In this era of minimally invasive procedures for diagnosis, prognosis, and treatment, pathologists are at the forefront of analyzing specimens and are expected to make more specific diagnoses, providing additional information from the material they receive.
To familiarize pathologists with the essential components of surgical pathology reports for colorectal liver metastases (CRLM) resections.
Colorectal cancer is the third most common cancer in the world and the liver is the most frequent site of metastases. Not all patients are candidates for surgery initially and may be treated with neoadjuvant chemotherapy, most commonly with FOLFOX (5-fluorouracil/leucovorin and oxaliplatin) and FOLFIRI (5-fluorouracil/leucovorin and irinotecan), after which they may become surgical candidates. When CRLM resections are received post neoadjuvant, the pathologist needs to not only report margin status but also report details regarding the tumor's response to treatment, and should evaluate the nonneoplastic parenchyma for chemotherapy-related injury, such as sinusoidal obstruction syndrome and/or steatohepatitis that may be caused by treatment. If ancillary tests, such as molecular studies (eg, KRAS, BRAF, NRAS, and microsatellite instability), have been previously conducted, these results should be included in the report. If not, they should be ordered for the resection specimen.
In this review, we will describe strategies and practical approaches to maximize the information gained from CRLM resections. A checklist is provided that may be used while signing out these cases to remind pathologists of additional components they may wish to include in their reports to best guide patient management.
Colorectal cancer is the third most common cancer in the world, has caused 774,000 deaths worldwide,1 and the most common site of metastases is the liver. Colorectal liver metastases (CRLM) can present as synchronous metastases in 15% to 25% of patients and metachronous metastases in 25% to 30%.2 Currently, patients with CRLM can undergo surgical resection if the tumor meets criteria. Unfortunately, not all patients are candidates for surgery initially owing to factors such as the number, size, or location of their tumors. For these patients, neoadjuvant chemotherapy is often used to decrease the tumor burden; if patients have an adequate response, they may then become surgical candidates. The most commonly used chemotherapy regimens include FOLFOX (5-fluorouracil/leucovorin and oxaliplatin) and FOLFIRI (5-fluorouracil/leucovorin and irinotecan), which often achieve excellent treatment responses; however, they may result in liver injury such as sinusoidal obstruction syndrome and steatohepatitis, respectively.3
Traditionally, the main role of a pathologist is to provide an accurate diagnosis. With constant advances in medicine, including pathology, a pathologist's role should extend beyond just reporting the type of tumor and margin status. Although in some cases these may be the only components to report, we can often provide additional information that may greatly improve patient care. Additional elements that are often not mentioned in the report include the tumor's response to chemotherapy, the presence or absence of chemotherapy-related injury in the nonneoplastic liver parenchyma, and the results of ancillary tests such as molecular testing, which may provide critical information regarding tumor behavior, probability of response to treatment, and prognostic data. The most efficient means to communicate these diagnostic details to the clinical team is for pathologists to include them in their surgical pathology report. We must remember that patients often undergo stressful, invasive procedures to obtain the tissue submitted to pathology; if we can potentially provide additional information in our reports that may improve their quality of care, we should include it. A common example of an incomplete pathology report would be one that properly addresses the patient's CRLM but forgets to comment on the patient's active steatohepatitis and fibrosis stage in the nonneoplastic hepatic parenchyma.
The first step to producing a more informative report requires reviewing the patient's history to confirm that the primary tumor was previously diagnosed. At this time, the original pathology report should be reviewed to confirm completeness. For example, were molecular studies (eg, KRAS, BRAF, NRAS, and microsatellite instability [MSI]) previously performed? If the report is not complete, the diagnosis is not clear or contradicts the current histopathologic findings, or appropriate studies have not been conducted, review the previous slides whenever possible and order the appropriate additional tests, such as KRAS/BRAF/NRAS molecular testing on the formalin-fixed paraffin-embedded (FFPE) tissue block.
In this review, we will discuss each of these additional components in more detail. We have provided a checklist that may be used while signing out these cases to remind pathologists of additional components they may wish to include in their surgical pathology reports to improve patient care (Figure 1).
TUMOR EVALUATION AND ASSESSMENT
It is important to report the size and number of metastatic lesions in the pathology report and to be sure they correlate with the radiologic findings or the surgeon's operative report. The number of CRLMs is one of the strongest prognostic factors for these patients.4 For patients with multiple liver metastases (more than 3), a positive margin after resection is more likely to occur and portends a worse outcome.5
The pathology report should clearly state the margin status and the distance of the tumor to the margin. Previously, it was the standard of care to have a 1-cm free margin; however, in some patients this is not achievable. A study performed by Hamady et al6 proposed that a 1-mm margin should be considered the standard of care in liver resections and stated that tumor biology is a more important factor in disease-free survival than surgical margin clearance. Nonetheless, having a negative margin is still important, since a positive margin also predicts poor long-term outcome.5 In larger resection specimens, such as from a segmentectomy or lobectomy, the margin status of large portal tracts and vessels is also important to assess, since CRLM can cause intraepithelial ductal spread and venous thrombosis.7
TUMOR RESPONSE TO CHEMOTHERAPY
In 2010, 85.7% of patients younger than 60 years with stage III colon cancer received adjuvant chemotherapy after surgery,8 thus, most cases with CRLM have been previously treated with chemotherapy. In these cases, assessing the tumor's response to the treatment is an essential component of the pathology report. This can be assessed grossly by measuring tumor size and microscopically by determining the percentage of viable tumor and/or fibrosis in the neoplastic regions of the tissue. Similar to the recommendations made by the College of American Pathologists for colorectal resection specimens, Rubbia-Brandt et al9 developed a tumor regression grade (TRG) score that is specifically used for CRLM cases, which assists the pathologist in assessing tumor response to chemotherapy and is able to predict disease-free survival and clinical outcome. The TRG scoring system consists of numerical values from 1 to 5, with 1 being complete response with extensive fibrosis and no residual tumor cells, and 5 being no response with diffuse viable tumor cells (Figure 2; Table 1). Recent studies have demonstrated that fibrosis is the predominant chemotherapy-related pathologic alteration that predicts outcome, not necrosis.10 In addition, approximately 20% of patients have a TRG response that is not adequately visualized by imaging studies, and the higher the percentage of viable tumor, the less chance the patient has for recurrence-free survival.11 If a tumor shows no response to a specific agent, the chemotherapeutic treatment regimen may need to be modified or discontinued.
ASSESSMENT OF THE BACKGROUND, NONNEOPLASTIC PARENCHYMA
It is important to assess the background, nonneoplastic liver, ideally 1.5 cm away from the tumor in order to avoid possible mass effect. The nontumor liver parenchyma should be assessed for underlying or superimposed liver disease, such as steatohepatitis, viral hepatitis, iron overload, or other diseases that might affect liver function or its ability to respond to chemotherapy after a hepatic resection. For example, if the patient has viral hepatitis type C, it is important to grade and stage the hepatitis and fibrosis, respectively, with one of the widely used scoring systems (eg, Batts-Ludwig, Metavir, Modified Hepatic Activity Index, Ishak).12,13 In patients with chronic liver disease, the fibrosis stage is often the most important prognostic factor, may affect a patient's ability to tolerate hepatic resections and/or chemotherapy, and should be included in all liver-related pathology reports whenever possible. With isolated hepatic metastasis, many patients have the potential to be cured; commenting on their active hepatitis and/or bridging fibrosis will remind clinicians that their patients have underlying liver disease that may be treatable (eg, in cases of viral hepatitis C) or offer an opportunity for patient education and counseling (eg, in cases with steatosis or steatohepatitis). However, if the patient has had a recent biopsy of the nonneoplastic liver before surgical resection, commenting on the background liver may not be necessary. Instead, referencing the previous case number and date would be more appropriate.
The nonneoplastic liver is also susceptible to chemotherapy-induced sinusoidal injury. Liver injury may occur with chemotherapy regimens such as irinotecan, which may cause steatohepatitis, and oxaliplatin, which may cause nodular regenerative hyperplasia or sinusoidal obstruction syndrome (previously known as venoocclusive disease). If steatohepatitis is identified in the resection specimen (whether from irinotecan or other risk factors), the pathologist should grade and stage the inflammation and fibrosis, respectively, using the non-alcoholic fatty liver disease scoring system.14 If a patient has received FOLFOX and the background liver shows sinusoidal dilatation, congestion, nodular regenerative hyperplasia changes, and/or venous obstruction, a diagnosis of chemotherapy-induced sinusoidal injury and/or sinusoidal obstruction syndrome should be diagnosed as described by Rubbia-Brandt et al.15 The characteristic histopathologic features of chemotherapy-induced injury are shown in Figure 3, A through F, and can be graded by using the histologic scoring system that we previously published (Table 2).16 We also determined that the use of an immunohistochemical panel consisting of CD34, smooth muscle actin, and glutamine synthetase is able to facilitate the diagnosis of chemotherapy-related injury in difficult cases by allowing the Chemotherapy-induced Sinusoidal Injury (CSI) score to be determined (Table 3).16
TUMOR BIOLOGY AND MOLECULAR STUDIES
Molecular studies and specific mutations are well documented in colorectal cancer. There are specific mutations that are able to predict tumor responsiveness to chemotherapeutic agents and prognosis—it is critical to include the results of molecular testing in surgical pathology reports, especially for patients with metastatic disease. If molecular testing was conducted on the previous specimen, it may be useful to refer to the previous case number and date, and mention the results in the comment section of the current report. This will ensure that these results will not be missed in the medical record and will avoid unnecessary repeated testing. According to the National Comprehensive Cancer Network (NCCN) guidelines (version 2.2017), all patients with metastatic colorectal adenocarcinomas should be tested for RAS (KRAS and NRAS) and BRAF mutations at least once (ie, in the primary tumor or metastasis). If patients are positive for a known KRAS or NRAS mutation, they should not be treated with cetuximab or panitumumab and BRAF mutations make tumor response to these agents unlikely.17–22 Importantly, these tests can be conducted on FFPE tissue from the primary tumor or the metastasis, as studies have shown that both specimen types provide similar results.23 Again, tumors only need to be tested once, in either the primary or metastatic tumor. The NCCN also states that all patients with colorectal adenocarcinoma should be tested for MSI or mismatch repair genes, including MLH1, PMS2, MSH2, and MSH6. These results may greatly impact patient care; for example, stage II, MSI-high patients may have a good prognosis and do not benefit from 5-fluorouracil chemotherapy treatment, and patients who are MLH-negative with positive BRAF mutations are excluded from a diagnosis of Lynch syndrome.24 See Figures 4 and 5 for examples of reports that include the recommended components for a pathology report in patients with CRLM.
With the increasingly busy schedules and workload of pathologists, it is tempting to keep reports brief. Although this may be appropriate in some cases, we must remember that our patients have undergone invasive procedures, from biopsies to extensive surgical resections, to provide the tissue we are evaluating. If including additional information in our reports has the potential to improve patient care and quality of life, we should not hesitate to include it. These additional components may not only guide treatment and possibly limit exposure to potentially toxic, ineffective chemotherapeutic agents, but also provide important prognostic information.
The authors would like to thank Judith Aronson, MD, from the University of Texas Medical Branch for providing the microscopic slides from which the images were taken. They would also like to thank Laura Lamps, MD, from the University of Michigan for her critical evaluation of the manuscript.
The authors have no relevant financial interest in the products or companies described in this article.