Immunohistochemistry in diagnosis of soft tissue tumours

Immunohistochemistry in soft tissue tumours, and especially sarcomas, is used to identify differentiation in the neoplastic cells. In some cases, specific antigens are expressed; however, an initial panel of antibodies is often required in order to establish the broad lineage, with a subsequent, more focused, panel to allow classification. Immunohistochemical evaluation must be employed with the clinical picture, the morphology, and, when necessary, other ancillary techniques such as molecular genetics and cytogenetics. Whereas some diagnoses are evident on morphology, many soft tissue neoplasms are seen microscopically as spindle cell, epithelioid cell, small round cell or pleomorphic tumours that need to be further characterized. This article reviews selected applications of immunohistochemistry in the diagnosis of each of the principal morphological groups, concentrating on areas of most use in daily practice.     

The comparative roles of electron microscopy and immunohistochemistry in the diagnosis of soft tissue tumours

Electron microscopy has contributed to the diagnosis of soft tissue tumours for four decades, and immunohistochemistry for two. Because of its relative ease of use and interpretation, the latter technique has become extensively and routinely applied to identify lines of differentiation in benign soft tissue tumours and in sarcomas. The use of electron microscopy has declined but retains a role because few antibodies are wholly specific or fully sensitive, some tumours are polyphenotypic or divergent in differentiation, and others have no specific antigens. Immunohistochemistry is superior in diagnosis of smooth muscle tumours, small round cell tumours, sarcomas with epithelioid morphology, and most synovial sarcomas. Electron microscopy is of particular value for peripheral nerve sheath tumours, marker-negative synovial sarcomas, pleomorphic sarcomas and mesotheliomas. As with all adjunctive techniques, immunohistochemistry and electron microscopy should be used in a complementary fashion according to the nature of the diagnostic problem.     

The value of immunohistochemistry in medullary thyroid carcinoma: a systematic study of 30 cases

Thirty cases of medullary thyroid carcinoma were investigated by immunoperoxidase staining techniques to evaluate the diagnostic significance of neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), somatostatin (SOM), a-subunit of human chorionic gonadotrophin (a-hCG), serotonin (5-HT) and adrenocorticotropic hormone (ACTH) immunoreactivity as diagnostic markers in comparison to different calcitonin (CT) staining patterns. Twenty three cases exhibited a strong (group I) or moderate (group II) staining intensity for CT and did not need further immunocytochemical proof for classifying them as medullary carcinoma. From seven cases which showed only a weak or borderline CT-immunoreactivity (group III), six stained positively for NSE and four positively for CEA. SOM-positive cells were identified in six cases and a-hCG or 5-HT-positive cells respectively in three cases of group III. Twenty follicular and 20 papillary carcinomas also included in this study did not react with any of the above mentioned antibodies. Therefore, NSE and CEA represent useful additional diagnostic markers particularly for the identification of medullary carcinoma with weak or borderline CT-immunoreactivity. The identification of other peptides may also be helpful in demarcating it from thyroid tumours of follicular cell origin.     

Cytochrome P450 expression is a common molecular event in soft tissue sarcomas

Two major xenobiotic metabolizing sub-families of cytochrome P450 (cytochrome P450 1A and cytochrome P450 3A) have been identified in soft tissue sarcomas. Cytochrome P450 1A was present in 70 per cent and cytochrome P450 3A was present in 78 per cent of tumours, respectively. A high proportion (86 per cent) of those tumours which contained cytochrome P450 1A or cytochrome P450 3A demonstrated co-expression of both sub-families. In each tumour, cytochrome P450 immunoreactivity was identified in all tumour cells and there was no intra-tumour heterogeneity. These results indicate that expression of cytochrome P450 is a common molecular event in soft tissue sarcomas and that the presence of different sub-families of cytochrome P450 has implications both for the pathogenesis and for the treatment of these tumours. Cytochrome P450 expression may influence the intrinsic drug resistance of these tumours and also provide a molecular target for anti-cancer drugs which can be activated by cytochrome P450.     

Immunohistochemistry in the diagnosis of soft tissue tumours

Immunohistochemistry is particularly important in the field of soft tissue tumours because of their variety and the frequent difficulty of diagnosis. The first part of this paper discusses useful or new antibodies, together with others that are no longer of use. The second part is devoted to the role of immunohistochemistry in the diagnosis of soft tissue tumours: identification of some rare or atypical benign lesions, identification of non-mesenchymal malignant tumours, and classification of sarcomas. The respective roles of immunohistochemistry and molecular biology are underlined.     

Atypical carcinoid tumour of the thymus: a study of eight cases

Atypical carcinoids of the thymus are rare neoplasms of uncertain prognosis. We have studied eight cases (six male, two female; age range 48–60 years, mean 55 years), none with evidence of a paraneoplastic neuroendocrine syndrome. Tumour size was large and ranged from 7.5 to 10 cm. Microscopically, all had a nesting/insular or trabecular pattern, eosinophilic cytoplasm, round nuclei with fine chromatin and small nucleoli. No small cell features were evident. Mitotic activity ranged from 2 to 21 per 1.52 mm². Focal necrosis was seen in all cases. All were positive for cytokeratin (AE1/AE3, CAM 5.2) and the neuroendocrine markers NSE, synaptophysin and chromogranin; five cases were positive for calcitonin. On electronmicroscopy all contained dense core granules, often numerous. Three cases were stage I and five stage III (infiltrating lung or chest wall). Follow-up information was available in four cases (one stage I and three stage III): the stage I tumour had local recurrence and metastasis to the lung within a year whilst the three patients with stage III tumours died of liver, bone and brain metastases within 3 years.     

Epigenetic and genetic changes in soft tissue sarcomas: a review

Soft tissue sarcomas are a versatile group of tumors with a proposed origin from mesenchymal stem cells. During recent years, the molecular biologic mechanisms behind the histogenesis of these tumors have become clearer. In addition to translocations and other genomic changes, epigenetic mechanisms have been shown to be greatly involved in the histogenesis of sarcomas as well as other cancers. Even though the molecular mechanisms behind sarcomas appear to be more complex than previously expected, epigenetic mechanisms bring new opportunities and means for the treatment of these complex diseases.     

Myofibroblasts in soft tissue sarcomas

Summary A series of 129 soft tissue sarcomas was examined ultrastructurally to determine in which neoplasms and to what extent myofibroblasts could be demonstrated. Twenty cases of fibromatosis and fasciitis served as controls.Myofibroblasts were identified in all 30 cases of malignant fibrous histiocytoma and all 4 cases of well-differentiated sclerosing liposarcoma. Though most numerous in areas of desmoplasia, in no instance did myofibroblasts constitute the dominant cellular constituent of either neoplasm. Myofibroblasts were identified with lesser frequency and in smaller numbers in fibrosarcoma, synovial sarcoma, malignant hemangiopericytoma and neuroblastoma. None were observed in a wide assortment of diverse sarcomas in which desmoplasia was not a feature. In comparison each lesion judged by light microscopy to represent either fibromatosis or fasciitis was composed principally of myofibroblasts.The demonstration of abundant myofibroblasts within a soft tissue lesion which has been subjected to wide sampling strongly suggests a benign proliferative process as opposed to a malignant neoplasm. It is hypothesized that myofibroblasts observed within collagenized regions of soft tissue sarcomas may constitute an expression of host response to neoplasia.     

Extra-medullary myeloid tumour (granulocytic sarcoma) is often misdiagnosed: a study of 26 cases

AIMS: To describe the clinicopathological and immunophenotypic features of 26 cases of extra-medullary myeloid tumour (EMMT)/granulocytic sarcoma, which remains poorly recognized and is frequently confused with malignant lymphoma, and to discuss the main diagnostic problems experienced by the referring pathologist. METHODS AND RESULTS: Haematoxylin and eosin (H & E) sections of 26 cases of EMMT were re-examined. Immunostains for myeloperoxidase, lysozyme, neutrophil elastase, LCA, CD79a, CD20, CD43, CD45RO, CD3, CD30, CD15, CD68, MAC387, VS38C, MIC2, and the Leder stain for naphthol-ASD-chloroacetate esterase were performed on all cases. Clinical and follow-up data were obtained through a questionnaire to the referring pathologist or from the notes of the patients where available. In the 10 cases with known myeloproliferative disease, the initial diagnosis was correct in 10 whereas all cases presenting with EMMT without a previous history of myeloproliferative disorder had an initial incorrect diagnosis. The most common suggested diagnosis was that of a non-Hodgkin's lymphoma. The morphology of the tumours varied from well differentiated which included all stages of myeloid differentiation to poorly differentiated or blastic showing little or no evidence of myeloid differentiation. The proportion of positive cells for each stain varied. Chloroacetate esterase, myeloperoxidase and CD15 stained a large proportion of cells of the majority of the well differentiated tumours and a smaller proportion of the poorly differentiated/blastic tumours with very focal staining of some of the cases. Lysozyme and CD43 were the most sensitive of the markers staining a large proportion of cells of the majority of the tumours in both groups. Neutrophil elastase was the least sensitive of the markers of myeloid differentiation. CD79a, CD20, CD3 and CD30 were negative in all cases. CD43 was positive in all cases. CD68 stained a substantial number of cells in the majority of tumours. A smaller proportion of the tumours stained with MAC387. Four of the tumours showed positivity for MIC2. One tumour was positive for VS38C. CONCLUSION: This series documents continuing difficulties in the diagnosis of EMMT. Even well differentiated tumours are frequently mistakenly diagnosed as malignant lymphomas when they present without any history of antecedent myeloproliferative disorder. Careful evaluation of morphology for evidence of myeloid differentiation and a high index of suspicion when confronted with a less differentiated neoplasm are required to avoid this important diagnostic error. We suggest that a panel which includes chloroacetate-esterase, myeloperoxidase, lysozyme and CD43, together with other B- and T-lineage markers, in particular CD79a and CD3 should be used to confirm the diagnosis.     

Epithelioid sarcoma mimicking angiosarcoma: The value of immunohistochemistry in the differential diagnosis

Summary Epithelioid sarcoma (ES) is a rare malignant tumour of young adults, usually presenting as a skin ulcer or subcutaneous nodule in the distal portion of the upper limb. Multiple recurrences and late metastases are typical, leading to fatality in a third to one-half of all cases. The slow evolution of the tumour is one reason for its delayed recognition. The other is its frequent histological misinterpretation, in particular, as a peculiar granulomatous reaction. In our case, the primary tumour presented a variant morphological pattern so closely mimicking a cavernous angiosarcoma as to mislead several reputable opinions. Later recurrences and metastases were typical of ES, while a focal angiomatoid pattern was maintained. The morphology and immunoreactivity to a wide spectrum of tumour markers is compared with that of six file cases of classical ES. Retrospectively, all neoplastic lesions in our patient were ES. In young adults, lesions of the upper extremity, even when angiomatoid or haemorrhagic, should raise a suspicion of ES. Once epithelioid sarcoma is suspected, the differential diagnosis can be elucidated on immunohistochemical grounds. Early diagnosis provides the best opportunity for radical surgery at a stage when the tumour has not spread locally or disseminated systemically.Presented at the combined meeting of the European Musculoskeletal Oncology Society (EMSOS) and the North American Musculoskeletal Tumor Society (MSTS), Bologna, 13 September 1989     

恶性小圆形细胞肿瘤的鉴别诊断：附79例免疫组化回顾性研究

应用免疫组化ＬＳＡＢ法，对原病理诊断意见分岐的７９例恶性小圆细胞肿瘤（ＭＳＲＣＴ）进行免疫组化鉴别诊断研究。结果除１例仍不能分类外，其余７８例（占９９％）得到明确诊断。其中有恶性淋巴瘤、未分化癌、胚胎性横纹肌肉瘤、无色素性恶、神经母细胞瘤、精原细胞瘤、骨原细胞瘤、骨外尤文瘤及未分化肉瘤。结果表明，采用多种肿瘤标志物联合标记是对不同组织起源而形态相近ＭＳＲＣＴ鉴别诊断的有效方法。     

Primary cardiac sarcomas may develop from resident or bone marrow‐derived mesenchymal stem cells: use of immunohistochemistry including CD44 and octamer binding protein 3/4

Hegyi L, Thway K, Fisher C & Sheppard M N
(2012) Histopathology  61, 966–973 Primary cardiac sarcomas may develop from resident or bone marrow‐derived mesenchymal stem cells: use of immunohistochemistry including CD44 and octamer binding protein 3/4 Aims: To provide evidence that cardiac sarcomas ‘not otherwise specified’ express markers that might indicate their cellular origin or identify any lines of differentiation. Methods and results: We reviewed all 11 cases of primary undifferentiated cardiac sarcomas found in the archives of the Royal Marsden and Royal Brompton Hospitals, London, UK during the period 2000–2009. Five cases with appropriate consent and archived material were investigated using immunohistochemistry. We found that the spindle, pleomorphic or occasionally epithelioid cell sarcomas showed no lineage‐specific differentiation other than partial myofibroblastic or ‘myoid’ differentiation (all cases). All tumours showed some degree of cytoplasmic positivity for the mesenchymal stem cell marker CD44. In contrast, no nuclear octamer binding protein 3/4 (Oct3/4) expression was seen in any of the tumours, although very patchy cytoplasmic positivity was seen in some tumours. Conclusions: The cytoplasmic positivity for CD44 and the absence of nuclear Oct3/4 suggest that the cells of these sarcomas may represent ‘daughter’ stem cells that no longer have the capacity for tumour initiation, but have subsequently developed new lines of partial differentiation. Primary cardiac sarcomas may arise from mesenchymal stem cells with the ability to generate tumours with multilineage differentiation.     

The diversity of soft tissue tumours with EWSR1 gene rearrangements: a review

Many soft tissue sarcomas have chromosomal translocations with resultant formation of new fusion genes. Among the genes that can be rearranged, the EWSR1 gene has been identified as a partner in a wide variety of clinically and pathologically diverse sarcomas as well as some non‐mesenchymal tumours. The former include Ewing sarcoma and similar (Ewing‐like) small round cell sarcomas, desmoplastic small round cell tumour, myxoid liposarcoma, extraskeletal myxoid chondrosarcoma, angiomatoid fibrous histiocytoma, clear cell sarcoma of soft tissue and clear cell sarcoma‐like tumours of the gastrointestinal tract, primary pulmonary myxoid sarcoma, extrasalivary myoepithelial tumours and sporadic examples of low‐grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma and mesothelioma. EWSR1 is a ‘promiscuous’ gene that can fuse with many different partner genes, but sometimes this results in phenotypically identical tumours. EWSR1 can, conversely, partner with the same genes in morphologically and behaviourally different neoplasms. This paper reviews the diversity of the several soft tissue tumour types that are associated with rearrangement of the EWSR1 gene.     

48例软组织平滑肌肉瘤的病理及免疫组化研究

目的：研究软组织平滑肌肉瘤（ＬＭＳ）组织学亚型的病理形态特点及其对各种肌源性标记的表达。方法：对４８例软组织ＬＭＳ作为形态学观察、组织学分型和免疫组化研究。结果：其组织学亚型依次分为普通型（Ｃ－ＬＭＳ）（７７．１％）,多形性（Ｐ－ＬＭＳ）（１２．５％）,上皮样（Ｅ－ＬＭＳ）（６．３％）和伴有破骨细胞样巨细胞（ＯＧＣ－ＬＭＳ）（４．２％）;后三种亚型和某些低分子化Ｃ－ＬＭＳ易误诊为恶性纤维组织细胞瘤     

Usefulness of immunohistochemistry in delineating renal spindle cell tumours. A retrospective study of 31 cases

AIMS: To assess the usefulness of immunohistochemistry in delineating tumour diagnoses on a series of morphologically diagnosed renal spindle cell tumours (RSCTs). METHODS AND RESULTS: Formalin-fixed paraffin-embedded tissues from 31 morphologically diagnosed tumours were reinterpreted in light of newly obtained immunohistochemical information. By morphology, six had originally been classified as sarcomatoid carcinoma, five as spindle cell tumour (NOS), four as sarcoma (NOS), three as leiomyoma, three as leiomyosarcoma, and one each as fibrous polyp, hamartoma, neurilemmoma, mesoblastic nephroma, medullary fibroma, angiomyolipoma, haemangiopericytoma, malignant rhabdoid tumour, malignant Triton tumour, and carcinosarcoma. The application of immunohistochemistry verified the original diagnosis in 18 cases (18/31, 58%), confirming the diagnosis of sarcomatoid renal carcinoma (4/6), leiomyoma (2/3), leiomyosarcoma (3/3), sarcoma (NOS) (2/4), carcinosarcoma (1/1), malignant rhabdoid tumour (1/1), malignant Triton tumour (1/1), fibrous polyp (1/1), mesoblastic nephroma (1/1), hamartoma (1/1), and angiomyolipoma (1/1). Different tumour designations were suggested in 13 cases (13/31, 42%), including carcinosarcoma, sarcoma (NOS), leiomyosarcoma, solitary fibrous tumour, monomorphic/biphasic angiomyolipoma, endometrial stromal tumour, and congenital mesoblastic nephroma. CONCLUSIONS: Our data indicate that although morphology is most important in formulating the initial differential diagnosis, the addition of immunohistochemistry is vital in arriving at the correct classification of RSCTs.