carcinoma subtypes. The slides of 26 pure and 23 mixed mucinous carcinomas of the breast were evaluated. The clinical, pathological and immunohistochemical features between PMCs and MMCs were compared. MMC displayed greater metastatic potential (p < 0.05), p53 positivity (p < 0.05) and c-erbB-2 positivity (p <0.001) than PMCs. PMCs smaller than 2 cm had less metastatic capacity and extranodal invasion compared to MMCs smaller than 2 cm (p < 0.001 and p < 0.01, respectively). MMCs smaller than 2 cm displayed weaker ER positivity but greater c-erbB-2 positivity than PMCs smaller than 2 cm (p < 0.01). In conclusion, MMC had worse prognostic factors than PMC with both types of mucinous carcinoma showing similar ER and PR positive status. Even if PMCs and especially smaller PMCs display more favourable prognostic features, including less axillary lymph node involvement, it is appropriate to use sentinel lymph node biopsy to make better axillary assessment.

Mixed-type gastric carcinomas exhibit more aggressive features and indicate the histogenesis of carcinomas.

To investigate the pathobiological behaviors of gastric mixed-type (MT) carcinomas and gastric carcinogenesis, the clinicopathological characteristics of MT carcinomas were analyzed and compared with intestinal-type (IT) and diffuse-type (DT) carcinomas. The expression of Ki-67, caspase-3, p53, fragile histine triad (FHIT), maspin, extracellular matrix metalloproteinase inducer (EMMPRIN), vascular growth factor (VEGF), MUC-2, 4, 5AC and 6, CD44, E-cadherin, beta-catenin, and phosphorylated glycogen synthase kinase 3beta-ser9 (P-GSK3beta-ser9) was examined on tissue microarrays using immunohistochemistry. It was found that MT carcinomas exhibited large size, deep invasion, frequent local invasion, and lymph node metastasis in comparison with IT and DT carcinomas (p < 0.05). All the markers except MUC-5AC showed higher expression in IT than DT carcinomas (p < 0.05). The expression of maspin, EMMPRIN, VEGF, MUC-4, and membrane E-cadherin was stronger in MT intestinal than diffuse component (p < 0.05). Immunoreactivities to Ki-67, EMMPRIN, and VEGF were weaker in IT carcinoma than in the MT intestinal portion (p < 0.05), while the opposite was true for CD44, MUC-2, and MUC-6 (p < 0.05). The MT diffuse component displayed a higher expression of FHIT, VEGF, and P-GSK3beta-ser9 than DT carcinoma (p < 0.05). The accumulative survival rate of the IT carcinoma patients was higher than the other types (p < 0.05). The invasive depth, venous invasion, lymph node, peritoneal or liver metastasis, and Lauren's classification were independent prognostic factors for gastric carcinomas (p < 0.05). These findings suggested that MT carcinomas were also indicated to be more aggressive than IT and DT carcinomas. Significant differences were observed in the proliferation, apoptosis, angiogenesis, mucin secretion, and cell adhesion between IT and DT carcinomas, whereas only a few of these characteristics showed differences between the MT intestinal and diffuse parts, thus suggesting that both the MT components might originate from the stem cells with similar genetic traits, but follow different histogenic pathways.

Transformed dermatofibrosarcoma protuberans: real time polymerase chain reaction detection of COL1A1-PDGFB fusion transcripts in sarcomatous areas.

BACKGROUND: Recent cytogenetic studies have shown that reciprocal translocation t (17;22)(q22;q13) and a supernumerary ring chromosome derived from the translocation r(17;22) are highly characteristic of dermatofibrosarcoma protuberans (DFSP). The chromosomal rearrangements fuse the collagen type Ialpha1 (COL1A1) and the platelet-derived growth factor B-chain (PDGFB) genes. The COL1A1-PDGFB fusion transcript has been shown not only in conventional DFSP but also in a small series of DFSP with fibrosarcomatons areas (DFSP-FS) using reverse transcriptase-based conventional polymerase chain reaction. Nothing is known about the status of the COL1A1-PDGFB chimaeric gene in the pleomorphic areas of DFSP-PleoSarc (formerly known as DFSP-malignant fibrous sarcoma). AIMS: To show the COL1A1-PDGFB fusion transcript in transformed malignant fibrous histiocytoma. METHOD: A real-time polymerase chain reaction assay for the COL1A1-PDGFB fusion transcript in a series of DFSP containing sarcoma was conducted to determine whether the chimaeric gene could be identified in both components of DFSP-FS and DFSP-PleoSarc. Eight cases were analysed. RESULTS: In seven cases, transcriptable RNA was detected, and in these cases, translocations were found between COL1A1 and PDGFB genes involving exons 27, 32, 34, 40 and 47 of the COL1A1 gene and exon 2 of the PDGFB gene. CONCLUSIONS: From a diagnostic aspect, this assay can be particularly useful in confirming the diagnosis of sarcomatous DFSP. On the other hand, the COL1A1-PDGFB fusion gene was shown in three cases of DFSP containing pleomorphic sarcoma, which supports the theory of the common histogenesis.

Sarcomatoid carcinoma with a predominant basaloid squamous carcinoma component: the first report of an unusual biphasic tumor of the ureter.

Malignant tumors of the ureter that display biphasic patterns are very rare; they include carcinosarcomas, sarcomatoid carcinomas and carcinomas with pseudosarcomatous stroma. Although the distinction between carcinosarcomas and sarcomatoid carcinomas has been extensively discussed in the past, the recent World Health Organization classification of urinary tract tumors (2004) does not distinguish the two lesions and use the term sarcomatoid carcinoma to represent these biphasic tumors. The epithelial components of previously reported ureteral biphasic tumors comprise transitional cell carcinoma, squamous cell carcinoma, carcinoma in situ, small cell carcinoma and adenocarcinoma. In this paper, we report the first case of sarcomatoid carcinoma of the ureter with a predominant basaloid squamous carcinoma component. A 63-year-old man who had developed asymptomatic gross hematuria was diagnosed with a right ureteral tumor and underwent a right nephroureterectomy. Macroscopic examination of the excised tumor revealed a polypoid mass. Histopathologic examination exposed a tumor with malignant epithelial and sarcomatous components. The malignant epithelial component was predominantly composed of basaloid squamous carcinoma, and the sarcomatous component was mostly composed of undifferentiated spindle cells. A small focus of a chondrosarcomatous component was present. There were also transitional zones between the two components. In addition, the spindle cells of the sarcomatous component were partially positive for cytokeratin 7. We believe that the findings of this case study will increase the morphological diversity used for diagnosing malignant tumors of the ureter.

Salivary gland-type tumors with myoepithelial differentiation arising in pulmonary hamartoma: report of 2 cases of a hitherto unrecognized association.

Reported is a hitherto unrecognized association of pulmonary hamartomas with salivary gland-type tumors showing myoepithelial differentiation, namely, a case of myoepithelioma arising in a otherwise classic hamartoma with cartilage predominance, and a case of malignant mixed tumor arising in a predominantly fibrous hamartoma resembling müllerian adenofibroma. The tumors occurred in middle-aged female patients of 35 and 44 years, respectively, and presented as 7 cm (treated with lobectomy) and 13 cm (treated with pneumonectomy) masses of the right upper lobe showing a short clinical history of cough, dyspnea, and wheezing. Both lesions did not present regional lymph node metastases after mediastinal lymphadenectomy. The myoepithelioma patient was well with no signs of recurrent disease at 6-month clinical control, but she was then lost to follow-up; the malignant mixed tumor patient is alive and well after 6 months since operation. Both tumors presented with morphologic and immunohistochemical features of myoepithelial cells, and we interpret them as being derived from a myoepithelial-like stromal cell population found within the hamartomatous areas, which is also consistently detected in classic pulmonary hamartoma. The lack of individual cell necrosis, mitotic activity, cell atypia, and pulmonary parenchyma infiltration supported a diagnosis of benign or unproven malignant potential tumor for the myoepithelioma, whereas the reverse held true for the other tumor in which the diagnosis of malignant mixed tumor of the lung was rendered. Their main importance of recognizing this association lies in separating these tumors histologically from other monophasic or biphasic tumors, either primary or secondary, such as pulmonary sarcomatoid carcinomas or true sarcomas, and metastatic salivary gland tumors, spindle cell carcinomas, melanomas, and soft tissue and visceral sarcomas.

Adenoid cystic/basal cell carcinoma of the prostate strongly expresses HER-2/neu.

Adenoid cystic/basal cell carcinoma (ACBCC) is a rare neoplasm in the prostate. Definitive treatment is warranted, as among 19 patients previously reported by us, 5 had extraprostatic extension and 4 were metastatic. The HER-2/neu (c-erbB-2) gene has been reportedly overexpressed in adenoid cystic carcinomas in other organs, but its status in prostatic ACBCC was uncertain. Immunohistochemical staining and in situ hybridisation were carried out in 13 patients with ACBCC (11 from transurethral resection, 2 prostatectomy). One patient had metastasis to the lung. Citrate buffer and steam heat were used for antigen retrieval. Ten acinar adenocarcinomas of varying grades were also immunostained as controls. Protein and mRNA expression were 2+ to 3+ (of 3+) in all patients with ACBCC, compared to a breast cancer control with strong reactivity, whereas protein expression was noted in only one acinar carcinoma and mRNA expression was absent in all acinar carcinomas. Benign acini expressed HER-2/neu only in the basal layer. The finding of strong, consistent HER-2/neu expression in ACBCC suggests that treatment with Herceptin (trastuzumab) may be effective in patients with this rare tumour.

Recent Updates on Neuroendocrine Tumors From the Gastrointestinal and Pancreatobiliary Tracts.

CONTEXT: -Gastrointestinal (GI) and pancreatobiliary tracts contain a variety of neuroendocrine cells that constitute a diffuse endocrine system. Neuroendocrine tumors (NETs) from these organs are heterogeneous tumors with diverse clinical behaviors. Recent improvements in the understanding of NETs from the GI and pancreatobiliary tracts have led to more-refined definitions of the clinicopathologic characteristics of these tumors. Under the 2010 World Health Organization classification scheme, NETs are classified as grade (G) 1 NETs, G2 NETs, neuroendocrine carcinomas, and mixed adenoneuroendocrine carcinomas. Histologic grades are dependent on mitotic counts and the Ki-67 labeling index. Several new issues arose after implementation of the 2010 World Health Organization classification scheme, such as issues with well-differentiated NETs with G3 Ki-67 labeling index and the evaluation of mitotic counts and Ki-67 labeling. Hereditary syndromes, including multiple endocrine neoplasia type 1 syndrome, von Hippel-Lindau syndrome, neurofibromatosis 1, and tuberous sclerosis, are related to NETs of the GI and pancreatobiliary tracts. Several prognostic markers of GI and pancreatobiliary tract NETs have been introduced, but many of them require further validation. OBJECTIVE: -To understand clinicopathologic characteristics of NETs from the GI and pancreatobiliary tracts. DATA SOURCES: -PubMed (US National Library of Medicine) reports were reviewed. CONCLUSIONS: -In this review, we briefly summarize recent developments and issues related to NETs of the GI and pancreatobiliary tracts.