Automated diagnosis of soft tissue tumors using Machine Learning

Novel uses of immunohistochemistry in the diagnosis and classification of soft tissue tumors

Placental alkaline phosphatase (PLAP) is normally produced by primordial germ cells and syncytiotrophoblasts, and the detection of its expression has been useful in the diagnosis of germ cell tumors. We have recently observed PLAP immunoreactivity in normal human adult and fetal muscle tissue. Based on this observation, we explored the possible role of PLAP in the diagnosis of soft tissue tumors. A total of 271 tumors were studied. These included tumors with myogenic, neural, fibrous, myofibroblastic, lipomatous, neuroepithelial, perivascular, and epithelial differentiation. A formalin-fixed, paraffin-embedded section from each tumor was stained with PLAP monoclonal antibody using standard immunohistochemical methods preceded by antigen retrieval. In addition, western blotting with PLAP monoclonal antibodies was performed on fresh samples from a uterine leiomyoma, grossly normal myometrium, and placenta. Also, formalin-fixed sections of fetal skeletal muscle were labeled with double immunohistochemistry techniques using antibodies to myogenin and PLAP. Cytoplasmic PLAP reactivity was detected in all leiomyomas and rhabdomyosarcomas (100%), 7 of 15 (46%) leiomyosarcomas, 15 of 19 (79%) desmoplastic small round cell tumors, 2 of 15 (13%) gastrointestinal stromal tumors, 1 of 8 (13%) Wilms' tumors, 1 of 9 synovial sarcomas (9%), and 2 of 7 (29%) myofibroblastic tumors. No PLAP reactivity was detected in hyperplastic scars, nodular fasciitis, or the other remaining soft tissue and epithelial tumors. Double immunohistochemistry studies showed coexpression of myogenin and PLAP in fetal skeletal muscle cells, and western blot analysis showed a 70-kDa band in samples derived from grossly normal placenta, benign myometrium, and a uterine leiomyoma. PLAP immunoreactivity is detected in soft tissue tumors with known myogenic differentiation. PLAP immunoreactivity seems to relate to the degree of myogenic differentiation in soft tissue tumors and is more frequently expressed in cells with skeletal muscle differentiation and least in those with myofibroblastic features. The biologic function of PLAP in muscle and tumors with myogenic differentiation is unknown and merits further investigation. In addition to its role as a germ cell marker, PLAP may also be used as a myogenic marker in the diagnosis of soft tissue tumors.

During the last two decades, there have been significant strides in the diagnosis of soft tissue tumors, including identification of various tumor entities, newer immunohistochemical markers, and an increasing number of molecular signatures, defining certain tumors. Lately, there are certain emerging tumor entities, defined by their molecular features with an impact on treatment. At the same time, there is a certain degree of overlap in the expression of certain immunohistochemical antibody markers, as well as genetic markers, with certain gene rearrangements and chimeric fusions observed among completely different tumors. Moreover, a certain amount of clinicopathological, immunohistochemical, and molecular proximity has been unraveled among certain tumor types. Over the years, the World Health Organization (WHO) fascicles on tumors of soft tissue have succinctly brought out these aspects. The present review describes recent updates in the diagnosis of soft tissue tumors, including certain newly described tumor entities; emphasizing upon newer, specific immunohistochemical and molecular markers, along with concepts, regarding "intertumor relationships".

For the detection of chromosome translocations/chimeric genes and specific genetic abnormalities in soft tissue tumors, we conducted fluorescence in situ hybridization (FISH) analysis on 280 cases of soft tissue and other tumors using formalin-fixed paraffin-embedded tissue sections. The detection rate of the FISH split-signal was 84% (129/154 cases) for the translocation-associated soft tissue tumors, such as Ewing's sarcoma/primitive neuroectodermal tumor, synovial sarcoma, alveolar rhabdomyosarcoma, myxoid liposarcoma, clear cell sarcoma and so forth. Positive split-signals from EWSR1, SS18 and FOXO1A probes were detected in 3% (2/64) of various histological types of carcinoma, lymphoma, melanoma, meningioma and soft tissue tumors. In FISH using the INI1/CEP22 probe, the INI1 deletion signal was detected in 100% (9/9) of epithelioid sarcoma. In well-differentiated and dedifferentiated liposarcomas, detection of MDM2 amplification signals in FISH using the MDM2/CEP12 probe were both as high as 85% (11/13) and 100% (13/13), respectively. In other adipocytic and non-adipocytic tumors requiring differentiation from these types, detection was only 13% (5/39), and CEP12 polysomy was frequently detected. As these results demonstrate the high sensitivity and specificity of FISH, we concluded FISH to be a useful pathological diagnostic adjunct for definite and differential diagnosis of soft tissue tumors.

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.

Fine needle aspiration cytology (FNAC) is a standard diagnostic tool and has several advantages which are specific to soft tissue tumors (STT). STT arises from non-epithelial and extra-skeletal tissue of the body, excluding the reticuloendothelial system, glia, and supporting tissues of organs. Primary STTs are very rare and encompass a wide range of different tumor types; therefore, the classification and diagnosis remain complex. If the tumor is diagnosed as benign, surgery may not be necessary. However, in the case of malignancy, a cytological diagnosis allows for the initiation of palliative treatment. This study was conducted to evaluate the role of FNAC in the diagnosis of STT by sub classifying them based on their cytology features and finally correlating their FNAC findings with histopathological results with special reference to immunohistochemistry (IHC) in diagnostic challenging cases. It was a hospital-based retrospective study conducted in a tertiary care center, over a period of 2 years, i.e., from July 2016 to May 2018. After obtaining approval from the ethics committee of the institution, the study was carried out. All STT cases subjected to FNAC followed by incisional, excisional, or core needle biopsy or complete resection for histopathological examination were studied. The slides of these patients were retrieved and reviewed to establish a proper diagnosis. IHC was carried out in most cases whenever there was a diagnostic dilemma. In our study, among 50 patients who presented with STT, 40 were benign, and 10 were malignant. The median age of incidence was 41, and male-to-female ratio was 0.85:1. The most common site was the trunk. There were four discordant cases, and the final evaluation of all results showed sensitivity, specificity, positive predictive value of tests, and negative predictive value of tests of FNAC as 100%, 76.92%, 92.5%, and 100%, respectively. In STT, most were benign tumors, with lipomas being the most common among them. While benign and malignant were easy to diagnose, intermediate spindle cell tumors were often missed on cytology. These intermediate tumors represent the diagnostic "grey zone." With increasing experience, STT can be diagnosed more accurately. FNAC is therefore a standard pre-operative diagnostic tool and a reliable alternative to open biopsy for diagnosing STT.

Soft tissue tumours are hard to diagnose because they look a lot like other brain conditions on Magnetic Resonance Imaging(MRI)scans, which can lead to delayed or wrong treatment. To solve this problem, we suggest a diagnostic system based on machine learning that combines preprocessing methods with a Convolutional Neural Network (CNN) to accurately classify tumours. The model sorts MRI images into four groups: glioma, meningioma, pituitary tumour, and no tumour. It uses Grad-CAM heatmaps to show and emphasise tumour areas, which makes the results easier to understand and more trustworthy for doctors. To make models work better on small datasets, data preprocessing includes resizing, normalisation, and augmentation. Experimental results show that the CNN can accurately find tumour areas and classify them correctly, even with limited data. The suggested method lessens the need for subjective manual interpretation, which lowers the chance of misdiagnosis.

Pictorial essay on selected new, emerging, and reclassified entities in the 2020 WHO classification of soft tissue tumors.

Dear sir, Lipomas are common soft tissue neoplasms and can be found anywhere in the body, especially in the head and neck region, as well as in the shoulder and back [1]. They are uncommon in the hand and are rarely found in the fingers with reported incidence of 1% [2]. According to WHO committee for the Classification of Soft Tissue Tumors, they are categorized into 9 entities, including lipoma, lipomatosis, lipomatosis of nerve, lipoblastoma, angiolipoma, myolipoma of soft tissue, chondroid lipoma, spindle cell/pleomorphic lipoma and hibernoma. Benign lipomatous lesions may also affect joints and tendon sheaths, either focally or diffusely [3]. Lipomas are often not considered in the initial differential diagnosis of digital swellings. We present a case with right middle finger lipoma involving the proximal interphalangeal joint. A 48-year-old male presented with swelling on the dorsomedial aspect of the proximal interphalangeal joint of the right middle finger, causing difficulty in finger movements (Fig. 1). The lesion had started one and a half year back and gradually increased in size thus causing discomfort in finger movements since last two months. Physical examination showed a 1.5 × 1.5 cm, nontender, subcutaneous swelling on the dorsomedial aspect of the proximal interphalangeal joint associated with some limitation of finger movements. Plain anteroposterior radiograph of the digit showed no invasion of the bone, thus excluding parosteal lipoma from the differential diagnosis. The patient was subjected to exploration of the finger under local anaesthesia using a longitudinal skin incision (Fig. 2). There was no difficulty in excising the swelling as its margins were free. It was excised completely and subjected to histopathology examination. After surgery, patient fully recovered the movements of the involved finger. Grossly, the swelling was 1.5 × 1.0 cm in size and was composed of fatty tissue. Histological results showed the swelling to be a lipoma. There was no evidence of recurrence or any restriction in finger movements during the two years of postoperative follow-up. Fig. 1 Lipoma of right middle finger Fig. 2 Lipoma protruding through incision Lipomas account for approximately 16% of soft tissue mesenchymal tumors. They are rarely encountered in the hand and are extremely rare in the digits. Neoplastic lesions (liposarcoma, lipoblastoma, Giant cell tumour, spindle cell lipoma, angiolipoma, and neural fibrolipoma) and non neoplastic lesions (implantation cyst, pyogenic granuloma, and nodular fasciitis) with clinical characteristics similar to those of a lipoma of the finger should be considered in the differential diagnoses of a mass in the finger. Careful dissection is necessary during the surgical procedure in order to avoid recurrence. Ultrasonography, computerized tomography, or magnetic resonance imaging are useful for more detailed investigations and differential diagnosis [4]. Although a lipoma in the finger is relatively rare, it should be included in the initial differential diagnoses of finger tumours. Although being rare entity, its awareness is imperative since the differential diagnosis from other soft tissue tumors is quite extensive so it should be included in the initial differential diagnoses of finger tumours.

Dentine matrix protein 1 (DMP-1) is a non-collagenous matrix protein found in dentine and bone. It is highly expressed by osteocytes and has been identified in primary benign and malignant osteogenic bone tumours. Bone formation and matrix mineralisation are seen in a variety of benign and malignant soft tissue tumours and tumour-like lesions, and in this study, we analysed immunohistochemically the DMP-1 expression in a wide range of soft tissue lesions (n = 254) in order to assess whether DMP-1 expression is useful in the histological diagnosis of soft tissue tumours. Matrix staining of DMP-1 was seen in all cases of myositis ossificans, fibro-osseous tumour of the digits, extraskeletal soft tissue osteosarcoma and in most cases of ossifying fibromyxoid tumour. DMP-1 was also noted in dense collagenous connective tissue of mineralising soft tissue lesions such as tumoural calcinosis, dermatomyositis and calcific tendinitis. DMP-1 was expressed in areas of focal ossification and calcification in synovial sarcoma and other soft tissue tumours. With few exceptions, DMP-1 was not expressed in other benign and malignant soft tissue tumours. Our findings indicate that DMP-1 is a matrix marker of bone formation and mineralisation in soft tissue tumours. DMP-1 expression should be particularly useful in distinguishing extraskeletal osteosarcoma and ossifying fibromyxoid tumour from other sarcomas and in identifying areas of osteoid/bone formation and mineralisation in soft tissue tumours.

The cytologic diagnosis of soft tissue neoplasms has undergone many advances due to the development of numerous useful immunohistochemical markers and molecular assays that target specific molecular alterations. Ancillary tests, when used in conjunction with clinical, radiologic, and cytomorphologic features, allow for more accurate classification and refinement of differential diagnoses of soft tissue neoplasms. Soft tissue tumors encompass a diverse group of tumors showing a wide range of cytomorphologies that can be broadly grouped as lipomatous, myxoid, spindled, pleomorphic, round cell, and epithelioid. This pattern-based classification enables the formation of appropriate differentials; however, entities that share these basic morphologic patterns may vary greatly in their clinical behavior. The breadth of soft tissue tumors that can be diagnosed on cytologic preparations continues to increase with identification of defining molecular alterations that can be detected by conventional means (eg, fluorescence in situ hybridization) or by immunohistochemical surrogates. Furthermore, the emergence of high-throughput molecular techniques (eg, next generation sequencing) has potential roles for additional discovery and diagnostic applications. This review highlights the diagnostic role of ancillary tests in the context of a pattern-based approach to soft tissue cytology. Cancer Cytopathol 2018;000:000-000. © 2018 American Cancer Society.

Soft tissue and bone tumors comprise a wide category of neoplasms. Their diversity frequently raises diagnostic challenges, and therapeutic options are continuously developing. The therapeutic success rate and long-term prognosis of patients have improved substantially due to new advances in immunohistochemical and molecular biology techniques. A fundamental contribution to these achievements has been the study of the tumor microenvironment and the reclassification of new entities with the updating of the molecular pathogenesis in the revised 5th edition of the Classification of Soft Tissue Tumors, edited by the World Health Organization. The proposed molecular diagnostic techniques include the well-known in situ hybridization and polymerase chain reaction methods, but new techniques such as copy-number arrays, multiplex probes, single-nucleotide polymorphism, and sequencing are also proposed. This review aims to synthesize the most recent pathogenetic and molecular classifications of soft tissue and bone tumors, considering the major impact of these diagnostic tools, which are becoming indispensable in clinicopathological practice.

Since immunohistochemical procedures started to be used in the field of tumor pathology, they have been actively applied to the study of soft tissue tumors as techniques which remove much of the difficulty involved in histological diagnosis. A number of reports are available to show that these procedures have successfully yielded objective findings which allow for diagnostic agreement in many cases. Another opinion is that what is most important in the diagnosis of soft tissue tumors is an accurate determination of the morphological characteristics, making it doubtful that immunostaining would be performed unnecessarily because the accurate determination of morphological characteristics allows for the diagnosis of almost all soft tissue tumors. Clearly, the point that it is important to determine morphological characteristics is quite right. It is also a fact that many soft tissue tumors can be diagnosed without immunostaining. However, there are also a large number of patients for whom definite diagnosis can be made only after immunostaining and in whom reconfirmation by immunostaining is needed before a final diagnosis is made.

Intramuscular sparganosis is not common, and its rarity makes it difficult to be distinguished from soft tissue tumors. A case of rare intramuscular sparganosis is reported. A 44-year-old man presented with a painful mass in the left thigh for 8 months, which was initially diagnosed a as soft tissue tumor. Ultrasonography and MRI revealed a multilobulated mass in the sartorius muscle. After the needle biopsy under the guidance of ultrasonography, sparganum was discovered under microscopic examination of the excised tissue. Surgical excision was performed, and a live larva of sparganum was removed. Sparganosis should be considered in the differential diagnosis of soft tissue tumors, especially among Koreans who have frequently ingested mountain water and consumed raw snakes or frogs.

The occurrence of endometriosis as a soft tissue tumor in orthopaedics is rare. We present a patient who had endometriosis in the inguinal subcutaneous region.A thirty four-year-old woman noticed a bean-sized tumor in the right inguinal region in 1982. The tumor responded to antibiotics. A bean-size painful tumor was again noticed in the same region in 1993. The mass and the pain were more prominent just after menses. Rediographs were normal. A subcutaneous soft tissue tumor with a 2.5cm in diameter could be seen on computed tomographic scans. On MRI the tumor was segmented, not enhanced with contrast medium, and demonstrated, moderate to high intensity on T1-weighted images and high intensity on T2-weighted images. Histological examination of the biopsy specimen revealed endometrial glands and stroma. We diagnosed endometriosis of the inguinal region and resected widely. Six months after the operation, the patient was asymptomatic and had resumed all of her usual activities.Several cases involving endometriosis have been reported in Japanese orthopaedic articles, so it is important to remember endometriosis in the differential diagnosis of soft tissue tumors.