bromochloroacetic-acid and Neoplasms--Complex-and-Mixed

In skin containing hair follicles, specialized epithelial structures known as "touch domes (TDs)" are located where the Merkel cells are clustered. We explored the histogenetic relationship between intraepidermal and dermal Merkel cell carcinomas (MCCs) and investigated which transformed progenitor cells can develop into intraepidermal MCC. We encountered an association between an extremely rare case of dermal and intraepidermal MCC with squamous cell carcinoma, which was examined using standard immunohistochemical methods with various epithelial, neuroendocrine, and TD markers including several immunohistochemical markers. Differential expression levels of CK20 and CD56 were found between intraepidermal and dermal MCCs, indicating molecularly distinct MCC populations. CK15 and CK17, expressed in TDs, were partially expressed in the intraepidermal neuroendocrine component at the tumor periphery in intraepidermal MCC with squamous cell carcinoma. These differences may suggest that the origin of dermal and intraepidermal MCCs is different under pathological conditions. We hypothesize that intraepidermal MCC is derived from tissue-specific stem cells localized within TDs.

Topics: Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Cell Lineage; Female; Humans; Immunohistochemistry; Keratins; Merkel Cells; Neoplasms, Complex and Mixed; Neoplastic Stem Cells; Skin Neoplasms

Metaplastic breast carcinoma (MBC) is relatively rare but accounts for a significant proportion of global breast cancer mortality. This group is extremely heterogeneous and by definition exhibits metaplastic change to squamous and/or mesenchymal elements, including spindle, squamous, chondroid, osseous, and rhabdomyoid features. Clinically, patients are more likely to present with large primary tumours (higher stage), distant metastases, and overall, have shorter 5-year survival compared to invasive carcinomas of no special type. The current World Health Organisation (WHO) diagnostic classification for this cancer type is based purely on morphology - the biological basis and clinical relevance of its seven sub-categories are currently unclear. By establishing the Asia-Pacific MBC (AP-MBC) Consortium, we amassed a large series of MBCs (n = 347) and analysed the mutation profile of a subset, expression of 14 breast cancer biomarkers, and clinicopathological correlates, contextualising our findings within the WHO guidelines. The most significant indicators of poor prognosis were large tumour size (T3; p = 0.004), loss of cytokeratin expression (lack of staining with pan-cytokeratin AE1/3 antibody; p = 0.007), EGFR overexpression (p = 0.01), and for 'mixed' MBC, the presence of more than three distinct morphological entities (p = 0.007). Conversely, fewer morphological components and EGFR negativity were favourable indicators. Exome sequencing of 30 cases confirmed enrichment of TP53 and PTEN mutations, and intriguingly, concurrent mutations of TP53, PTEN, and PIK3CA. Mutations in neurofibromatosis-1 (NF1) were also overrepresented [16.7% MBCs compared to ∼5% of breast cancers overall; enrichment p = 0.028; mutation significance p = 0.006 (OncodriveFM)], consistent with published case reports implicating germline NF1 mutations in MBC risk. Taken together, we propose a practically minor but clinically significant modification to the guidelines: all WHO_1 mixed-type tumours should have the number of morphologies present recorded, as a mechanism for refining prognosis, and that EGFR and pan-cytokeratin expression are important prognostic markers. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Topics: Antigens, CD; Biomarkers, Tumor; Breast Neoplasms; Cadherins; Class I Phosphatidylinositol 3-Kinases; Cross-Sectional Studies; Epithelial-Mesenchymal Transition; ErbB Receptors; Female; Genetic Predisposition to Disease; Humans; Keratins; Metaplasia; Middle Aged; Mutation; Neoplasm Grading; Neoplasms, Complex and Mixed; Neurofibromin 1; Phenotype; PTEN Phosphohydrolase; Tumor Burden; Tumor Suppressor Protein p53

Gangliocytomas originating in the sellar region are rare; most are tumors composed of gangliocytic and pituitary adenomatous elements, forming the so-called mixed gangliocytoma-pituitary adenoma. The majority of mixed gangliocytoma adenomas are associated with endocrinopathies, mainly acromegaly and less often Cushing disease and hyperprolactinemia. In the present study, 10 cases of mixed gangliocytoma and somatotroph adenomas were evaluated for patterns of cellular differentiation and expression of lineage-specific transcription factors. The tumors were characterized by immunohistochemistry for pituitary hormones, cytokeratins, Pit-1, and the neuronal markers NeuN, neurofilaments (NFP), and MAP2. Double-labeling immunohistochemistry for Pit-1/GH, Pit-1/NFP, Pit-1/MAP2, and NeuN/GH was performed in 9/10 tumors. Our data demonstrate that both adenomatous and ganglionic cells express the acidophilic lineage transcription factor Pit-1. Although mixed gangliocytomas and somatotroph adenomas show histologically distinct cellular populations, there is at least a small population of cells that coexpress the Pit-1 transcription factor and neuronal-associated cytoskeletal proteins favoring the theory of transdifferentiation of neuroendocrine cells into neuronal elements of these mixed tumors.

Topics: Adenoma; Adult; Antigens, Nuclear; Biomarkers, Tumor; Biopsy; Cell Differentiation; Cell Lineage; Female; Ganglioneuroma; Hormones; Humans; Immunohistochemistry; Keratins; Male; Microtubule-Associated Proteins; Middle Aged; Neoplasms, Complex and Mixed; Nerve Tissue Proteins; Neurofilament Proteins; Pituitary Neoplasms; Transcription Factor Pit-1

We describe the clinicopathological, immunohistochemical, and molecular features of 3 primary juxtacortical myoepithelioma/mixed tumor of bone. The patients were 2 males (13 and 23 years of age) and a 15-year-old female. The juxtacortical lesions were all located in the femur, and were surgically removed, 2 with wide margins and one with marginal margins. This latter tumor recurred locally 18 months later. The 3 patients were free of disease at 6 to 17 months follow-up. Histologically, all lesions showed a prominent multinodular architecture, and were formed by epithelioid and stellate elements, organized in solid sheets, or embedded in myxoid or chondroid matrix. Areas of osteoid formation were also observed. One tumor had the appearance of classical mixed tumor, showing aspects of duct formation and focal squamous differentiation. Immunohistochemically, all cases were positive for cytokeratins, epithelial membrane antigen, and S100 protein. The expression of other myoepithelial markers, including p63, glial fibrillary acid protein and calponin was more limited. No rearrangement of Ewing sarcoma region 1 (EWSR1) and fused in sarcoma (FUS) genes was observed by fluorescent in situ hybridization. To our knowledge, this is the first report of primary myoepitheliomas of bone arising at juxtacortical sites. These lesions must be distinguished from other benign and malignant bone and cartilage-forming surface tumors, including periosteal chondroma and chondrosarcoma, juxtacortical chondromyxoid fibroma, and periosteal and paraosteal osteosarcoma. The clinicoradiologic presentation and their histological and immunohistochemical features are distinctive enough to allow the separation from these entities.

Topics: Adolescent; Biomarkers, Tumor; Bone Neoplasms; Disease-Free Survival; DNA, Neoplasm; Female; Femur; Humans; In Situ Hybridization, Fluorescence; Keratins; Male; Mucin-1; Myoepithelioma; Neoplasms, Complex and Mixed; Radiography; Recovery of Function; Retrospective Studies; S100 Proteins; Treatment Outcome; Young Adult

This report describes 3 cases of a distinctive, hitherto unreported gastric epitheliomesenchymal biphasic tumor that differs from other biphasic tumors of the stomach and elsewhere: carcinosarcoma, biphasic synovial sarcoma, teratoma, and mixed tumor. The tumors occurred in young adults, 2 males and 1 female, of ages 19, 27, and 30 years. Two tumors were located in the greater curvature in the gastric body and one in the antrum. The tumors measured 5, 6, and 15 cm in maximum diameter, and their mitotic rates were 0, 4, and 30 mitoses per 50HPF. There were 2 components: uniform oval or spindled cells in diffuse sheets, and clusters or cords of epithelial cells occasionally forming glandular structures with small lumens. The epithelial elements were positive for keratin cocktail AE1/AE3, keratin 18, and partly for keratin 7, but were negative for keratins 5/6, 20 and epithelial membrane antigen. The spindle cells were positive for vimentin and CD10. All components were negative for CD34, CD99, estrogen receptor, KIT, smooth muscle actin, desmin S100 protein, p63, calretinin, chromogranin, synaptophysin, CDX2, and thyroid transcription factor 1. In situ hybridization for SS18 rearrangement was negative in all cases separating this tumor from synovial sarcoma. All 3 patients were alive after follow-up of 3.5, 5, and 14 years. Because these tumors have some resemblance to blastomas of other organs, we propose the term "gastroblastoma" for this distinctive, at least low-grade malignant epitheliomesenchymal tumor of the stomach.

Topics: Adult; Biomarkers, Tumor; Carcinosarcoma; Disease-Free Survival; DNA, Neoplasm; Female; Gastrectomy; Humans; In Situ Hybridization, Fluorescence; Keratins; Male; Neoplasms, Complex and Mixed; Neprilysin; Stomach Neoplasms; Treatment Outcome; Vimentin; Young Adult

Biphasic ductal and myoepithelial lesions of the breast are uncommon. A majority of these rare lesions behave in a benign fashion. Malignancy is rare, and preferentially involves the epithelial component. Malignancy in both epithelial and myoepithelial components is even rarer. We report such a case, employing the use of a range of cytokeratins and myoepithelial markers to delineate the extent of each component. In addition, we apply the relatively novel technique of multi-immunolabeling combined with Adobe Photoshop imaging to highlight the different components of the neoplasm on the same tissue section. These ancillary tests can provide much needed information about the contribution of epithelial or myoepithelial components to malignant tumors, hence providing the gateway to further study into their histogenesis and natural history.

Topics: Antigens, Neoplasm; Breast; Breast Neoplasms; Epithelial Cells; Female; Fluorescent Antibody Technique; Humans; Immunohistochemistry; Immunophenotyping; Keratins; Middle Aged; Myoepithelioma; Neoplasms, Complex and Mixed

An unusual tumor of the neck in a 56-year-old female is reported. The tumor was composed of tubules and small cords of epithelial cells dispersed in the fibromyxoid and adipose stroma. At the periphery, the tumor was not encapsulated and its border was intermingled with the subcutaneous fat. Lack of decapitation secretion and the absence of long tubules suggested an eccrine origin; however, in some of the tumor areas, the cells showed brightly eosinophilic copious cytoplasm that may indicate an apocrine differentiation. As an area of chondroid metaplasia was identified, the diagnosis of a mixed tumor was rendered. This unusual type of skin adnexal neoplasm with unique relation of the epithelial component to the surrounding adipose tissue requires differentiation with the primary cutaneous and metastatic carcinomas.

Topics: Adipocytes; Adipose Tissue; Biomarkers, Tumor; Diagnosis, Differential; Female; Head and Neck Neoplasms; Humans; Immunohistochemistry; Keratins; Lipoma; Middle Aged; Neoplasm Metastasis; Neoplasms, Complex and Mixed; Skin Neoplasms

Benign mixed epithelial and stromal tumor of the kidney (MEST) is a new, rare entity. These tumors are composed of two components: a stromal and an epithelial one. Clinical outcome is usually good, no specific cytogenetic alterations have been described up to now. We describe for the first time a case with translocation t (1; 19).

Topics: Actins; Adult; Biomarkers, Tumor; Carcinoma, Renal Cell; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Cysts; Desmin; Diagnosis, Differential; Humans; Keratins; Kidney Neoplasms; Male; Neoplasms, Complex and Mixed; Neoplasms, Glandular and Epithelial; Nephrectomy; Stromal Cells; Translocation, Genetic

A mixed epithelial and mesenchymal tumor of the liver arising in an adult is rare and is mostly classified as sarcomatoid hepatocellular carcinoma (HCC). In this study, a case of sarcomatoid HCC in an adult with hepatoblastoma (HB)-like features, which produced difficulty in the differential diagnosis between sarcomatoid HCC and mixed HB, is presented. The epithelial component of the tumor composed of poorly differentiated HCC, Edmondson's grade III, and more primitive components, which were embryonal and small cell undifferentiated components of HB-like areas. The small undifferentiated cells surrounded HCC and the embryonal component of HB-like area, and revealed transition partly to areas of rhabdomyosarcoma. A small portion of chondrosarcoma was also noted. Immunohistochemical analysis showed that HCC and the embryonal component of HB-like areas expressed alpha-fetoprotein (AFP) and cytokeratin 8. The small undifferentiated cells were negative for AFP but stained with cytokeratin 8 as well as CD56, which is a marker of primitive cells in many sarcoma and HB. It is not certain whether small undifferentiated cells belong to hepatic progenitor cells or primitive mesenchymal cells. Polymerase chain reaction-single-strand conformation polymorphism analysis for beta-catenin mutation using microdissection revealed no mutation of any components. A review was undertaken of the cases previously reported as adult hepatoblastoma without detailed immunohistochemical study and consider many of them may be sarcomatoid HCC. These primitive and sarcomatoid components would be arising from the dedifferentiation process of HCC.

Topics: Aged; alpha-Fetoproteins; Biomarkers, Tumor; Carcinoma, Hepatocellular; CD56 Antigen; Diagnosis, Differential; Fatal Outcome; Hepatoblastoma; Humans; Immunoenzyme Techniques; Keratins; Liver Neoplasms; Male; Neoplasms, Complex and Mixed; Sarcoma; Tomography, X-Ray Computed

We report a case of asymptomatic mesoblastic nephroma in a 54-year-old woman. The tumor showed immunohistochemical reactions similar to developing nephrons. Electron microscopy showed immature tubules with numerous intracytoplasmic intermediate filaments. Recent studies support the concept of pathogenesis of the mesoblastic nephroma originating from collecting ducts. However, this case exhibited a complex pattern of antigenic expression not restricted to the collecting ducts, but including the glycoprotein CD24 and the neural cell adhesion molecule (NCAM). The following differential diagnoses will be discussed: benign mixed epithelial and stromal tumor, metanephric adenoma, and nephrogenic adenofibroma.

Topics: Adenofibroma; Adenoma; Antigens, CD; Biomarkers, Tumor; CD24 Antigen; Diagnosis, Differential; Female; Humans; Immunoenzyme Techniques; Intermediate Filaments; Keratin-7; Keratins; Kidney Neoplasms; Membrane Glycoproteins; Middle Aged; Neoplasms, Complex and Mixed; Neoplasms, Glandular and Epithelial; Nephroma, Mesoblastic; Neural Cell Adhesion Molecules; Tomography, X-Ray Computed

Transgenic mice which express the simian virus 40 large T-antigen (Tag) under the regulatory control of the hormone responsive rat C3(1) gene develop unusual lesions of heterotopic bone growth associated with mixed tumor formation arising from eccrine sweat glands found only in the foot pads of mice, ischiocavernosus muscle adjacent to bulbourethral glands and occasionally the salivary and mammary glands. These lesions are very similar to mixed tumors arising in several types of human cancers. Based upon electron microscopic examination and immunocytochemical analyses of cellular differentiation markers, the mixed proliferative lesions in this transgenic mouse model begin with the Tag-induced proliferation of epithelial and myoepithelial cells. The proliferation of these two types of cells results in hyperplasia and adenomatous transformation of the epithelial component, whereas the proliferating myoepithelial cells undergo metaplasia to form chondrocytes which deposit extracellular matrix, including collagen fibers. Cartilage develops focally between areas of epithelial proliferation and subsequently ossifies through a process of endochondrial bone formation. The metaplasia of myoepithelial cells to chondrocytes appears to require the inductive interaction of factors produced by the closely associated proliferating epithelial cells, including members of the TGF-beta superfamily. We demonstrate that TGF-beta1 protein accumulates in the extracellular matrix of the lesions, whereas RNA in situ hybridization reveals that BMP-2, another strong inducer of heterotopic bone formation, is overexpressed by the proliferating epithelial cells during the development of ectopic bone. The formation of sarcomatous tumors within the mixed tumors appears to be androgen-dependent and more frequent in mice lacking a normal allele of p53. This process of cartilage and bone induction may mimic epithelial-mesenchymal interactions which occur during embryonic bone formation. These transgenic mice may provide new insights into the processes of ectopic endochondrial bone formation associated with mixed tumor formation and serve as a useful model for human heterotopic bone disease.

Topics: Actins; Androgen-Binding Protein; Animals; Antigens, Viral, Tumor; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Ectodysplasins; Female; Foot Diseases; Gonadal Steroid Hormones; Immunohistochemistry; In Situ Hybridization; Keratins; Male; Membrane Proteins; Mice; Mice, Transgenic; Mutation; Neoplasms, Complex and Mixed; Ossification, Heterotopic; Phosphatidylethanolamine Binding Protein; Proliferating Cell Nuclear Antigen; Prostatein; Secretoglobins; Tolonium Chloride; Transforming Growth Factor beta; Tumor Suppressor Protein p53; Uteroglobin; Vimentin