|Year : 2021 | Volume
| Issue : 3 | Page : 326-335
Grossing and reporting of bone tumor specimens in surgical oncology: Rationale with current evidence and recent updates
Bharat Rekhi1, Shantveer Uppin2, Jayasree Kattoor3, Nirmala A Jambhekar4, Pradyumn Singh5, Vinita Pant6, Satish Rao7, Nishat Afroz8
1 Department of Surgical Pathology, Bone and Soft Tissues, Disease Management Group, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI) University, Parel, India
2 Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
3 Regional Cancer Centre, Thiruvananthapuram, Kerala, India
4 Formerly, Department of Surgical Pathology, Tata Memorial Hospital, Parel, India
5 Ram Manohar Lohia Hospital, Lucknow, India
6 Centre for Oncopathology, Mumbai, Maharashtra, India
7 Krishna Institute of Medical Sciences, Hyderabad, Telangana, India
8 Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
|Date of Submission||13-Jan-2021|
|Date of Decision||17-Jan-2021|
|Date of Acceptance||25-Jun-2021|
|Date of Web Publication||14-Sep-2021|
Department of Surgical Pathology, Bone and Soft Tissues, Disease Management Group, Tata Memorial Hospital, Homi Bhabha National Institute (HBNI) University, Parel
Source of Support: None, Conflict of Interest: None
Primary bone tumors, including sarcomas, are rare tumors and require a multidisciplinary approach, including inputs from a radiologist, pathologist, medical oncologist, and surgical and radiation oncologist, for optimal management. Over the years, there has been a paradigm shift toward the treatment of bone sarcomas, from radical resections to conservative surgical procedures, to achieve improved clinical and functional outcomes. This has led to receiving and processing various types of specimens in orthopedic oncopathology. Grossing and reporting of bone tumors require expertise. This review focuses upon the types of biopsies, grossing techniques of various specimens in orthopedic oncology and reporting, with rationale and recommendations from pathologists, actively involved in reporting and pursuing a special interest in bone tumors, based on current evidence. Furthermore, there is a section on some of the updates in the diagnosis of bone tumors, based on the recent fifth edition of the World Health Organization classification of tumors of soft tissues and bone.
Keywords: Bone tumors, grossing bone tumors, neoadjuvant chemotherapy in Ewing sarcoma, neoadjuvant chemotherapy in osteosarcoma, post-denosumab-treated giant cell tumors
|How to cite this article:|
Rekhi B, Uppin S, Kattoor J, Jambhekar NA, Singh P, Pant V, Rao S, Afroz N. Grossing and reporting of bone tumor specimens in surgical oncology: Rationale with current evidence and recent updates. Indian J Cancer 2021;58:326-35
|How to cite this URL:|
Rekhi B, Uppin S, Kattoor J, Jambhekar NA, Singh P, Pant V, Rao S, Afroz N. Grossing and reporting of bone tumor specimens in surgical oncology: Rationale with current evidence and recent updates. Indian J Cancer [serial online] 2021 [cited 2021 Oct 28];58:326-35. Available from: https://www.indianjcancer.com/text.asp?2021/58/3/326/325981
| » Introduction|| |
Presently, the management of bone tumors, especially sarcomas, is based upon the principle of excision (salvage) and reconstruction to achieve improved oncological and functional outcomes in a patient.
Grossing bone tumor specimens is challenging because of inherent anatomical characteristics, type of surgeries, nature of the tumor, and most often, unfamiliarity among general pathologists because of the rarity of these tumors. Moreover, there is a unique method of handling post-treatment specimens, especially high-grade osteosarcomas and Ewing sarcomas.
This review is designed to answer the three key questions related to grossing bone tumor specimens, namely, (i) purpose (ii) requirements, and (iii) steps for grossing. This is followed by an account of reporting bone tumors, including recent updates according to the latest World Health Organization (WHO) classification of bone tumors.
Evaluation of a bone tumor specimen
A preoperative biopsy is useful for achieving a specific diagnosis, especially whether the tumor is benign—an osteoma, chondroma, and a chondroblastoma; intermediate malignant—a giant cell tumor of bone (GCTB); or malignant—osteosarcoma or chondrosarcoma. In the case of a sarcoma, further grading is imperative. For example, conventional high-grade osteosarcoma is treated with chemotherapy in neoadjuvant or adjuvant settings, in contrast with low-grade osteosarcoma (parosteal), which is preferably treated with a wide local excision.,
The purpose of grossing is as follows:
- To establish the extent of tumor involvement by margin assessment, especially in resection specimens of most bone sarcomas, except atypical cartilaginous tumor in the extremities. The latter tumor in the long bones is treated with extensive intralesional curettage and local adjuvant treatment, leading to optimal local control.
- To evaluate prognostic parameters, such as post-therapy response, for example, neoadjuvant chemotherapy, in cases of conventional osteosarcoma and Ewing sarcoma, since this has significant prognostic implications., Lately, post-denosumab-treated specimens of giant cell tumors are also being evaluated for residual tumor.,
- To identify the involvement or spread of the tumor into lymph nodes and lungs. To evaluate skip lesions, in case identified.
- To further confirm the diagnosis and the tumor grade, as there could be areas of a higher grade or de-differentiation in a low-grade or parosteal osteosarcoma, diagnosed on a preoperative biopsy.
Therefore, adequate grossing and sampling of the tumor is crucial.
The requirements for grossing a bone tumor specimen include access to clinical, laboratory, and radiological findings; bone saw (preferably electrical) and an optimal tissue fixative (20 times the volume of the tissue).
At most centers, acetic acid–zinc formalin (AZF) is used for fixing small biopsy specimens that can further be triaged for immunohistochemistry and molecular studies.
For decalcification, 10% nitric acid (strong) or formic acid (weak) (20% formic acid in 10% formalin [400 ml of formic acid in 1600 ml of 10% formalin]). Considering acid chemicals can damage nucleic acids, freezing the tumor tissue and/or fixing noncalcified portions of the tumor in 10% neutral buffered formalin (NBF) is suggested.
The mineralization status of the specimen should be carefully monitored, which can be done by a radiographic test, chemical test, and physical method. Bone specimens should not be kept in nitric acid for more than 24 hours, as it significantly compromises the morphological details and the tissue antigenicity for immunohistochemistry. Strong acids compromise the cellular nucleic acid, and therefore, molecular test results.
According to the European Society of Medical Oncology (ESMO), ethylenediaminetetraacetic acid (EDTA) may be preferred over acid decalcifying agents, as it provides better preservation of tissue, cytomorphological details, and antigenicity, the latter for immunohistochemistry as well as for molecular techniques. It is suggested that a few tumor sections from a resected specimen may be preserved in EDTA to salvage the nucleic acid for future molecular studies.
Types of bone specimens
- Jamshidi (J) needle biopsy or core needle biopsy: This was found to be diagnostic in 89% of cases. It should be performed by a specialized orthopedic surgeon.,
- Incisional biopsy/surgical biopsy: This is performed in case the J-needle biopsy fails to provide representative material, especially when there is a mismatch between radiological and pathological findings.
- Curettage specimen (Intralesional, R2): This is performed especially in cases of benign tumors, such as chondromas, GCTB, chondroblastomas, etc.
- Segmental/wide resection, en bloc resection: This is mostly performed in cases of sarcomas. A wide excision (R0) includes the removal of a cuff of normal bone, apart from the resected bone, that contains the lesion.
In cases where the tumor is removed with its pseudocapsule along with a small amount of adjacent tissue, it is termed as marginal resection (R1). Despite grossly free margins, these resections might have microscopically positive margins.
- Radical resection: This includes amputation and disarticulation, which are performed in sarcomas involving more than one tissue compartment.
- Resection specimen for evaluation of neoadjuvant chemotherapy response in cases of high-grade osteosarcoma and Ewing sarcoma.,
- Resection specimen in a case of a post-treatment extracorporeal radiotherapy (ECRT).,
- Resection specimen or curettage procedure in a case of giant cell tumor after denosumab treatment.[9.10]
Before initiating grossing, it is prudent to check the clinical details, laboratory findings, and radiological details, including a plain radiograph, along with computed tomography (CT) scan and/or magnetic resonance imaging (MRI). It is useful to know which lesions occur in the different areas of the bone and within which age group of patients. A plain radiograph provides information about the nature of the lesion, such as benign or malignant. An MRI helps estimate an exact tumor location, especially concerning adjacent structures.,
A clinical history of trauma can be useful in identifying tumor-like lesions like a hematoma or pseudosarcoma, such as myositis ossificans.
Laboratory investigations should be accessible. Osteomyelitis and hematolymphoid malignancies can present with an increased erythrocyte rate (ESR) and white blood cell counts. While serum alkaline phosphatase levels could be elevated in osteosarcoma, a fracture, a brown tumor of hyperparathyroidism, Paget's disease, and blastic-type of metastatic lesions, serum acid phosphatase levels are increased in metastatic prostatic carcinoma. In suspected cases of multiple myeloma, a myeloma workup is recommended.
A frozen section is mainly utilized to assess the adequacy of the biopsy specimen and for assessment of margin, including marrow, rather than for a primary diagnosis., Frozen section examination can also be useful in differentiating a neoplastic lesion from an inflammatory lesion. Moreover, it provides an opportunity to collect fresh tissue and triaging it for culture studies, in cases of suspected infective process, for molecular studies, especially imprint specimens, prepared from the fresh tissues kept in cold storage (−70°C) of the tissue bank, and for future genotypic studies.
Steps to grossing
Fresh tissue biopsy specimens must be fixed, preferably in AZF for at least 6 hours. Core needle biopsy specimens, in case properly fixed, may be subjected to overnight acid decalcification or in a chelating agent. In most cases, at least three representative tissue cores are needed.
The gross characteristics of the specimen should be noted by gentle palpation and recorded. Tissues could be hard (bony), resilient (cartilage), or soft.,
The harder tissue bits should be separated and subjected to light/gentle decalcification. Individual tissue bits should be described. Softer bits should be subjected to routine processing. It is noteworthy that the entire biopsy and curettage specimen should be processed, considering bone tumors are heterogeneous.
Wide excision in case of tumor involving long bones
The bone should be oriented, including the structures, and the specific bone involved should be identified. The measurements should be done in toto, including soft tissues and skin, which should also be separately measured. The condition of the skin, if included (ulceration, pigmentation, etc.), should be documented. The external aspect should be inked; the soft tissue cut margins should be resected. In case of any pedicle or neurovascular margin, the same should be recorded.
The bony cut margin should be resected by transection (shave margin). Next, the underlying bone should be cleared of all the soft tissues. The close/adherent portions should be saved and documented. After clearing the soft tissues, the bare bone will be ready to be cut (bisected), in a coronal plane to expose the maximum area. With extreme care, the bone should be bisected.
The cut surface should be described, in terms of the exact site, whether epiphysis, metaphysis, and/or diaphysis; involvement of the cortex, medulla, or both; any cortical breach, soft tissue involvement articular surface; and joint space involvement. The exact size of the tumor should be measured in three dimensions. Details regarding the color, appearance, consistency, and extent of tumor spread should be recorded. While conventional osteosarcomas are destructive tumors, with areas of hemorrhage and necrosis, chondrosarcomas appear as lobulated tumors involving the medulla with a translucent cut surface [Figure 1]. GCTB and aneurysmal bone cysts appear as cystic, hemorrhagic lesions, on the cut surface.
|Figure 1: Specimen from a case of pelvic chondrosarcoma, showing the evaluation of a close margin (fascia lifted with forceps). The resection surface is painted with Indian ink|
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Sections to be sampled
Ideally, one section, per centimeter of the tumor in its largest dimension should be submitted, unless there are very large, homogeneous tumors. At least four sections or more, representative of the tumor, should be sampled, including heterogeneous areas, tumor with cortex, medulla, articular cartilage, periosteal surface, additional structures (scar of biopsy tract), along with soft tissue and bony cut margins.
Wide excision of flat bones
These include rib, skull, and scapula. Gross appearances should be described. Flat bones are cut transversely. This is useful for assessing pleural and lateral soft tissue margins and level of involvement, in case multiple ribs are excised.
The sections that should be submitted include representative tumor sections, along with bony and soft tissue cut margins (inked, preferably radial).
Pelvectomies (For bone and soft tissue tumors of the pelvic and gluteal region)
Depending upon the location of the tumor and its extent, various types of hemipelvectomies are performed. The surgical resection for a pelvic sarcoma with limb salvage is an internal hemipelvectomy, unlike an external hemipelvectomy, wherein the adjacent leg is also resected.
Types of internal hemipelvectomy include the following:
- Type I (Ilium resected)
- Type II (periacetabular region resected)
- Type III (ischiopubic resection)
- Type IV (sacral ala removal).
Amputations and disarticulations
These specimens should be preferably grossed in the fresh state, after studying the clinical history and radiological features, for accurate localization and extent of the tumor.
Depending upon the location of the tumor and the extent of tumor spread, various types of amputations are performed. The different types of amputations include the following:
Below the elbow, above the elbow, shoulder disarticulation, below the knee, above the knee, hip disarticulation, and radial amputation of toes and fingers.
It is crucial to study the plain radiograph, site, and location of the tumor; bone and soft tissue involvement; any skip lesion; distance from the joint; the presence of nail, plates, cement, etc., The presence of skip lesions can be a reason for radical resection, such as an amputation.
The type of amputation should be specified, including its exact measurements and its external appearance. In such specimens, margins are often redundant, as the resection is beyond the joint. Subsequently, the soft tissues around the tumor should be removed, unless the tumor is seen involving the adjacent soft tissues. It is appropriate to initiate around the scar tract.
Any lymph nodes identified during dissection should be noted and submitted for processing, apart from the primary tumor and other sections.
En bloc resection
An en bloc resection is performed to evaluate preoperative chemotherapy (neoadjuvant) response in cases of Ewing sarcoma and osteosarcoma.,
The rationale is that preoperative chemotherapy leads to systemic and local effects. Most importantly, the tumor shrinks in size, and margins are better defined. This further leads to reduced morbidity and a possibility of limb-sparing surgery. Moreover, this helps to gauge chemotherapy response. The extent of chemotherapy response is a strong prognostic marker in cases of high-grade osteosarcoma., At the same time, there have been a few studies with contrary results. Nonetheless, detailed histopathological assessment of postchemotherapy-treated cases of osteosarcoma and Ewing sarcoma remains part of the standard of care.,,,,
Grossing of a postchemotherapy-treated en block specimen has been previously mentioned. A coronal/cross-section is made for exposing the maximum area, including the tumor. A 5 mm thick slab may be obtained by a longitudinal section. The entire bone and soft tissue section (grid-wise) should be labeled, in terms of the tumor extent, along with the cut margins and articular surfaces.,
An acceptable margin of normal tissue is not universally agreed upon. Lately, a threshold of more than 2 mm was chosen as an acceptable limit to qualify surgical resection as safe (R0). This was found to be the optimal parameter for predicting local recurrence (level of evidence = IV).
Evaluation of post-NACT response
In cases of high-grade osteosarcoma, chemotherapy response is microscopically seen in the form of necrosis, calcification, fibrosis, empty lacunae, and ghost-like cells, especially in osteoblastic and chondroblastic osteosarcomas, loss of nucleo-cytoplasmic details, granulation tissue, and inflammation. It is noteworthy that post-treatment nuclear atypia is not interpreted as a response.
The histopathological response is subclassified into four grades, based on the Huvos grading system., Cases with less than 90% response are classified as poor responders, while those with 90% necrosis and more constitute good responders [Figure 2],[Figure 3],[Figure 4]. In a study by Jeys et al., the authors reported that recording of surgical margins in millimeters and the response to neoadjuvant chemotherapy (NACT) can more accurately predict the risk of local recurrence than the current Musculoskeletal Tumor Society (MSTS) margin classification. Besides, evaluation of resection margins and histopathological assessment of necrosis in postchemotherapy-treated osteosarcomas, the presence of microscopic lymphovascular invasion has also been reported to be associated with poor overall survival.
|Figure 2: Resected specimen (femur) in a case of post-NACT-treated high-grade osteosarcoma, for histopathological assessment of treatment response (necrosis). (a) Cut surface of the bisected specimen, showing a gray–white tumor involving the metadiaphyseal region, including medullary cavity of the distal end of the femur. (b) A complete cross-section of the entire specimen blocked out (grid), including tumor, further cut into multiple sections for processing. (c) A corresponding drawing of the tumor, including the tumor, with sections, accordingly labeled along with cut end (shave margin); NACT: Neoadjuvant chemotherapy|
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|Figure 3: Pathological features in post-NACT-treated case of osteosarcoma. (a) Gross features. Cut surface showing greyish-white areas, indicative of chemotherapy response. (b) Microscopy, depicting residual bone with mostly empty lacunae and hyalinization, devoid of sarcoma cells (H and E), ×200; NACT: Neoadjuvant chemotherapy|
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|Figure 4: Another, post-NACT treated case of high-grade osteosarcoma. (a) Gross findings. Cut surface, showing a gray–white to brownish area (hemorrhage), indicative of the residual tumor. (b) Microscopic examination revealing areas of osteoid and reactive fibrosis. (treatment response). H and E, ×200. (c) Areas showing residual sarcomatous cells (40% in this case/poor responder) (H and E, ×200); NACT: Neoadjuvant chemotherapy|
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In post-treated cases of Ewing Sarcoma, only the ones showing 100% response are classified as good responders [Figure 5].
|Figure 5: Case of Ewing sarcoma. (a) Microscopic examination of the initial biopsy, showing a malignant round cell tumor (H and E, ×400). (b) Tumor cells displaying cytoplasmic membranous positivity for MIC2/CD99. Diaminobenzidine, ×400. (c) Post-NACT, microscopic assessment, revealing no residual tumor, in this case (100% response). H and E, ×400; NACT: Neoadjuvant chemotherapy|
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The stratification of patients with Ewing's sarcoma into “good” and “poor” responders might be useful in guiding the administration of progressively more intensified chemotherapy.
Other, relatively newer specimens in orthopedic oncopathology
Post-denosumab-treated giant cell tumor resection
Lately, denosumab (a human monoclonal antibody against RANK-ligand) is being offered to patients harboring large and recurrent giant cell tumors to facilitate surgery. Post-denosumab-treated specimens of GCTB are sclerotic and microscopically resemble osteosarcoma, especially low-grade. A bone pathologist must be aware of gross and microscopic features in such cases to avoid overdiagnosis of osteosarcoma or other lesions in such cases. A prior history of the same would be crucial, as denosumab induces changes that are morphologically similar to osteosarcoma. Post-denosumab-treated changes include reduction or absence of osteoclastic giant cells and replacement by fibro-osseous tissue, including reactive woven bone/osteoid, spindle cell proliferation, hyalinization, fibrosis, and a variable amount of inflammatory cells.,, However, it is difficult to assess residual tumor cells in such cases because the tumor cells in the GCTB are the stromal cells. It has been reported that significant numbers of giant cells constitute a predictive indication of an optimal histologic response to denosumab treatment in GCTB [Figure 6].
|Figure 6: (a) Cut-section of a resected specimen (right-sided internal hemipelvectomy) of post-denosumab-treated giant cell tumor, showing predominantly firm to hard gray–white areas, indicative of a significant response that was microscopically confirmed. (b) Microscopic appearance of another case of post-denosumab-treated GCTB showing a residual focus of giant cell tumor with predominant replacement by fibro-osseous tissue (H and E, ×200)|
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As ECRT is being offered to certain diaphyseal-based sarcomas, post-ECRT-treated specimens are processed for evaluating residual tumors.
Classification of primary bone tumors
The classification of primary bone tumors is based on the lineage or pathway of tumor cell differentiation, which is reflected in the type of matrix formed by the tumor cells (bone-forming, cartilage forming, etc.). Apart from typing, bone sarcomas are graded as Grade 1 (low grade): parosteal osteosarcoma, low-grade central osteosarcoma clear cell chondrosarcoma, and osteofibrous dysplasia-like adamantinoma; Grade 2 (intermediate-grade): periosteal osteosarcoma, conventional osteosarcoma, pleomorphic sarcoma, Ewing sarcoma, and classical adamantinoma; and Grade 3 (high-grade): dedifferentiated and mesenchymal chondrosarcoma poorly differentiated and dedifferentiated chordoma.
Bone sarcomas are staged using the eighth edition of the T (tumor) N (regional lymph nodes) M (metastasis) classification. This applies to all primary bone malignancies, except malignant lymphoma, multiple myeloma, surface/juxtacortical osteosarcoma, and juxtacortical chondrosarcoma. After the histopathological disease confirmation, the malignant tumors must be subclassified into the histological type and grade. While tumors occurring in the appendicular skeleton, trunk, skull, and facial bones are subclassified as T1, T2, and T3, tumors occurring in the spine are subclassified into T1, T2, T3, T4a, and T4b. Tumors occurring in the pelvis are subclassified as T1a, T1b, T2a, T2b, T3a, T3b, T4a, and T4b. N0 and M0 represent no regional lymph node and distal metastasis, respectively. M1a represents distant metastasis into the lung and M1b represents metastasis into other sites. Tx, Nx, and Mx represent tumor, regional lymph nodes, and metastasis cannot be identified, respectively.
Recent updates in the fifth edition of WHO 2020 classification
Some of the updates in the recent WHO classification of bone tumors include the designation of atypical cartilaginous tumor (ACT) in the appendicular bone for a grade 1 chondrosarcoma (CS1) in bones of the axial skeleton. Microscopically, host bone permeation or entrapment of pre-existing bone is an essential criterion for diagnosing chondrosarcoma. Increasing nuclear atypia, mitotic figures, and mitotic rate continue as parameters for grading a chondrosarcoma [Figure 7]. Certain entities such as benign fibrous histiocytoma and well-differentiated liposarcoma of bone have been removed; whereas, intraosseous hibernoma has been included.
|Figure 7: Microscopic examination in a case of chondrosarcoma. (a) Distinct foci of a cellular, atypical chondroid tumor, permeating through the host bone (H and E, ×200) (b) Higher magnification displaying increased cellularity, binucleation, and atypia (H and E, ×400)|
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Specific histone H3.3 alterations and their corresponding proteins have been identified in certain giant cell-rich tumors of bone. These include H3F3B, leading to p.Lys36Met alterations in a chondroblastoma, and H3FEA, leading to p.Gly34Trp, or in one case, p.Gly34Leu alterations in a GCTB, including its malignant counterpart. Identification of these gene alterations and their corresponding immunoexpression is further useful in differentiating these tumors from their diagnostic mimics [Figure 8] and [Figure 9]. Certain newer and relatively rarer tumor types have been more clearly described, such as a poorly differentiated chordoma, mostly in the clivus/skull base of pediatric patients, and dedifferentiated chordoma, predominantly in the sacrococcygeal region.,, While a poorly differentiated chordoma histopathologically, might lack physaliphorous cells and is immunohistochemically characterized by loss of INI1; a dedifferentiated chordoma shows classic areas of chordoma, juxtaposed with areas of a high-grade sarcoma, the latter component lacking notochordal differentiation. Immunohistochemically, a poorly differentiated chordoma displays diffuse brachyury/T (marker of notochordal differentiation) immunostaining; whereas, a dedifferentiated chordoma displays brachyury immunostaining in the differentiated area, sparing the areas of nonchordomatous differentiation. Both these tumor types are associated with a relatively aggressive clinical course.,,, Undifferentiated round cell sarcomas have been further subtyped as Ewing sarcoma, round cell sarcoma with EWSR1- non-ETS fusions, CIC-rearranged sarcoma, and sarcoma with BCOR-genetic alterations. Immunohistochemically, these tumors express WT1, BCOR, CCNB3, and SATB2.,,,
|Figure 8: Giant cell tumor of bone (a-d). (a) Uniformly distributed osteoclast-like giant cells (OCGCs) and mononuclear tumor cells (H and E, ×100). (b) Features at higher magnification (H and E, ×200). (c) Diffuse nuclear positivity for antihistone H3.3G34W (DAB, ×100). (d) H3.3 G34W immunostaining within mononuclear cells (DAB, ×200). (e-h) Post-denosumab-treated GCTB. (e) Woven bone and bland spindle cells (H and E, ×200). (f) Spindle cells and lack of OCLGCs (H and E, ×200). (g) Diffuse histone H3.3 G34W immunostaining in residual mononuclear cells (DAB, ×200). (h) Histone H3.3 G34W immunostaining (DAB, ×200)|
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|Figure 9: Chondroblastoma (a and b). (a) Cellular tumor comprising polygonal mononuclear with interspersed osteoclast-like giant cells and adjacent eosinophilic cartilaginous matrix (H and E, ×200). (b) Tumor cells showing well-defined, eosinophilic cytoplasm, vesicular nuclei, and intranuclear grooves (H and E, ×400). (c) Diffuse antihistone H3.3 K36M immunostaining within tumor cells, sparing osteoclast-like giant cells (DAB, ×400). (d) Immunohistochemical staining with antihistone H3.3 G34W antibody shows negative staining (DAB, ×400)|
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To summarize, grossing and reporting of bone tumors requires expertise, especially in the present times of limb salvage in musculoskeletal oncology. Pathological reporting of bone tumors essentially requires a multidisciplinary approach, including a specialist pathologist, radiologist, and oncologist (surgical, medical, and radiation). A surgical pathology report of bone tumors, including sarcomas, should include all the essential parameters, including those with prognostic significance. An exact recognition of a tumor type, including certain newer immunohistochemical and genetic markers, is a crucial step toward precision oncology. Certain immunohistochemical markers, such as BCOR, CCNB3, and SATB2 can be used to triage undifferentiated sarcomas for BCOR-CCNB3 testing, while WT1 and ETV4 can be used for triaging cases for CIC-rearrangement and CIC-DUX4 testing by FISH and molecular techniques, which constitute as essential diagnostic criteria for these rare tumors.
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| » References|| |
Luetke A, Meyers PA, Lewis I, Juergens H. Osteosarcoma treatment-where do we stand? A state of the art review. Cancer Treat Rev 2014;40:523-32.
Nouri H, Ben Maitigue M, Abid L, Nouri N, Abdelkader A, Bouaziz M, et al
. Surface osteosarcoma: Clinical features and therapeutic implications. J Bone Oncol 2015;4:115-23.
Dürr HR, Bakhshai Y, Rechl H, Tunn PU. Tumorresektion: Wie weit ist weit genug? [Resection margins in bone tumors: What is adequate?]. Unfallchirurg 2014;117:593-9.
Gelderblom H, Hogendoorn PC, Dijkstra SD, van Rijswijk CS, Krol AD, Taminiau AH, et al
. The clinical approach towards chondrosarcoma. Oncologist 2008;13:320-9.
Chui MH, Kandel RA, Wong M, Griffin AM, Bell RS, Blackstein ME, et al
. Histopathologic features of prognostic significance in high-grade osteosarcoma. Arch Pathol Lab Med 2016;140:1231–42.
García-Castellano JM, Atallah Yordi N, Reyes C, Healey JH. Histopathologic and radiologic assessment of chemotherapeutic response in Ewing's sarcoma: A review. Sarcoma 2012;2012. doi: 10.1155/2012/357424.
Erdogan KE, DevecI MA, Paydas S, Gonlusen G. Morphologic evaluation of the effect of denosumab on giant cell tumors of bone and a new grading scheme. Pol J Pathol 2016;67:392-7.
Rekhi B, Verma V, Gulia A, Jambhekar NA, Desai S, Juvekar SL, et al
. Clinicopathological features of a series of 27 cases of post-denosumab treated giant cell tumors of bones: A single institutional experience at a tertiary cancer referral centre, India. Pathol Oncol Res 2017;23:157-64.
Bonds LA, Barnes P, Foucar K, Sever CE. Acetic acid-zinc-formalin: A safe alternative to B-5 fixative. Am J Clin Pathol 2005;124:205-11.
Casali PG, Bielack S, Abecassis N, Aro HT, Bauer S, Biagini R, et al
. Bone sarcomas: ESMO-PaedCan-EURACAN clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29(Suppl 4):iv79-95.
Pramesh CS, Deshpande MS, Pardiwala DN, Agarwal MG, Puri A. Core needle biopsy for bone tumors. Eur J Surg Oncol 2001;27:668-71.
Mitsuyoshi G, Naito N, Kawai A, Kunisada T, Yoshida A, Yanai H, et al
. Accurate diagnosis of musculoskeletal lesions by core needle biopsy. J Surg Oncol 2006;94:21-7.
Hong AM, Millington S, Ahern V, McCowage G, Boyle R, Tattersall M, et al
. Limb preservation surgery with extracorporeal irradiation in the management of malignant bone tumor: The oncological outcomes of 101 patients. Ann Oncol 2013;24:2676-80.
Sharma DN, Rastogi S, Bakhshi S, Rath GK, Julka PK, Laviraj MA, et al
. Role of extracorporeal irradiation in malignant bone tumors. Indian J Cancer 2013;50:306-9.
] [Full text]
Plant J, Cannon S. Diagnostic work up and recognition of primary bone tumours: A review. EFORT Open Rev 2017;1:247-53.
Miwa S, Otsuka T. Practical use of imaging technique for management of bone and soft tissue tumors. J Orthop Sci 2017;22:391-400.
Mangham DC, Athanasou NA. Guidelines for histopathological specimen examination and diagnostic reporting of primary bone tumours. Clin Sarcoma Res 2011;1:6.
Meyer MS, Spanier SS, Moser M, Scarborough MT. Evaluating marrow margins for resection of osteosarcoma. A modern approach. Clin Orthop Relat Res 1999;363:170-5.
Abdul-Karim FW, Bauer TW, Kilpatrick SE, Raymond KA, Siegal GP. Association of directors of anatomic and surgical pathology. recommendations for the reporting of bone tumors. Association of directors of anatomic and surgical pathology. Hum Pathol 2004;35:1173-8.
Rubin BP, Fletcher CD, Inwards C, Montag AG, Peabody T, Qualman SJ, et al
. Protocol for the examination of specimens from patients with soft tissue tumors of intermediate malignant potential, malignant soft tissue tumors, and benign/locally aggressive and malignant bone tumors. Arch Pathol Lab Med 2006;130:1616-29.
Guder WK, Hardes J, Gosheger G, Henrichs MP, Nottrott M, Streitbürger A. Analysis of surgical and oncological outcome in internal and external hemipelvectomy in 34 patients above the age of 65 years at a mean follow-up of 56 months. BMC Musculoskelet Disord 2015;16:33.
Athanasou NA, Mangham DC. Dataset for histopathology reports on primary bone tumors. 2010. Royal College of Pathologists. Available from: www.rcpath.org
. [Last accessed on 2020 Dec 31].
Desai SS, Rekhi B, Jambhekar NA. Musculoskeletal system. Soft tissues. In: Desai SS, Bal M, Rekhi B, Jambhekar NA, editors. Grossing of Surgical Oncology Specimens. Tata Memorial Hospital. ISBN: 978-93-80251-11-0. 2011. p. 70-9.
Bielack SS, Kempf-Bielack B, Delling G, Exner GU, Flege S, Helmke K, et al
. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 2002;20:776-90.
Whelan JS, Jinks RC, McTiernan A, Sydes MR, Hook JM, Trani L, et al
. Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials. Ann Oncol 2012;23:1607-16.
Bajpai J, Chandrasekharan A, Talreja V, Simha V, Chandrakanth MV, Rekhi B, et al
. Outcomes in non-metastatic treatment naive extremity osteosarcoma patients treated with a novel non-high dosemethotrexate-based, dose-dense combination chemotherapy regimen 'OGS-12'. Eur J Cancer 2017;85:49-58.
Lewis IJ, Nooij MA, Whelan J, Sydes MR, Grimer R, Hogendoorn PC, et al
. Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: A randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst 2007;99:112-28.
Picci P, Rougraff BT, Bacci G, Neff JR, Sangiorgi L, Cazzola A, et al
. Prognostic significance of histopathologic response to chemotherapy in nonmetastatic Ewing's sarcoma of the extremities. J Clin Oncol 1993;11:1763-9.
Gomez-Brouchet A, Mascard E, Siegfried A, de Pinieux G, Gaspar N, Bouvier C, et al
. Assessment of resection margins in bone sarcoma treated by neoadjuvant chemotherapy: Literature review and guidelines of the bone group (GROUPOS) of the French sarcoma group and bone tumor study group (GSF-GETO/RESOS). Orthop Traumatol Surg Res 2019;105:773-80.
Bui MM, Smith P, Agresta SV, Cheong D, Letson GD. Practical issues of intraoperative frozen section diagnosis of bone and soft tissue lesions. Cancer Control 2008;15:7-12.
Rosen G, Marcove RC, Caparros B, Nirenberg A, Kosloff C, Huvos AG. Primary osteogenic sarcoma: The rationale for preoperative chemotherapy and delayed surgery. Cancer 1979;43:2163-77.
Provisor AJ, Ettinger LJ, Nachman JB, Krailo MD, Makley JT, Yunis EJ, et al
. Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: A report from the Children's Cancer Group. J Clin Oncol 1997;15:76-84.
Jeys LM, Thorne CJ, Parry M, Gaston CL, Sumathi VP, Grimer JR. A Novel system for the surgical staging of primary high-grade osteosarcoma: The Birmingham classification. Clin Orthop Relat Res 2017;475:842-50.
Tsuda Y, Tsoi K, Stevenson JD, Parry MC, Fujiwara T, Sumathi V, et al
. Is microscopic vascular invasion in tumor specimens associated with worse prognosis in patients with high-grade localized osteosarcoma? Clin Orthop Relat Res 2020;478:1190-8.
Albergo JI, Gaston CL, Laitinen M, Darbyshire A, Jeys LM, Sumathi V, et al
. Ewing's sarcoma: Only patients with 100% of necrosis after chemotherapy should be classified as having a good response. Bone Joint J 2016;98-B: 1138-44.
Branstetter DG, Nelson SD, Manivel JC, Blay JY, Chawla S, Thomas DM, et al
. Denosumab induces tumor reduction and bone formation in patients with giant-cell tumor of bone. Clin Cancer Res 2012;18:4415-24.
Wojcik J, Rosenberg AE, Bredella MA, Choy E, Hornicek FJ, Nielsen GP, et al
. Denosumab-treated giant cell tumor of bone exhibits morphologic overlap with malignant giant cell tumor of bone. Am J Surg Pathol 2016;40:72-80.
Treffel M, Lardenois E, Larousserie F, Karanian M, Gomez-Brouchet A, Bouvier C, et al
. Denosumab-treated giant cell tumors of bone: A clinicopathologic analysis of 35 cases from the French group of bone pathology. Am J Surg Pathol 2020;44:1-10.
Puri A, Byregowda S, Gulia A, Patil V, Crasto S, Laskar S. Reconstructing diaphyseal tumors using radiated (50 Gy) autogenous tumor bone graft. J Surg Oncol 2018;118:138-43.
Flanagan AM, Blay JY, Bovee JVMG, Bredella MA, Cool P, Nielsen GP, et al
. Bone tumors: Introduction. In: Bovee JVMG, Flanagan AM, Lazar AJ, Nielsen GP, Yoshida A, editors. WHO Classification of Tumors of Soft Tissue and Bone. 5th
ed. Lyon: IARC Press; 2020. p. 338-9.
Brierley JD, Gospodarowicz MW, Wittekind C, editors. TNM Classification of Malignant Tumors. 8th
ed. Oxford (UK): Wiley Blackwell; 2017. UICC[Internet]. Geneva (Switzerland): Union of International cancer control; 2019. TNM publications and resources; updated 2019 Feb 4. Available from: https://www.uicc.org/resources/tnm/publications-reources.
Bovee JVMG, Bloem JL, Flanagan AM, Nielsen GP, Yoshida. Central atypical cartilaginous tumor/chondrosarcoma grade 1. In: Bovee JVMG, Flanagan AM, Lazar AJ, Nielsen GP, Yoshida A, editors. WHO Classification of Tumors of Soft Tissue and Bone. 5th
ed. Lyon: IARC Press; 2020. p. 370-2.
Kumar R, Deaver MT, Czerniak BA, Madewell JE. Intraosseous hibernoma. Skeletal Radiol 2011;40:641-5
Behjati S, Tarpey PS, Presneau N, Scheipl S, Pillay N, Van Loo P, et al
. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nat Genet 2013;45:1479-82.
Mobley BC, McKenney JK, Bangs CD, Callahan K, Yeom KW, Schneppenheim R, et al
. Loss of SMARCB1/INI1 expression in poorly differentiated chordomas. Acta Neuropathol 2010;120:745-53.
Rekhi B, Kosemehmetoglu K, Rane S, Soylemezoglu F, Bulut E. Poorly differentiated chordomas showing loss of INI1/SMARCB1: A report of 2 rare cases with diagnostic implications. Int J Surg Pathol 2018;26:637-43.
Hanna SA, Tirabosco R, Amin A, Pollock RC, Skinner JA, Cannon SR, et al
. Dedifferentiated chordoma: A report of four cases arising 'de novo'. J Bone Joint Surg Br 2008;90:652-6.
Jambhekar NA, Rekhi B, Thorat K, Dikshit R, Agrawal M, Puri A. Revisiting chordoma with brachyury, a “new age” marker: Analysis of a validation study on 51 cases. Arch Pathol Lab Med 2010;134:1181-7.
De Alva E, Lessnick SL, Stamenkovic I. Ewing sarcoma. Undifferentiated round cell sarcomas of bone and soft tissues. In: Bridge J, editor. World Health Organization Classification of Tumours. 5th
ed. Soft Tissue and Bone Tumours. Lyon, France: IARC Press; 2020. p. 323-5.
Le Loarer F, Szuhai K, Tirode F. Round cell sarcoma with EWSR1-nonETS fusions. Undifferentiated round cell sarcomas of bone and soft tissues. In: Bridge J, editor. World Health Organization Classification of Tumours. 5th
ed. Soft Tissue and Bone Tumours. Lyon, France: IARC Press; 2020, P
Antonescu CR, Puls F, Tirode F. Sarcoma with BCOR-genetic alterations. Undifferentiated round cell sarcomas of bone and soft tissues. In: Bridge J, editor. World Health Organization Classification of Tumours. 5th
ed. Soft Tissue and Bone Tumours. Lyon, France: IARC Press; 2020. p. 333-5.
Rekhi B, Kembhavi P, Mishra SN, Shetty O, Bajpai J, Puri A. Clinicopathologic features of undifferentiated round cell sarcomas of bone and soft tissues: An attempt to unravel the BCOR-CCNB3-
-positive sarcomas. Indian J Med Res 2019;150:557-74.
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