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  Table of Contents    
Year : 2019  |  Volume : 62  |  Issue : 2  |  Page : 199-205
Small round cell lesions of the bone: Diagnostic approach, differential diagnoses and impact on treatment

1 Department of Surgical Pathology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Pathology, All Indian Institute of Medical Sciences, New Delhi, India
3 Department of Pathology, Regional Cancer Centre, Thiruvananthpuram, Kerala, India

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Date of Web Publication10-Apr-2019


Small round cell lesions of the bone encompass a heterogeneous group of tumors and tumor-like lesions, including Ewing sarcoma, small cell osteosarcoma, mesenchymal chondrosarcoma, neuroblastoma, non-Hodgkin's lymphoma (NHL), “Ewing-like” undifferentiated round cell sarcomas, metastasizing small cell carcinoma, along with plasma cell dyscrasia and Langerhan's cell histiocytosis. At the same time, there are tumor mimics, for example, chronic osteomyelitis, which has overlapping radiologic features with Ewing sarcoma and a primary intraosseous NHL. An exact diagnosis necessitates integration of clinical, radiologic, pathologic, and ancillary test results, including immunohistochemical and molecular results. Currently, there are several immunohistochemical markers and specific molecular signatures, driving most of these tumors, available, for an exact diagnosis. This review focuses on a pragmatic approach towards uncovering specific small round cell lesions of the bone, emphasizing upon integration of traditional morphology with ancillary techniques, including immunohistochemical markers and molecular techniques, the latter, especially in cases of Ewing sarcoma, Ewing-like undifferentiated round cell sarcoma, mesenchymal chondrosarcoma, and neuroblastoma. Subsequent to the diagnostic approach, including an impact on treatment, individual intraosseous round cell lesions have been described in detail. The references include updated articles from PUBMED.

Keywords: Ewing sarcoma, immunohistochemistry of round cell sarcomas, intraosseous lymphoma, Langerhans's cell histiocytosis, mesenchymal chondrosarcoma, molecular cytogenetics in bone tumors, neuroblastoma, small round cell lesions of the bone

How to cite this article:
Rekhi B, Mridha A, Kattoor J. Small round cell lesions of the bone: Diagnostic approach, differential diagnoses and impact on treatment. Indian J Pathol Microbiol 2019;62:199-205

How to cite this URL:
Rekhi B, Mridha A, Kattoor J. Small round cell lesions of the bone: Diagnostic approach, differential diagnoses and impact on treatment. Indian J Pathol Microbiol [serial online] 2019 [cited 2022 Jul 7];62:199-205. Available from: https://www.ijpmonline.org/text.asp?2019/62/2/199/255837

   Introduction Top

Primary round cell lesions of the bone constitute a heterogeneous group, including malignant mesenchymal neoplasms and tumor-like lesions, mostly occurring in pediatric patients, including adolescents. These can be clinic-radio-pathologically overlapping, leading to diagnostic challenges in sorting out the individual entities. An exact diagnosis in such cases is extremely important as most of the small round cell tumors (RCTs), although aggressive, are curable with their tailored chemotherapy regimens.[1],[2],[3],[4],[5]

Various RCTs with their specific chemotherapy protocols are as follows:

  1. Ewing sarcoma/primitive neuroectodermal tumor (PNET): This tumor is treated by Ewing family of tumors (EFT) 2001 chemotherapy protocol. These tumors are also radiosensitive.
  2. Undifferentiated “round” cell (“Ewing-like”) sarcoma: These tumors are treated similarly as EFTs. These include a heterogeneous group of genetically defined sarcomas, such as BCOR-CCNB3 and CIC-DUX4-positive sarcomas, characterized by relatively aggressive clinical outcomes, especially the latter subtype.
  3. Mesenchymal chondrosarcomas: These are treated similarly as EFTs; however, they are characterized by relatively aggressive clinical outcomes.
  4. High-grade, small cell osteosarcoma: These are treated by a specific chemotherapy in adjuvant settings, mostly preceding surgical resection. These tumors are not radiosensitive
  5. Neuroblastoma: Treated by children's oncology group (COG) protocol.
  6. Non-hodgkin's lymphomas (NHLs): High-grade, large B-cell (CD20-positive) lymphomas are treated by CHOP-Rituximab (R) (anti-CD20), anaplastic large cell lymphomas (ALCLs) are treated by MCP842 protocol. Radiotherapy is also considered while treating these tumors.
  7. Small cell osteosarcoma. Treated similarly as a conventional osteosarcoma, by OGS 2012 chemotherapy protocol, at Tata Memorial Hospital, Mumbai.[6]
  8. Other entities, such as plasma cell tumors and Langerhans's cell histiocytosis (LCH) constitute as differential diagnoses of the various intraosseous small RCTs.[1],[2],[3],[4],[5],[6]

An ideal approach towards diagnosis and management of these tumors is practising a multidisciplinary approach, which includes integration of clinical, radiologic, and histopathologic findings. Most of these lesions, including tumors occur in pediatric patients.

During the initial diagnostic “work-up” of any intraosseous lesion, a reasonably well-exposed radiologic image, especially a plain X-ray/radiograph is usefulwhile differentiating a Ewing sarcoma from a small cell osteosarcoma. Lytic lesions are noted in LCH, whereas sclerotic, destructive lesions with periosteal reactions are seen in Ewing sarcomas and osteosarcomas, with different types of periosteal reactions, in both these lesions.[4] Computed tomogram (CT) scan and magnetic resonance imaging (MRI) are useful in staging these tumors. Other modalities, such as a metaiodobenzylguanidine (MIBG) scan and other functional imaging are valuable in the diagnosis of a neuroblastoma.[7]

Certain laboratory investigations are equally crucial, such as alkaline phosphatase levels in osteosarcomas, urinary vanillyl mandelic acid (VMA) levels in neuroblastomas, lactate dehydrogenase levels in NHLs, and beta 2 microglobulin levels with serum electrophoresis in cases of plasma cell dyscrasia.[8]

In the present times, where “needle is preceding the scalpel,” efforts should be made for exact categorization of malignant RCTs, either on smears, cell blocks, or histopathology, with immunocyto- or immunohistochemistry (IHC).[9]

Morphology remains the initial point that helps in deciding which immunohistochemical markers or other ancillary tests would be required in diagnosing a particular case. On pathologic examination, malignant round cells are mostly characterized by small, round, relatively undifferentiated appearing nuclei with scant cytoplasm. However, to a morphologist these might appear in one of the two forms as follows:

  1. Small blue round cells: Tumor cells with round cells and scant cytoplasm. For example, Ewing sarcoma, neuroblastoma, etc.
  2. Relatively large, blue to “pink” round cells: Tumor cells with round nuclei and abundant eosinophilic to amphophilic cytoplasm. For example, plasmacytoma/plasma cell dyscrasia, anaplastic large cell lymphoma (ALCL), rhabdomyosarcoma (mostly in soft tissues), etc.

Furthermore, certain morphological features or “clues” such as rosettes in Ewing sarcoma, “salt and pepper-like” chromatin and neuropil in neuroblastomas, plasmacytoid appearance of tumor cells with “cartwheel-like chromatin” in a plasma cell dyscrasia etc., are helpful in formulating morphological differential diagnoses at the upfront.

An exact subtyping of malignant RCTs requires ancillary techniques such as IHC and molecular techniques (reverse transcriptase polymerase chain reaction and/or fluorescence in situ hybridization). The utility of electron microscopy has reduced over the years, in view of cost and logistic reasons.

Optimal panels of various immunohistochemical antibody markers for individual malignant RCTs are as follows:

  • Ewing sarcoma: MIC2/CD99 (invariably diffuse, cytoplasmic membranous immunoexpression), NKX2.2, Fli1, Caveolin, coupled with negative expression of LCA.
  • Neuroblastoma: Synaptophysin, chromogranin, neuron-specific enolase (NSE), and CD56.
  • Non-Hodgkin's lymphomas: LCA, CD20, and other lineage specific markers, such as CD30 for ALCL (ALK+ or ALK-), Tdt for lymphoblastic lymphoma, etc.
  • Small cell osteosarcoma: SATB2. Considering a small cell ostosarcoma can be positive for MIC2, similar to Ewing sarcoma, further molecular testing is recommended as Ewing sarcoma is characterized by a specific underlying translocations t (11; 22) (EWS-FLI1), in most cases.
  • Plasma cell dyscrasia/myeloma: CD138 (Syndecan-1), Kappa, and lambda for evaluating light chain restriction
  • Rhabdomyosarcoma: Desmin, MyoD1, Myogenin
  • Mesenchymal chondrosarcoma: MIC2/CD99 and Leu7. S100 protein highlights the chondroid component.

    It is noteworthy that CD99/MIC2 is also positive in cases of lymphoblastic lymphoma, poorly differentiated synovial sarcoma, mesenchymal chondrosarcoma, and melanoma, to name but a few tumors.[1],[2],[3],[4],[5],[10],[11],[12],[13],[14],[15],[16],[17]

    Individual small round cell lesion/tumor

    Ewing sarcoma

    As per the World Health Organization (WHO) classification of tumors of soft tissue and bone, Ewing sarcoma or Ewing sarcoma family of tumors (ESFTs) are a group of small round cell sarcomas showing varying degree of neuroectodermal differentiation, detected by light microscopy, IHC, and/or by electron microscopy.[15] Microscopically, these tumors display uniform, small round cells with round nuclei, scant cytoplasm, and fine nuclear chromatin. By IHC, most of these tumors display diffuse cytoplasmic membranous immunostaining for CD99/MIC2 and intranuclear staining for Fli1.[11],[15] Both these markers are sensitive, however not specific for diagnosis of a Ewing sarcoma. Lately, NKX2.2 has been idenified as a useful IHC marker for diagnosing Ewing sarcomas. Howver, it has limited specificity.[12]

    Ewing Sarcoma is genetically characterized by recurrent translocations between EWSR1 (Ewing sarcoma RNA binding protein 1) and ETS family of transcription factors. Most of the tumors harbor t (11; 22) – EWSR1-FLI1 or t (21; 22) – EWSR1-ERG transcripts.[17],[18] Detection of these chimeric trascripts and their interpretation in a clinico-radio-pathologic context constitutes as the diagnostic “gold standard” for a Ewing sarcoma.

    In the recent WHO classification of tumors of soft tissue and bone, a new category of sarcomas has been introduced, namely undifferentiated/unclassified round cell sarcomas, characterized by cells with relatively monotonous round to ovoid cytomorphology with high nuclear to cytoplasmic (N: C) ratios, but no distinct line of differentiation. These tumors lack consistent genetic abnormalities, seen in cases of Ewing sarcoma. Clinically, these tumors are usually found in younger patients, at any location, more frequently in somatic soft tissue sites and are characterized by a relatively more frequent rapid growth and a variable response to presently available conventional chemotherapy regimens [Figure 1], [Figure 2], [Figure 3], [Figure 4].[1]
    Figure 1: Ewing sarcoma (a-d). (a) Plain radiograph: diaphyseal, permeative lesion, involving fibula with layered periosteal reaction. (b) Microscopy: malignant small round cells in a diffuse pattern (H and E, ×400). (c) By immunohistochemistry (IHC), tumor cells displaying diffuse, intense cytoplasmic membranous staining for CD99/MIC2 (Diaminobenzidine, ×400). (d) Diffuse intranuclear Fli1 immunoreactivity (Diaminobenzidine, ×400). (e) Focal immunostaining synaptophysin positivity (Diaminobenzidine, ×400)

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    Figure 2: Ewing sarcoma (a and b). (a) Perivascular, rosettoid arrangement of malignant small round cells (H and E, ×400). (b) Diffuse, immunostaining for CD99/MIC2 (Diaminobenzidine, ×400). Case of Ewing sarcoma treated with neoadjuvant chemotherapy (c-e). (c) Pre-treatment microscopic features of Ewing sarcoma (H and E, ×400. (d) Diffuse CD99/MIC2 immunostaining (Diaminobenzidine, ×400). (e) Post-chemotherapy response: hyalinization and scattered inflammatory cells with no residual tumor (H and E, ×200)

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    Figure 3: (a) Case, initially reported as an osteosarcoma (in view of an associated cartilaginous fragment) (H and E, ×200). (b) Post-chemotherapy showing residual tumor cells (H and E, ×200). (c) Microscopic examination of an adrenal lesion, raising suspicion of Ewing sarcoma (H and E, ×400). (d) Tumor cells displaying EWSR1 rearrangement (red green split signals) by fluorescence in-situ hybridization (FISH), confirming a diagnosis of Ewing sarcoma. (DAP1, 1000)

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    Figure 4: (a) Intraosseous tumor, comprising malignant round to polygonal cells with interspersed osteoid, indicative of a small cell osteosarcoma (H and E, ×400). (b) Tumor cells lacking EWSR1 rearrangement (red green fused signals) by FISH, ruling out a Ewing sarcoma (DAP1, 1000)

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    Furthermore, gene expression profiling has unraveled specific transcripts within these undifferentiated, “Ewing-like,” round cell sarcomas, most commonly CIC-DUX4, and BCOR-CCNB3 gene fusions, as recently documented.[13],[14],[19],[20]

    CIC-DUX4-positive tumors mainly affect young adults in the third or fourth decades of life and affect soft tissues more frequently than bones. These tumors represent a clinically aggressive subset of undifferentiated round cell sarcomas.[14],[19],[21] BCOR-CCNB3- positive sarcomas, occurring in extremities, are associated with a relatively favorable clinical course.[13]

    Although a diagnosis of Ewing sarcoma is considered on histology, it should be confirmed by immunohistochemistry and molecular testing, according to the recent European Society of Medical Oncology (ESMO) guidelines.[22],[23]

    Mesenchymal Chondrosarcoma

    Mesenchymal chondrosarcoma is one of the rarest bone sarcomas, histologically characterized by a bimorphic growth pattern consisting of islands of more or less differentiated cartilage, admixed with a small cell malignancy frequently associated with a hemangiopericytomatous pattern. About 1/3 of cases occur in the soft tissues.

    Majority of the cases are reported in the jaw bones, followed by spine, ilium, and ribs. Involvement of skull bones is extremely rare. Among the extra skeletal sites, meninges are reported to be a preferred site of involvement.

    Mesenchymal chondrosarcoma consists of two distinct elements–malignant small round cells and islands of cartilage in varying proportions. The nuclei of small cells are usually round, but may be oval or even spindle shaped. Cytoplasm is scanty and nuclei have usually dense chromatin. One of the characteristic features is thin walled vessels, leading to a hemangiopericytomatous growth pattern.

    Immunohistochemically, S100 protein is positively expressed in chondroid islands and CD99/MIC2 is expressed in the small cells [Figure 5].[24],[25] Sox 9 (transcription factor) has been shown to be helpful in differentiating a mesenchymal chondrosarcoma from other small cell malignancies.[26] An identical Robertsonian translocation involving chromosomes 13 and 21 [der (13; 21) (q10; q10)] was reported in mesenchymal chondrosarcoma.[27] Ten years later, a recurrent HEY1-NCOA2 fusion was identified in mesenchymal chondrosarcomas.[28]
    Figure 5: Plain radiograph pelvis showing a tumor involving pelvic bone and soft tissues (arrow head) with areas of calcification ('ring' and 'arc'). (b) Microscopy: tumor comprising malignant round cells arranged in a hemagiopericytomatous pattern, juxtaposed with cartilaginous component (asterix) (H and E, ×400). (c) Immunohistochemically, tumor cells displaying cytoplasmic positivity for CD99/MIC2 (Diaminobenzidine, ×400). (d) S100 protein distinctly highlighting the chondroid component (Diaminobenzidine, ×400)

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    Some patients present with disseminated metastasis, but others survive for decades. A long term follow-up is mandatory in such cases, since metastasis after 20 years has been reported.[24]

    Neuroblastoma (metastatic)

    Neuroblastoma is a primitive neoplasm of neuroectodermal origin. It is the third most common malignant tumor in the childhood, following lymphoma/leukemia and brain tumors. The peak incidence is 0-4 years (40% in less than 1 year). It is rarely diagnosed prenatally during the 3rd trimester, on ultrasonogram. It occurs anywhere in the sympathoadrenal neuroendocrine system.

    All patients with metastatic (stage 4) disease diagnosed after 18 months of age are in the high-risk category. At the time of diagnosis, the defining characteristics of high-risk neuroblastoma include an age of more than 1 year, metastases, amplification of the MYCN oncogene, and histologic findings.

    Histologically, malignant round cells with or without rosettes and neurofibrillary material are seen. If there are no rosettes or neurofibrillary material, IHC is mandatory. In children more than 5 years, the most important differential diagnoses are Ewing's Sarcoma, lymphoma/leukemia, and rarely small cell osteosarcoma. A panel of antibodies consisting of synaptophysin, chromogranin, CD99, LCA, and Tdt is mandatory. Cells of a neuroblastoma are diffusely positive for synaptophysin and chromogranin, while negative for CD99, LCA, and Tdt [Figure 6].[29] PHOX2 is a useful marker in the diagnosis of peripheral neuroblastic tumors.[30] There is an unequivocal role of genetics in diagnosis and prognosis of neuroblastomas, including N-myc amplification. Lately, there is a focus towards developing risk-based therapies and, ultimately, improving outcome in such cases.[31],[32]
    Figure 6: Case of neuroblastoma metastasizing to the bone (a-d). (a) Cluster of malignant small round cells showing crushing artefact, infiltrating the bone. (H and E, ×400). (c) Diffuse synaptophysin positivity (Diaminobenzidine, ×400). (d) Diffuse chromogranin positivity (Diaminobenzidine, ×400)

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    Primary lymphomas of bone and “look-alikes”

    On radiologic imaging intraosseous lymphomas, Ewing sarcomas and chronic inflammatory lesions have overlapping appearances, including metadiaphyseal involvement, lytic lesions, permeative appearance, and layered/lamellated periosteal reaction.[33] Hitopathologically, the most frequently identified subtype is a diffuse large B cell type of a non-Hodgkin's lymphoma (DLBCL). Considering primary bone lymphomas have relatively better outcomes, as compared with other intraosseous round cell tumors, their differentiation from tumors, such as Ewing sarcomas is important, especially in view of different chemotherapy regimens for treating these two subtypes of RCTs [Figure 7].[6],[34]
    Figure 7: (a) Plain radiograph (post nail fixation) showing a sub trochanteric fracture and a lytic lesion in proximal right femur. (b) Malignant round cell tumor (H and E, ×400). (c) Diffuse CD20 positivity, confirming a Diffuse Large B-cell Non-Hodgkin's lymphoma (Diaminobenzidine, ×400). (d) High Ki67 expression (Diaminobenzidine, ×400) (e) BCL2 positivity (Diaminobenzidine, ×400). Metastatic acute leukemia in parasapinal tissue (D6-D7). (f) Malignant round cell tumor with rosettes (H and E, ×400). Inset: CD99/MIC2 positivity (Diaminobenzidine, ×400). (g) Diffuse Tdt, positivity (Diaminobenzidine, ×400)

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    At the same time, chronic osteomyelitis can mimic intraosseous lymphomas [Figure 8]. Certain features, such as increase in C-reactive protein and a characteristic radiologic feature, namely penumbra sign (a higher signal intensity feature of the thin layer of granulation tissue which lines the abscess cavity on T1-weighted MRI images), is used to differentiate the two lesions.[35] Although not a classic RCT, a plasma cell dyscrasia/tumor can constitute a differential diagnosis of a small RCT, in view of certain overlapping morphological features [Figure 9]a and [Figure 9]b.
    Figure 8: Case of chronic osteomyelitis (a-c). (a) Plain radiograph showing a permeative, 'moth-eaten' lesion involving metadiaphyseal region of humerus with periosteal reaction. (b) Microscopic examination revealing presence of inflammatory cells, including lymphocytes and macrophage, along with necrotic bony fragment. (H and E, ×200). (c) Scattered inflammatory cells, including plasma cells with focal reactive woven bone formation (H and E, ×400)

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    Figure 9: Case of plasma cell tumor, referred as a malignant round cell tumor (a-b). (a) Plasma cells, focally arranged around blood vessel (H and E, ×400). (b) Diffuse CD138/syndecan-1 positivity (Diaminobenzidine, ×400). (c) Case of Langerhans's cell histiocytosis (LCH), in form of a lytic lesion in lower humerus, with periosteal reaction (double contour). (d) Microscopy: Eosinophils, multinucleate giant cells and polygonal cells with intranuclear grooves (H and E, ×400). (e) S100 protein positivity (Diaminobenzidine, ×200). (f) CD1a positivity (Diaminobenzidine, ×200)

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    Langerhans cell histiocytosis (LCH)

    This is an uncommon histiocytic disorder, which accounts for ~0.5-5.4 cases/million persons/year. Although it primarily occurs in the pediatric patients, any age group can be affected. It has a wide spectrum of clinical presentation, ranging from an isolated skin or bone lesion to a life-threatening multisystem disease and the manifestation depends upon the extent of involvement.

    The bone lesions are often asymptomatic and detected incidentally during radiographic investigation for unrelated disorders. Unifocal bone lesions (eosinophilic granuloma) are usually solitary and characteristically affect the calvaria, vertebra, rib, mandible, femur, ilium, and scapula. Bone pain, soft tissue mass, neurologic manifestations because of extension of calvarial lesions into the nervous system, spontaneous long bone fracture, and vertebral collapse with spinal cord compression can occur. Otitis media in temporal and mastoid bone involvement, loose teeth in mandibular lesion, and pituitary dysfunction in sella turcica involvement may be seen. Multifocal lesions might have a protean history depending on the location and degree of bone and adjacent tissue involvement. Diabetes insipidus, exophthalmos, and bony lesion especially in the cranium occur in Hand-—Schüller-Christian disease.

    LCH can involve single system with unifocal or multifocal lesions with i) extraosseous, ii) osseous, iii) skin (seborrheic involvement of scalp, purplish papules on body, red papular rash on groin, abdomen, back, chest, etc.), iv) lymph node, v) hypothalamic/pituitary/central nervous system, or vi) other organs such as thyroid involvement.[36] In a multisystem disease more than or two organs or systems including bone, gastrointestinal tract (liver and spleen), lungs, bone marrow, endocrine and CNS, skin and lymph nodes are affected. Liver and spleen are high-risk organs as any involvement of these organs indicates an unfavorable prognosis. Sclerosing cholangitis is a serious complication. Lungs are more frequently involved in adults. Tachypnea with rib retractions and cystic/nodular pattern are usual clinical signs. Pulmonary involvement is seen in ~25% of children with multisystem disease. Thrombocytopenia and anemia with or without neutropenia are associated with marrow involvement. Patients with hemophagocytosis involving the bone marrow are also at a very high-risk group.

    Radiologically, LCH appears as a lytic lesion, which seems poorly defined in its early phase and relatively well-defined with a sclerotic margin during its late phase of development[37] [Figure 9]c. Microscopically, the lesion contains polymorphous cells with a monoclonal population of CD1a+ histiocytes [Figure 9]d,[Figure 9]e,[Figure 9]f. About 50% cases show activating mutations in proto-oncogene BRAF V600E. Somatic MAP2K1 mutations are present in ~50% of patients, who lack BRAF V600E mutation. Most mutations are “in frame” deletions. Mutations in BRAF and MAP2K1 are mutually exclusive. A debate exists on whether LCH represents a true malignancy. Monoclonality (non-pulmonary lesions), immature appearance of neoplastic cells, cell-cycle dysregulation, telomere shortening, BRAF and MAP2K1 mutation suggest it as a malignancy. Low-risk LCH patients have an excellent prognosis with a long-term survival rate of 99%, whereas the high-risk patients have a survival rate close to 80%. Adult patients usually present with limited skin or bone involvement that can be treated by local therapy, resulting in an overall survival rate of 100%. Smoking cessation can result in the improvement of respiratory symptoms and the spontaneous resolution of pulmonary LCH. Targeted therapy with BRAF inhibitors has been used in select patients with LCH, and the results have been encouraging.[38],[39]

       Conclusion Top

    It is crucial to diagnose individual small cell lesions, especially tumors of the bone, in view of their different treatment regimens. An exact diagnosis required application of ancillary techniques, such as IHC and molecular diagnosis. Morphology remains the cornerstone in the diagnosis and is a guide towards choosing optimal immunohistochemical markers and molecular tests. The value of radiologic correlation in the diagnosis of various bone tumors cannot be overemphasized. At all times, one needs to be aware of “look-alikes,” such as osteomyelitis, which can mimic a Ewing sarcoma. Newer genetic transcripts have been unraveled driving certain undifferentiated round cell/Ewing-like sarcomas. High throughput techniques, such as next-generation sequencing can be utilized in designing and application of panels for RCTs.

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    Correspondence Address:
    Bharat Rekhi
    Room Number 818, Department of Surgical Pathology, 8th Floor, Annex Building, Tata Memorial Hospital, Dr E.B. Road, Parel, Mumbai - 400 012, Maharashtra
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    Source of Support: None, Conflict of Interest: None

    DOI: 10.4103/IJPM.IJPM_675_18

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      [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]

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