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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 3  |  Page : 240-245

Tumor histopathological response to neoadjuvant chemotherapy in bone sarcomas: A single-institutional experience


1 Department of Pathology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India
2 Department of Orthopaedics, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi, India

Date of Submission03-Jan-2020
Date of Decision20-Apr-2020
Date of Acceptance23-Apr-2020
Date of Web Publication28-Jul-2020

Correspondence Address:
Dr. Safia Rana
Assistant Professor, Department of Pathology, Hamdard Institute of Medical Sciences and Research, Jamia Hamdard, New Delhi - 110 062
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijhas.IJHAS_119_19

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  Abstract 

BACKGROUND : The histological response to chemotherapy is regarded as an independent prognostic variable in bone tumours. The surgical pathologist, thus has an important role in the management of primary malignant bone tumors like osteosarcomas and Ewing's sarcoma subsequent to neoadjuvant chemotherapy.
AIMS AND OBJECTIVES: We report a short series of fifteen cases of osteosarcoma and three cases of Ewing's sarcoma in which the histological response of the tumor after giving neoadjuvant chemotherapy to the patient of bone tumours was assessed and graded.
MATERIAL AND METHODS: Bone tumours was assessed and graded by Huvos grading. The correlation of this histopathologic tumor response with clinical outcome is a well-established routine investigation in patients with bone sarcomas and the grading of the tumor response is based on definable histopathologic criteria.
RESULT: Fifteen out of eighteen cases in this study showed a response to neoadjuvant chemotherapy, which was categorized as Huvos Grade 1 (%50%) and Huvos Grade 2 (50% to 90%). One case of osteosarcoma showed a Grade 4 response with a total absence of tumor cells in all the sections. One case of osteosarcoma and Ewing's sarcoma each were categorized as Grade 3, showing tumor foci.
CONCLUSION: It was concluded that necrosis of tumor area when greater than 90%, is regarded as a powerful positive prognostic indicator for survival in patients of high grade bone sarcomas.

Keywords: Bone, chemotherapy, tumors


How to cite this article:
Jetley S, Jairajpuri ZS, Rana S, Walvir NM, Khetrapal S, Khan S, Hassan MJ, Jameel J. Tumor histopathological response to neoadjuvant chemotherapy in bone sarcomas: A single-institutional experience. Int J Health Allied Sci 2020;9:240-5

How to cite this URL:
Jetley S, Jairajpuri ZS, Rana S, Walvir NM, Khetrapal S, Khan S, Hassan MJ, Jameel J. Tumor histopathological response to neoadjuvant chemotherapy in bone sarcomas: A single-institutional experience. Int J Health Allied Sci [serial online] 2020 [cited 2020 Aug 6];9:240-5. Available from: http://www.ijhas.in/text.asp?2020/9/3/240/290707


  Introduction Top


The histological response to chemotherapy as assessed by microscopic examination of tissues is regarded as an independent prognostic variable in bone sarcomas, both osteosarcoma and Ewing's sarcoma. The surgical pathologist, thus, has an important role in the management of primary malignant bone tumors such as osteosarcomas and Ewing's sarcoma subsequent to neoadjuvant chemotherapy. Surgical treatment has made possible the histopathological examination of tumor and assessment of the response to therapy. It is seen that survival rates are better in good responders to neoadjuvant chemotherapy with high tumor necrosis as compared to those with a poor response.[1] The correlation of this histopathologic tumor response with clinical outcome is a well-established routine investigation in patients with bone sarcomas, and the grading of the tumor response is based on definable histopathologic criteria.[2],[3],[4] We report a short series of 15 cases of osteosarcoma and 3 cases of Ewing's sarcoma, in which the histological response of the tumor to neoadjuvant chemotherapy was objectively assessed and graded.


  Materials and Methods Top


The present study was conducted at the Hakeem Abdul Hameed Centenary Hospital, New Delhi, over a 3-year period. This hospital caters to the population from the nearby slums and the adjoining areas around this hospital in New Delhi. This was a retrospective analysis of the histological response to chemotherapy observed in 15 cases of osteogenic sarcoma and 3 cases of Ewing's sarcoma. Data on the age and presenting clinical features were retrieved from the accompanying laboratory request forms or patients records wherever available. All the patients were children and young adults. Of the 18 cases in this study, except for two cases of osteogenic sarcoma, the initial diagnoses of osteogenic sarcoma and Ewing's sarcoma and also the neoadjuvant chemotherapy administrations were done at another institution and the patients reported to our hospital only for the surgical management following neoadjuvant chemotherapy. The pretreatment biopsy was reviewed in all the cases, and no discrepancy in the pretreatment diagnoses was noted by us in any of the cases.

On receiving the surgical resected gross bone specimens in the laboratory, they were first bi-valved by using the electric bone cutting saw in the histopathology department so that the entire extent of the tumor involvement was exposed. Multiple sections of the resection specimens of the entire cut surface were taken to include the full cut surface of the tumor with properly labeled line diagrams in our gross records. Sampling of all the relevant tumor margins was also done. Huvos grading system for assessment of the response of the tumor to neoadjuvant chemotherapy, in which microscopic evaluation is based on the extent of necrosis as compared to the percentage of residual viable tumor, was applied in all the 18 cases.


  Results Top


This retrospective study showed that 18 cases of bone sarcomas (15 osteosarcomas and 3 Ewing's sarcomas) underwent postneoadjuvant chemotherapy surgical resection at our institution during the study period of 3 years. The patients in this study were all young adults and from both the sexes. Fifteen patients diagnosed as osteosarcomas had an age range between 6 years and 31 years, of which 10 were males and 5 were females. Three cases of Ewing's sarcoma were reported, in a 13-year-old female, a 17-year-old male, and a 25-year-old male [Figure 5] and [Figure 6]. The most common clinical presentation in these 18 cases was local bony pain, tenderness, and swelling in 12/18 cases, while the clinical presentation of a pathological fracture was seen in 6/18 cases in this study. These findings are depicted in [Table 1].
Table 1: Bone sarcomas undergoing postneoadjuvant chemotherapy: Age distribution with site and clinical pres

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With these suggestive clinical presentations of bony pain with swelling and pathological fractures, the patients were worked up to reach a conclusive diagnosis. A definitive diagnosis of conventional osteosarcoma was made in 15 cases, whereas 3 cases were reported as Ewing's sarcoma. Magnetic resonance imaging, which is regarded as an important investigation to determine the extent of the tumor within and outside the bone, was performed in all the cases. It specifically identifies the extent of the tumor in the soft tissue, the medullary canal, or the joint space and also delineates the proximity and/or encasement of neuromuscular bundles by the tumor.[5] In our study, a large extraosseous component and knee joint space involvement was seen in three cases. Neurovascular encasement was seen in one case. This was followed by neoadjuvant chemotherapy regimens before the patient was subjected to a radical surgery.

The appropriate treatment for bone sarcomas has been established over the years as a multidisciplinary approach. It includes preoperative chemotherapy (neoadjuvant), surgery, and postoperative chemotherapy (adjuvant). Neoadjuvant chemotherapy was administered as per the standard protocol. The cycles of vincristine, actinomycin D, cyclophosphamide/ifosfamide, and etoposide or vincristine, ifosfamide, doxorubicin, and etoposide regimen were used in Ewing's sarcoma, and methotrexate, doxorubicin, and cisplatin regimen was used in osteosarcoma. A multicentric retrospective study showed that a combination of surgery and chemotherapy is a standard choice of treatment and, chemotherapy may give better results if used both preoperatively and postoperatively.[6]

The surgical resected gross bone tumor specimens after neoadjuvant chemotherapy were received in the histopathology laboratory and processed. An objective assessment of the response of the bone sarcoma to the neoadjuvant chemotherapy by applying the Huvos grading system for response to neoadjuvant chemotherapy for osteosarcoma and Ewing's sarcoma was done. These findings are depicted in [Table 2].
Table 2: Bone sarcomas undergoing postneoadjuvant chemotherapy: Histopathological diagnosis and response to therapy by Huvos grading

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Majority of the cases in this study (15/18 cases) showed a response to neoadjuvant chemotherapy, which was categorized as Huvos Grade 1 (<50%) and Huvos Grade 2 (50% to 90%). One case of osteosarcoma showed a Grade 4 response with a total absence of tumor cells in all the sections. One case of osteosarcoma and Ewing's sarcoma each were categorized as Grade 3, showing scattered foci of tumor cells [Figure 1], [Figure 2], [Figure 3], [Figure 4].
Figure 1: Microphotograph taken from the tumor of osteosarcoma patients with Huvos Grade 1 (H and E, ×40)

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Figure 2: Microphotograph taken from the tumor of osteosarcoma patients with Huvos Grade 3

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Figure 3: Microphotograph taken from tumor of patients with Ewing's sarcoma with Huvos Grades 1 and 3

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Figure 4: Gross photograph showing osteosarcoma in the proximal tibia

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Figure 5: (a) Pie chart showing gender distribution of cases. (b) Bar graph showing age-wise distribution of cases

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Figure 6: Bar graph showing anatomical site-wise distribution of cases

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  Discussion Top


Osteosarcomas are osteoid matrix producing malignant mesenchymal tumors which are rare and occur in children, teenagers, and young adults. On the other hand, Ewing's sarcoma is a rare, primitive, highly cellular, malignant, round-cell tumor of bone and soft tissue, which was first described by Ewing in 1921. It is the second most common primary malignant tumor of bone in children after osteosarcoma. The most common sites for osteosarcoma are the distal femur, the proximal tibia, and the proximal humerus, at the metaphysis of the extremities. Rapid bone growth as suggested by the increased incidence during the adolescent growth spurt and the frequent location in the metaphyseal region adjacent to the growth plate of long bones appear to be predisposing factors for developing osteosarcoma. Ewing's sarcoma has also been mostly reported in children and young adults, and approximately 50% are found in the diaphysis of long bones. Other common locations of Ewing's sarcoma include the paraspinal tissues, the pelvis, and the chest wall.

Investigators, over the years, have concurred that the degree of tumor necrosis induced by preoperative chemotherapy is an important prognostic factor in relation to the survival of patients with primary osteosarcoma.[6],[7] Similarly, Wunder et al. have reported that the extent of postneoadjuvant chemotherapy tumor necrosis in Ewing's sarcomas directly correlated with improved survival of the patients.[8]

The Huvos grading system provides a semi-quantitative histological evaluation of the tumor response to neoadjuvant chemotherapy in which the amount of necrosis relative to the remaining viable tumor is reported. This was the method adopted in this study. The four grades included were Grade 1: little or no evidence of necrosis; Grade 2: necrosis of 50%–90%; Grade 3: necrosis between 90% and 99%; finally, Grade 4: 100% necrosis.[9] Rosalvo et al. evaluated the prognostic value of the degree of tumor necrosis as assessed by the Huvos grading system based on the local recurrence-free survival, metastasis-free survival, and overall survival.[10] They concluded that patients with tumor necrosis of Huvos Grades I and II after neoadjuvant chemotherapy have similar prognostic behavior, despite the wide difference in the percentage range of tumor necrosis in these two groups, when collated together, i.e., 0% to 90%.

Salzer-Kuntschik et al. of the German-Austrian Swiss Cooperative Osteosarcoma Study Group devised a six-tier histological grading system of the response to chemotherapy in osteosarcoma.[11] In this system, the extent of the viable tumor was documented, unlike the Huvos system in which the histological grade is based on the amount of necrosis in response to the neoadjuvant chemotherapy. The six grades were classified as Grade I – no viable tumor cells, Grade II – single tumor cells or clusters <0.5 cm, Grade III – viable tumor cells <10% seen, Grade IV – viable tumor cells 10%–50% seen, Grade V – viable tumor cells >50% seen, and Grade VI – no tumor response seen.

Yet another histological grading system of the response to neoadjuvant chemotherapy in osteosarcoma was developed by Picci et al. of the Instituti Ortopedico Rizzoli in Bologna.[12] They proposed evaluating the amount of remaining viable tumor and developed a method that requires calculating the absolute quantity of viable tumor cells after neoadjuvant chemotherapy. Four histological grades of tumor response, including total tumor response, good tumor response, fair tumor response, and poor tumor response, were created. Grading system developed by Salzer Kuntchik et al., and Picci et al., have not found great acceptance in most of the tertiary level management centres for bone tumours.[11],[12]

Diverse histological changes were seen in response to the neoadjuvant chemotherapy in both the sarcomas, similar to those reported by previous workers.[13] Reactive bone formation, sclerotic bony trabecular with cortical thickening, and necrosis were seen in the cases of Ewing's sarcoma. Osteosarcoma cases showed both tumor necrosis with degenerative and reparative changes such as hyalinization and a dense sclerotic osteoid matrix. Other common findings included hemorrhagic cystic change, congested dilated vessels and marrow infarction in the adjacent marrow spaces with granulation tissue, dystrophic calcification, and hemosiderin deposition.


  Conclusion Top


Necrosis of tumor resection, especially when greater than 90%, is regarded as a powerful positive prognostic indicator for survival in patients with high-grade bone sarcomas. Thus, effective stratification of these patients using a histological scoring system is useful and plays an important role in the management of these patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
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.  Back to cited text no. 1
    
2.
Thapa JB. Histological assessment of the effect of neoadjuvant chemotherapy on conventional high grade osteosarcoma of the long bones. J Pathol Nepal 2011;1:60-2.  Back to cited text no. 2
    
3.
Sook Min BH, Kang HG, Ro JY. Therapy related changes in osteosarcoma and Ewing sarcoma of bone. Open Pathol J 2009;3:99-105.  Back to cited text no. 3
    
4.
Garcıa-Castellano JM, Yordi NA, Reyes C, Healey JH. Histopathologic and radiologic assessment of chemotherapeutic response in Ewing's sarcoma: A review. Sarcoma 2012;2012:1-8.  Back to cited text no. 4
    
5.
Heck RK, Canale ST Jr., Beaty JH. Malignant bone tumors. In: Campbell's Operative Orthopedics. Missouri: Mosby Year Book; 2008.p. 901–38.  Back to cited text no. 5
    
6.
Pakos EE, Nearchou AD, Grimer RJ, Koumoullis HD, Abudu A, Bramer JA, et al. Prognostic factors and outcomes for osteosarcoma: an international collaboration. Eur J Cancer 2009;45:2367-75.  Back to cited text no. 6
    
7.
Ferrari S, Bertoni F, Mercuri M, Picci P, Giacomini S, Longhi A, et al. Predictive factors of disease-free survival for non-metastatic osteosarcoma of the extremity: An analysis of 300 patients treated at the Rizzoli Institute. Ann Oncol 2001;12:1145-50.  Back to cited text no. 7
    
8.
Wunder JS, Paulian G, Huvos AG, Heller G, Meyers PA, Healey JH. The histological response to chemotherapy as a predictor of the oncological outcome of operative treatment of Ewing Sarcoma. J Bone Joint Surg 1998;80:1020-33.  Back to cited text no. 8
    
9.
Huvos AG, Rosen G, Marcove RC. Primary osteogenic sarcoma; Pathologic aspects in 20 patients after treatment with chemotherapy en bloc resection, and prosthetic bone replacement. Arch Pathol Lab Med 1977;101:14-8.  Back to cited text no. 9
    
10.
Rosalvo ZB Jr., de Camargo OP. Is there any difference in the prognosis for patients with primary osteosarcoma with a poor response to neoadjuvant chemotherapy between Huvos Grades I and II? Rev Bras Ortop. 2011;46:420-23  Back to cited text no. 10
    
11.
Salzer-Kuntschik M, Delling G, Beron G, Sigmund R. Morphological grades of regression in osteosarcoma after polychemotherapy study COSS 80. J Cancer Res Clin Oncol 1983;106:21-4.  Back to cited text no. 11
    
12.
Picci P, Bacci G, Campanacci M, Gasparini M, Pilotti S, Cerasoli S, et al. Histological evaluation of necrosis in osteosarcoma induced by chemotherapy. Regional mapping of viable and nonviable tumour. Cancer 1985; 56:1515-21  Back to cited text no. 12
    
13.
Lucas DR, Kshirsagar MP, Biermann JS, Hamre MR, Thomas DG, Schuetze SM, et al. Histologic alterations from neoadjuvant chemotherapy in high-grade extremity soft tissue sarcoma: Clinicopathological correlation. Oncologist 2008;13:451-8.  Back to cited text no. 13
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2]



 

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