What Is the Clinical Impact of Sending Tissue for Histopathology During Surgery for Known, Diffuse Metastatic Disease to Bone?

Discussion

Despite a high annual volume of patients who undergo surgery for MBD, there are no current data that assess whether sending tissue in the setting of diffuse metastasis affects the subsequent clinical course. The current study recorded a low incidence of clinical changes after a positive MBD tissue sample for these patients. Again, it must be emphasized that each case involved patients with only diffuse and multifocal MBD. Patients with a recent cancer diagnosis and no distant disease, or an active cancer without known metastasis, were excluded as this group would have required a tissue diagnosis outright.

In total, there were six instances in which the clinical management changed as a direct result of a positive tissue sample. One change occurred in the form of additional imaging to help obtain a more specific origin of the primary tumor. Therefore, there may be a benefit for sending tissue in patients with carcinoma of an unknown primary. The diagnosis of a cancer origin is often difficult, and some studies suggest an increased incidence of skeletally related events in patients with a prolonged time to diagnosis (15-17). The patient in this study was initially treated with internal fixation of the humerus for a lesion consistent with adenocarcinoma of unknown origin. However, the patient eventually developed femoral, tibial, and vertebral metastasis before additional tissue during a subsequent procedure revealed possible sinonasal origin. Eventually during later surgery, the histopathology resulted in a change in management including referral and further imaging. Although anecdotal, sending tissue for diffuse metastasis of unknown primary may expediate identification of the tumor, direct medical treatment, and possibly prevent additional skeletally related events.

The other five changes after a positive tissue sample were with medication. As mentioned above, patients with an unknown primary may require additional testing. Typically, a bone biopsy in this setting reliably confirms the origin, and recent studies suggest that the rate of a positive sample following bone biopsy for an unknown primary is 97.9% (17). When the biopsy is inconclusive, however, additional tissue during surgery may be needed. We observed one patient in whom serial bone biopsies up until surgery were inconclusive. While the suspicion of the multidisciplinary group was a hematologic malignancy based off labs and imaging, lymphoma was eventually confirmed during surgery from femoral reamings and resulted in directed medical therapy. These data therefore might encourage the practice of sending tissue in the setting of known or diffuse MBD when previous biopsies are inconclusive.

Although the incidence of changes was low overall, we observed a possible role for sending tissue in select cases of breast metastasis as the receptor profile from lesional tissue may differ from that of the primary. One such change was observed in the current study, in which a positive tissue sample prompted a change from cytotoxic to targeted therapy. With respect to lung cancer, one positive sample demonstrated an immunohistochemical pattern requiring additional treatment based off a PDL-1 assay from skeletal tissue retrieved during internal fixation. Finally, the remaining two changes occurred in a patient with colon cancer who was switched to a targeted regimen after tissue revealed cecal origin, in addition to a patient with prostate cancer who was switched to abiraterone acetate based off MBD tissue assays, respectively. Ultimately, however, changes in clinical management are rare. While there may exist a possible role for sending tissue in select cases, a discussion within a multidisciplinary setting is crucial to identify patients that may benefit from additional tissue evaluation by pathology as well as identify any change in management that may arise thereafter.

Of note, the current study recorded a lower positive sample rate in reamings-only cases than for cases in which tissue was sent during resection/intralesional procedure with primary arthroplasty, endoprosthetic reconstruction, or methylcrylation. This was likely due to a lower volume of tissue obtained during reamings than resection, which was suggested by the trend towards increased likelihood of reaching a positive sample with more tissue sent. Another possible reason for low positive rate from reamings could be destruction of the tissue or dilution of the sample with normal tissue. To our knowledge, this is the first identifiable study that describes the clinical utility of sending femoral reamings, which is a common practice though has no evidenced-based data supporting its role in surgery for MBD.

As mentioned above, any patient without confirmed, multicentric MBD deserves a tissue diagnosis. Alternatively, in those cases of known multifocal MBD, a multidisciplinary discussion should take place to determine whether sending additional tissue may be helpful in the patient’s care plan. Our study found that for the majority of these patients, sending tissue only increases the time and cost and often does not yield a positive sample. More importantly, however, the majority of positive samples do not lead to a change in the clinical management. It appears that following a positive sample it is very uncommon to pursue additional procedures or work-up except in select cases of breast, lung, or hematologic malignancies, and unknown primaries. Therefore, a multidisciplinary team discussion is warranted prior to sending these additional tissues. This is important because there is no doubt that the prevalence of patients with MBD continues to increase, and cost-effective care of these patients will be a growing part of orthopedic oncology practice in the decades ahead.

This study is primarily limited by its retrospective nature. An additional though important limitation is the fact that this study was conducted within a single institution. As such, the generalizability of the results is limited, as certain treatment algorithms and indications for sending tissue during surgery for MBD may vary by institution. With respect to interpreting any change in clinical management, this study is limited by data available in the medical record. For example, medical records often do not include details on the decision-making process by medical oncologists following confirmation of MBD from skeletal tissue. While most treating oncologists likely followed the expected algorithm that they had in place prior to surgery, it was impossible to know whether changes were initially considered following a positive tissue sample of MBD. Lastly, the study mentions the financial burden of receiving and interpreting metastatic tissue from a histological perspective. Given the increasing volume of MBD patients seen routinely in clinical practice, there likely needs to be a discussion regarding the cost-effectiveness of routine histologic examination of tissue sent from patients with diffuse, known MBD. While we did not include data on cost, other studies have proposed that a routine histologic examination during orthopedic procedures is not cost-effective and often has a high rate of discordant or discrepant findings (14).

In summary, this study provides some of the first identifiable evidence of the clinical utility of sending tissue during surgical cases of diffuse, multifocal MBD. Despite the routine practice of sending tissue for histology in this setting, a change in the subsequent clinical management is rare. More often, these patients continue the same systemic treatment algorithm pre- and post-operatively.