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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2021  |  Volume : 64  |  Issue : 4  |  Page : 717-724
Bone metastases: A compilation of 365 histologically verified cases spanning over two decades from a single center


1 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
2 Department of Orthopaedics, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
3 Department of Neurosurgery, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India

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Date of Submission14-Sep-2020
Date of Decision05-Oct-2020
Date of Acceptance06-Dec-2020
Date of Web Publication20-Oct-2021
 

   Abstract 


Objective: To analyze the clinicopathological features of metastatic bone tumors over a period of two decades and identify the primary site of malignancy in metastasis of unknown origin. Materials and Methods: A total number of 365 cases were included in the study. The clinical features and location of the tumors were noted. The histopathological features of all the cases were studied. Immunohistochemistry (IHC) was done either to categorize or confirm the primary diagnosis using organ specific/organ restricted markers. Results: A total 712 bony sites were involved by metastasis in 365 patients, of which spine was the most commonly affected. Metastasis was the initial presentation in 69.5% patients. The primary site was known in 220 patients and almost half of them were detected after the diagnosis of metastasis. IHC was used as adjunct to suggest the possible origin in cases with unknown primary in 27.4%. Among the metastatic carcinoma, adenocarcinoma was the most common histological subtype with thyroid being the most frequent primary site of origin followed by lung and breast. Conclusion: More than two-third of cases in surgical pathology practice present as initial manifestations. Detection rate of primary depends on extent of metastatic work-up and IHC with organ specific/organ restricted markers to facilitate treatment with bone targeting agents.

Keywords: Bone, metastases, secondaries

How to cite this article:
Hui M, Balu B, Uppin SG, Uppin MS, Chandrasekhar P, Rao K N, Bhattarcharjee S, VijayaSaradhi M, Krishna Y V. Bone metastases: A compilation of 365 histologically verified cases spanning over two decades from a single center. Indian J Pathol Microbiol 2021;64:717-24

How to cite this URL:
Hui M, Balu B, Uppin SG, Uppin MS, Chandrasekhar P, Rao K N, Bhattarcharjee S, VijayaSaradhi M, Krishna Y V. Bone metastases: A compilation of 365 histologically verified cases spanning over two decades from a single center. Indian J Pathol Microbiol [serial online] 2021 [cited 2021 Nov 27];64:717-24. Available from: https://www.ijpmonline.org/text.asp?2021/64/4/717/328517





   Introduction Top


Metastatic cancer is the most common malignant tumor affecting the skeleton.[1] After lung and liver, skeletal system is the third most common site of metastases. The overall incidence of bone metastases in cancer is approximately 30%. It may present either as initial manifestation or may be sole manifestation in malignancy with unknown origin.[2] Although any malignant tumor can metastasize to the skeleton, majority of them are epithelial and originate from breast, prostate, lung, thyroid, and kidney.[3],[4],[5] In children, metastatic malignancies involving the bone includes neuroblastoma, Ewings sarcoma, rhabdomyosarcoma, teratocarcinoma, and Wilm's tumor.[6]

Routine investigations are non-specific. Apart from alkaline phosphatase which is elevated in more than 50% of cases, SGOT, LDH, and uric acids are higher in patients with bone metastasis. The tumor markers like carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP), carbohydrate antigens (CA 15-3, CA 19-9, CA125), prostate-specific antigen (PSA), tissue polypeptide antigen (TPA) have been shown to be diagnostically nonspecific.[7]

Imaging studies provide valuable diagnostic information to the pathologist in skeletal metastasis. Conventional X-ray techniques as the initial imaging modality lack sensitivity as 50–70% of bone destruction or lesions of more than 1.5 cm is required to demonstrate a change on routine study.[5],[8],[9],[10] Bone scan is more sensitive test but lacks specificity.[4] Hence pathological examination is essential to establish the diagnosis. It not only provides diagnosis but also is helpful in suggesting possible primary if previously unknown. In this study, the clinicopathological features of metastatic bone tumors spanning over a period of two decades were analyzed and an attempt was made to identify the primary site of malignancy in metastasis of unknown origin.


   Materials and Methods Top


All histologically documented cases of metastatic bone tumors diagnosed over a period of 20 years from January 2000 to December 2019 were included in the study. The primary bone tumors and hematolymphoid malignancies were excluded from the study. This was a retrospective observational study and the study was approved by the Institutional Ethics Committee.

The demographic data, clinical details, tumor markers, and imaging findings were retrieved from the medical records. Curetted material and resected specimens from suspected cases of bone metastasis was processed for routine paraffin sections after fixation in 10% buffered formalin. Decalcification was carried out with 10% nitric acid whenever necessary prior to processing. In addition to routine hematoxylin-eosin stain, special stains such as Alcian-PAS were carried out wherever necessary. Immunohistochemistry (IHC) was done either to categorize or confirm the primary diagnosis. The panel of immunohistochemical markers varied depending on the clinical features and morphology of the tumors. A panel of CK7, CK20, and organ specific/organ restricted markers were performed in metastatic carcinoma to suggest or confirm the primary origin of metastasis. The patients were divided into two groups based on the information regarding the primary site. Group I included patients with known primary and Group II included patients with unknown primary. The Group I was further subdivided into Group IA and Group IB depending on whether the primary was known prior to or detected after the diagnosis of metastatic disease, respectively. Group II was divided into Group IIA, where the primary remained occult even after metastatic work-up and Group IIB where work-up was not done or details not available.


   Results Top


Of the total 365 cases of metastatic tumors involving the bone, the age of the patients ranged from 3 to 90 years (median, 53 years) with a male to female ratio of 1.2:1. Majority of the patients were between fifth to seventh decades of life. The two youngest patients were 3-year-old males with metastatic involvement of femur and pelvis from adrenal neuroblastoma.

Pain was the single most common presenting complaint noted in 227 patients. The patients with spinal involvement presented with weakness in limbs, paresthesia, bladder, and bowel disturbances. Pathological fracture was noted in 74 patients.

Skeletal distribution

A total 712 bony sites were involved by metastasis in 365 patients under study. The number of metastatic sites per individual ranged from 1 to 14 (average, >2 sites/patient). The distribution of the affected skeletal sites are summarized in [Figure 1]. The axial skeleton was more commonly involved than the appendicular skeleton, of which spine was the most frequent site was biopsied in the present study accounting for 190 cases (52.1%). Majority of the cases involving the spine affected the thoraco-lumbar segment (146/190). In the appendicular skeleton, metastases were uncommon beyond knee and elbow joint. None of our patients had acral metastases. Other visceral organs concomitantly involved were lung (10 patients), liver (4 patients), brain (4 patients), and adrenal (2 patients).
Figure 1: Distribution of skeletal metastasis. The numbers within the parenthesis indicate non-histologically verified sites evident on imaging

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Radiographic features

Plain radiographs were available in 65 patients, CT scan in 69 patients and MRI in 94 patients. Majority of the patients showed mixed osteolytic and osteosclerotic lesions (69%) followed by osteolytic lesions (29%) with only few showing osteosclerosis (9%). Bone scan findings were available in 59 patients and were helpful in detecting the multiple sites. Apart from metastasis, a differential diagnosis of giant cell tumor, osteomyelitis, tuberculosis, neurofibroma, chondroid lesion, osteosarcoma, and round cell tumor were considered on imaging. The imaging findings of patients from various sites are depicted in [Figure 2].
Figure 2: Representative images of (a) osteolytic lesion involving the spine causing wedge compression. (b) Expansile osteolytic lesion involving the right femur. (c) Involvement of the humerus with pathological fracture. (d and e) Expansile osteosclerotic lesion involving the skull (f and g) Lytic lesion in mandible (h and i) Metastatic neuroblstoma involving proximal femur and tibia. (j) Expansile lytic lesion in the proximal humerus in metastatic paraganglioma

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Histological features

Initially the metastases were broadly categorized into carcinomas and non-epithelial malignancies/sarcomas. The distribution and IHC of metastatic carcinomas with known primary is summarized in [Table 1]. Of the metastatic carcinomas, adenocarcinoma was the most common histological subtype accounting for 190 cases (52%). The others included poorly differentiated carcinoma (41), thyroid carcinoma (60), renal cell carcinoma (23), and squamous cell carcinoma (22). There were two cases each of small cell carcinoma lung, adenosquamous carcinoma, and sarcomatoid carcinoma, one case each of hepatocellular carcinoma, acinic cell carcinoma of the salivary gland, and a single case of adenocarcinoma arising in a testicular teratoma metastatic to spine. The non-epithelial tumors metastasizing to the bone are summarized in [Table 2]. These primarily comprised of neuroblastoma, osteosarcoma, and Ewings sarcoma.
Table 1: Distribution and immunohistochemistry of metastatic carcinoma with known primary

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Table 2: Distribution of metastatic non epithelial/mesenchymal tumors

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Classification of cases

Metastasis was the initial presentation in majority of the patients (254, 69.5%) in the present study. The primary site was known in 220 patients with almost half of them being detected after the diagnosis of metastasis. The distribution of cases in various groups are shown in [Table 3]. Thyroid was the most common primary site followed by lung, breast, kidney, and prostate. Most of the thyroid, lung, and renal cell carcinomas presented with metastasis at initial diagnosis. In contrast majority of the breast carcinomas were primarily diagnosed prior to metastasis.
Table 3: Distribution of cases in various groups

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Among the 60 metastatic thyroid carcinomas, 45 were follicular carcinoma, 11 conventional papillary carcinoma, and 3 follicular variant of papillary carcinoma. Of these, 44 patients presented initially with metastasis. IHC with CK7 TTF1 and thyroglobulin confirmed the diagnosis in 13 cases. Rests of the cases were diagnosed based on morphology in correlation with imaging findings. There was one case of medullary thyroid carcinoma who presented with lytic lesion in the C7 vertebrae on plain radiograph and PET scan. IHC with calcitonin confirmed the diagnosis.

Among the 49 patients with metastatic lung carcinomas, 45 were adenocarcinoma, and the rest were two patients each of squamous cell carcinoma and small cell carcinoma. Of the 45 metastatic lung adenocarcinoma, 38 were diagnosed at the metastatic site based on morphology and IHC with CK7, TTF1 and napsin A. One patient with prior history of glioblastoma had multiple lytic lesion in the rib. Biopsy revealed metastatic lung adenocarcinoma. Of the two metastatic squamous cell carcinoma, the primary was detected later in one case. There were two case of small cell lung carcinoma involving the L3 L4 and C7 vertebrae. On IHC, the tumor cells were positive for TTF1, chromogranin, and synaptophysin. Later hilar mass was detected on CECT chest and biopsy of the hilar mass confirmed the primary.

All the 35 patients with metastatic breast carcinoma were morphologically duct cell carcinomas. All except three patients had a prior history of breast carcinoma. Immunostaining for CK7, CK20, GATA 3, mamaglobin, GCDFP, estrogen, and progesterone receptors done in latter three cases to confirm the primary. The biopsy findings of metastatic thyroid, lung, and breast carcinoma are depicted in [Figure 3].
Figure 3: Metastatic carcinoma from primary thyroid, lung and breast.(a) Metastatic follicular carcinoma showing follicles lined by cuboidal cells with dark staining nuclei (H and E; X100). (b) Metastatic follicular variant of papillary carcinoma showing follicles by cuboidal cells with nuclear overlapping and clearing (H and E; X200).(c) Metastatic papillary thyroid carcinoma:(c) Papillary structures with central fibrovascular cores infiltrating irregular bony trabeculae (H and E; X40). Inset show cells lining the papillae displaying nuclear overlapping, clearing, inclusion (black arrowhead) and groove (black arrow) ((H and E; X400). (d-f) Metastatic adenocarcinoma of lung: (d) Tumor cells arranged in acinar pattern (H and E; x400). (e) Nuclear positivity of tumor cells with TTF-1(poly HRP x 400). (f) Cells show granular cytoplasmic positivity for Napsin –A (poly HRP x 400). (g and h) Metastatic breast carcinoma: (g) Nests of tumor cells infiltrating bony trabeculae (H and E; x 400 (h) Cells are positive for GATA 3 (poly HRP x 400)

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Of the 23 renal cell carcinoma, 14 patients had conventional clear cell carcinoma on histology. There were 16 patients who did not have a prior history of kidney mass. Of these 16 patients, the primary was confirmed on IHC with pancytokeratin, vimentin, and CD10 in nine patients and the rest were diagnosed based on morphology and imaging findings.

Apart from the eight cases of metastatic prostatic adenocarcinoma who had a known primary, an additional four cases were diagnosed based on morphology and IHC in correlation with ultrasound findings and serum PSA levels. The histopathological features of metastatic carcinoma from kidney, liver prostate and signet ring cell carcinoma are shown in [Figure 4].
Figure 4: Metastatic carcinoma from kidney, liver prostate and signet ring cell carcinoma. (a-c) Metastatic renal cell carcinoma (clear cell variant) (a) Nest of clear cells with small nuclei separated prominent thin vascular channels. (H and E; X200). Tumor cells showing strong cytoplasmic positivity with (b) Pancytokeratin (poly HRP x200) and (c) Vimentin (poly HRP x 200). (d) Metastatic adenocarcinoma from prostate showing cribriform pattern of tumor deposits within the intertrabecular space (H and E; x400). (e) Hepatocellular carcinoma displaying cords and trabeculae of polygonal cells separated by sinusoids (H and E; X200). (f) Signet ring cell carcinomas showing nests of signet cells with eccentrically placed nuclei and vacuolated cytoplasmc (H and E; X200)

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There was an unusual case of metastatic adenocarcinoma involving D9-D12 vertebrae that developed as somatic malignancy in a testicular immature teratoma and had metastasized 12 years after initial diagnosis and treatment of testicular tumor. This case has been published elsewhere.[11]

All except three cases of non-epithelial tumors had known primary prior to metastasis. The primary was detected later on imaging in one patient of metastatic neuroblastoma and a single case each of paraganglioma. There was a single case of metastatic paraganglioma involving the humerus in a 45 year old female. The tumor cells showed positivity for chromogranin and S100. However, further details of metastatic work \-up was not available. The histopathological features of metastatic non-epithelial tumors/mesenchymal tumors are illustrated in [Figure 5] and [Figure 6].
Figure 5: Metastatic non-epithelial tumors/mesenchymal tumors. (a and b) Metastatic neuroblastoma showing monomorphous small round cells in fibrillary background (H and E; (a) X100, (b) X200). (c and d) Metastatic Ewings sarcoma (c) Sheets of small round cells with scant cytoplasm and round hyperchromatic nucleus. (H and E; x400). (d) Tumor cells are positive for CD99 (poly HRP x 400).(e) Osteoid is laid down in between the tumor cells in metastatic osteosarcoma (H and E x400). (f) Interlacing fascicles of spindle cells in a known case of leiomyosarcoma (H and E; x 400)

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Figure 6: Metastatic paraganglioma, rhabdomyosarcoma and angiosarcoma.(a and b) Metastatic Paraganglioma: (a) Nests of polygonal cells with clear vacuolated to pale eosinophilic cytoplasm separated by thin vascular channels infiltrating the marrow (H and E; x 400). Cells are positive for (b) chromogranin (poly HRP x 400). (c) Sheets of undifferentiated cells in a known case of rhabdomyosarcoma (H and E; x 400). (d) Spindle cells arranged in patternless sheets with stag horn blood vessels in a known case of solitary fibrous tumor. (H and E; x 400). (e-g) Metastatic Angiosarcoma (g) Infiltrating tumor composed of polygonal to spindle cells with pleomorphic hyperchromatic nucleus. (H and E; x400). Cells are positive for (f) CD31 and (g) CD34 (poly HRP; x 400)

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In the present study, primary site remained unknown in 146 patients. In 85 of these patients, metastatic work-up was either not done or details not available as many of these case were outside referral cases. In rest, the type of work-up was inconsistent ranging from simple investigation to extensive work-up. Almost all the patients of metastatic carcinoma with unknown primary had either metastatic adenocarcinoma or poorly differentiated carcinoma on histology.


   Discussion Top


The skeleton is one of the most common sites for metastases, and studies on extent of skeletal metastases have been reported in literature.[4],[5],[12],[13] The recent rise detection rate of skeletal metastasis can been attributed both to early detection becauseof better imaging techniques and progress in the management of primary cancers with consequent prolonged survival.

More than two-third of the affected patients are in the age group of 40–60 years.[12] In the present study, 70% of patients were between the age group of 40 and 70 years. Skeletal metastases in children included neuroblastoma, Ewings sarcoma, and rhabdomyosarcoma in the present study.

Pain, swelling, fracture, and neurological symptoms were the common presenting features in our patients, which has also been the experience of other authors.[5],[14],[15],[16] Patients with spinal involvement mainly presented with pain and neurological symptoms such as weakness, paresthesia and bowel, and bladder disturbances. Pathologic fractures occur in 10–30% of patients, most commonly affecting proximal parts of femur.[17] Pathological fractures are encountered in 60% of breast cancer and 10% of lung carcinoma.[18],[19]

Metastases has predilection for bones with persistent red marrow such as vertebra, proximal femur, ribs, sternum, pelvis, skull, and shoulder girdle. Metastases tend to involve long bones in children and axial skeleton in adults. More than 80% of bone metastasis involve the axial skeleton with spine being commonest site.[16],[20] The lumbar part of the spine, is most commonly involved, followed by thoracic, cervical, and sacral portions.[21] In the present study, more than half of the cases involved the axial skeleton, most frequently affecting the thoraco-lumbar spine. Metastases distal to elbow and knees (acral metastases) and to facial bones are unusual.[22] The most common site distal to elbow and knee is reported to be the tibia. In the present study, of the total 712 metastatic skeletal sites, those distal to elbow and knee were only 7 (tibia-6, ulna-1). Though scaphoid, phalanges and semilunar bones are most commonly affected in acral metastasis, none were involved in the present study. A high incidence of acrometastasis is known to occur in lung carcinomas where tumor cells embolize to all the organs, without a capillary bed that acts as a filter.[22]

In comparison to plain radiographs which is less sensitive, CT scans, MRI, positron emission tomography scans have better sensitivity.[15] Plain radiographs in cases of bone metastases reveal lytic (most common), blastic, or mixed pattern. Lung and breast are deposits usually cause lytic destruction, but are occasionally osteobalstic. Thyroid and kidney deposits are usually purely lytic with prostatic deposits being osteoblastic. 599mTc bone scintigraphy is an effective method for screening the whole body for bone metastases especially in detecting osteolytic lesions. It also has an added advantage to screen the whole body to rule out visceral involvement.[20]

Adenocarcinomas constitute the predominant histological type among the metastatic bone tumors. Similar was noted in the present study. Soft tissue and bone sarcomas metastasize to bone with a frequency of 18%.[12] Literature suggests that breast, prostate, lung, thyroid, and kidney account for 80–92.6% of bone metastases.[12] In the present study, these accounted for 81.3% of known primaries with thyroid being the most common site. Other studies in literature reveal lung and breast to be the most frequent sources of skeletal metastases.[12],[23] This could be because of the fact that thyroid metastases have characteristic morphology even at metastatic site leading over representation in case with known primaries. In contrast, the adenocarcinoma arising in other sites do not have specific morphology. Since number of cases with unknown primaries was high in our series, we consider that other primary sites are underrepresented in comparison to thyroid carcinoma among Group I patients.

Studies have shown that primary is unknown in 3–15% of all cancer patients and 5–20% present with skeletal metastases. In the present study, the primary remained undetected in 40% of the patients which is higher than that reported by similar study from India.[12] The detection rate of primaries depends upon the diagnostic strategies used. In one series skeletal metastases of unknown primary, a diagnostic strategy consisting of the following: medical history, physical examination, laboratory analysis, plain radiography involving bone and chest, whole-body techtnetium-99-m-phosphonate bone scan, computed tomography of chest, abdomen and pelvis, and finally, biopsy of the most accessible osseous lesion, led to identification of the primary in 85% of cases.[24] However, one of the limitation of the present study is relatively higher percent of cases with undetected primary. One of the reasons could be reluctance on the part of oncologists to go for extensive diagnostic work-up in search of primary because of lack targeted therapy in earlier years. Added to this is limited use of IHC in metastatic work-up and lack of organ specific/organ restricted markers in earlier years. Immunohistochemistry with a panel of markers were used as adjunct suggests the possible origin in cases with unknown primary in 27.4% cases in the present study. Errani et al. in their study used IHC to establish the primary in 52% cases in metastasis of unknown origin.[25] Recent advances in development of multidisciplinary treatment strategy including loco regional therapy and systemic use of bone targeting agents with inhibitors of bone resorption prompts adequate diagnostic work up for effective management.[26]


   Conclusion Top


Metastases are commonest malignancy affecting skeletal sites. More than two-third cases of bone metastases encountered in surgical pathology practice are as initial presentations. Spine, femur, and pelvis are most commonly affected site. Metastatic adenocarcinomas constitute majority of cases with thyroid, breast, lungs, prostate, and kidney being common primary sites. Detection rate of primary depends on extent of metastatic work-up. Use of IHC, especially with increasing available organ specific/organ restricted markers increases the detection of primary in unknown cases which in turn facilitates treatment with targeted agents wherever available.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Correspondence Address:
Shantveer G Uppin
Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad - 500 082, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_1132_20

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