Detection of Distant Metastases in Malignant Pleural Mesothelioma by Radiology

Localized spread and destructive infiltration define malignant pleural mesothelioma (MPM). It takes thirty to forty years before symptoms appear and a doctor can diagnose you with mesothelioma after being exposed to asbestos. An epithelioid subgroup of MPM is the most common type, with cells ranging from polygonal to oval to cuboidal in shape. It is possible to have a combination of both epithelial and spindle cells in the same tumor, which is called biphasic MPM. sarcomatoid MPMs are less common.

The pattern of disease dissemination in MPM has been defined as local in the past. Case reports and autopsy series have been the primary sources of evidence for unusual or unexpected patterns of metastatic dissemination in MPM in recent years. According to a case series of 318 patients’ postmortem exams, there were 32% of patients with liver metastases, 11% with splenic metastases, 7% with thyroid metastatic disease, and 3% with brain metastatic disease. One further study that looked at data from cadaveric autopsies found a prevalence of brain metastases of 2.7%. Others say that 40% of patients have nodal metastases. In spite of advances in imaging and radiography, there is still a lack of documentation of how MPM metastatic dissemination occurs.

A platinum compound and the folate antimetabolite, pemetrexed, are the standard anticancer treatments for MPM. Second- and third-line chemotherapy treatments include vinorelbine, which has low response rates. A promising early-stage experiment of immunotherapy has yet to be fully disclosed. As a result, many people with MPM are referred to clinical trials for new drugs. Patients participating in early-phase trials tend to be healthier and more physically fit than the general cancer community, because to the stringent criteria for study eligibility. In addition to normal haematological and biochemical measurements and underlying organ function, these include a near-perfect performance status.

In numerous research, performance status has been found to be an independent predictor of overall survival and better prognosis. There is a unique chance to record distant metastatic spread in MPM in this trial cohort since it includes MPM patients who may live longer than the projected median survival time and have thorough diagnostic imaging as part of trial enrolment.

At the Drug Development Unit (Royal Marsden Hospital/Institute of Cancer Research), we set out to review our MPM patient cohort referred for early phase clinical studies. Metastatic disease from mesothelioma was studied to see whether there was a correlation between where it appeared clinically and radiologically and where it manifested itself clinically.

This type of mesothelioma is known as metastatic, and arises when cancerous cells from the initial tumor travel to other parts of the body. Lymph nodes are a common site for mesothelioma cells to metastasis. Metastasis is influenced by the cancer’s stage, cell type, and therapy method.

In what stage of the disease can metastasize mesothelioma occur?

Stage 4 mesothelioma patients with distant metastases account for 10% to 50% of all cases. Cancer cells can spread both locally and regionally, as well as far away.

Lymphoma can be found in the lymph nodes of patients in stages 1-3 of cancer progression. When mesothelioma reaches stage 4, it can spread throughout the body.

More often than not, the disease will spread throughout the cavity where it was first discovered. This is referred to as a local spread in the medical community.

Diagnostic imaging studies, such as MRIs, PET scans, and CT scans, are used to track the course of cancer. When a patient complains of symptoms that are not typically linked with mesothelioma, doctors frequently suspect that the disease has spread. Tests or biopsies will be carried out to look for distant metastases at that time.

The Mesothelioma Metastasis: Where Is It Found?

Mesothelioma can spread to different parts of the body in a variety of ways.

It is common for cancer cells to spread to other parts of the body via the bloodstream or lymphatic system. A secondary tumor can form if mesothelioma cells migrate throughout the body and infect other tissues and cells.

Angiogenesis, the body’s process of creating new blood vessels, is how cancer cells enter the bloodstream. Researchers are researching strategies to enhance and hinder angiogenesis to produce a multitude of anti-angiogenic drugs. These medicines may be the key to delaying or arresting the spread of cancer.

Drugs being studied for mesothelioma metastasis include semaxanib (SU5416), thalidomide and tetrathiomolybdate. In clinical trials, the three drugs have shown an ability to stabilize the condition and increase survival.

Methods

A prospectively kept database was mined for information on MPM patients and the results were analyzed retrospectively. The local research and audit committee gave their blessing to the plan. There was no restriction on the number of MPM patients who were enrolled in clinical trials after visiting the Drug Development Unit at the Royal Marsden Hospital in London and the Institute of Cancer Research. The Drug Development Unit collected demographic, clinical, pathological, and radiological data on MPM patients from January 1992 to January 2017, with follow-up information available through January 2018. All preceding treatments and the tumor’s response to these treatments were included in the data collection. Tumor response rates and information on the investigational medication were obtained throughout the early stages of clinical trials. In order to conduct an overall survival analysis, we gathered data on the last date of clinical review or known survival dates.

Finding metastatic lesions

The search for metastatic illness sites incorporated every radiological test and imaging platform at our disposal. X-rays, computed tomography, ultrasound, isotope bone scans, magnetic resonance imaging (MRI), echocardiography, and positive electron tomography (PET) were all included (PET).

For eligibility and response evaluations, imaging was examined by a single, dedicated early-phase trial radiologist who has extensive experience in the field. Because the vast majority of patients were referred from another facility, we only had access to the scans they had at the time of referral.

The Royal Marsden Hospital’s whole image library was examined for any discrepancies. Documented clinical locations of metastasis comprised cutaneous and subcutaneous lesions, as well as drain site metastases, in addition to radiological data that were thoroughly evaluated. The final survival analysis was conducted excluding any data that was missing or incomplete.

The study of statistics

Patients’, previous treatments’, and tumors’ characteristics were summarized using descriptive statistics. This included the various metastatic spread sites discovered through radiological review. Average number of months it takes to die after being diagnosed with MPM. Overall survival (OS) and hazard ratios (HRs) were computed using univariate Cox regression models, which were presented as Kaplan-Meier analysis.

Survival plots were used to display the data. In all cases, we used two-sided tests, and a value of P 0.05 was deemed statistically significant. Stata, version 13.1, was used for both descriptive and survival analyses. Version 7 of Graphpad Prism was utilized in other analyses.

Results

More than 100 individuals were eligible for early phase clinical trials that could be evaluated for metastatic disease locations and survival within the time period. They were 76% male and had a median age of 64 when diagnosed with MPM (Table 1). All reports and referral letters with histopathology were examined. In 84% of cases (n = 138), the subtype of mesothelioma (n = 115, 83%) was epithelioid (n = 115, 83%), with 9% biphasic (n = 12) and 8% sarcomatoid (n = 11).

Metastatic illness was assessed using a median of three imaging modalities, ranging from one to five. Most of these were CT scans, with patients reviewing an average of two scans (ranging from one to nine), and plain radiographs, with patients reviewing an average of one (ranging from zero to six), almost all of which were chest radiographs.

As many as six prior chemotherapies were administered to individuals in early clinical trials; the median was two. There were five patients who were referred to the early phase trials unit before receiving traditional first-line medicines. More than seventy percent of the remaining 159 patients were given a platinum-based chemotherapy treatment with pemetrexed in the first-line scenario (n = 117). Pemetrexed was not given to any of the remaining patients, who instead received vinorelbine, clinical trials, or MVP (mitomycin-C, vinblastine, and cisplatin) (17, 10 percent ).

One hundred and seventy percent of patients who came to the early phase trial unit had already completed a second anticancer treatment regimen (117, 71%). (58, 50 percent ). A quarter of the remaining 59 patients were given a platinum and pemetrexed combination for a second time (27, 23 percent ). The rest were treated with a range of second-line chemotherapies, the most common of which was vinorelbine (17, 15 percent), but others included ifosfamide, gemcitabine, MVP, and TACE as well as others (mitomycin-C, gemcitabine and cisplatin).

The main and metastatic sites of MPM

64 percent (n = 106) of the MPM included in the study were right-sided, whereas the remaining 36 percent (n = 58) were left-sided.

Table 3 depicts the spread of metastatic illness to local and distant areas. In 102 patients with MPM, pleural effusions were reported along the course of the disease (62 percent ). 101 patients exhibited lymphadenopathy in the mediastinum and paratrachea, which was deemed “pathological” by radiology (62 percent ).

In 68 cases, the chest wall was found to be inflamed (42 percent ). There was evidence of a pericardial effusion in 19 out of 47 patients who had an infiltrated pericardium (29 percent) (12 percent total).

It’s possible to see how far the sickness has spread by looking at Table 3. At least 110 individuals (67%) had at least one verified distant metastasis, with many patients having numerous distant locations detected simultaneously or in a sequential manner. In 55 patients (35%) and 42 patients (42%) with multiple parenchymal lung metastases, respectively, these are the two most common findings (26 percent ). The radiographic appearances of patients with parenchymal lung metastasis were of a diffuse military-type metastatic pattern in 17 cases, which accounted for 10% of the overall patient cohort. Ascites was seen in 24 of the 36 patients with peritoneal illness and/or omental involvement (22 percent).

Thirty-one patients had bone metastases discovered (19 percent ). Bone lesions were classified as “lytic” by radiologists in the majority of cases (60 percent), with 7 (23 percent) being classified as “sclerotic” and 5 (17 percent) remaining unidentified. Distant spread to the major intra-abdominal organs such as the liver, kidney, adrenal, and spleen were all examples of visceral metastatic cancers. Twenty-three patients had illness in 27 different locations (14 percent of total).

Twenty-seven percent of these visceral lesions were found to be localized in the liver, with a small percentage (8%) found to have splenic metastases detected by radiology. Only five individuals’ brain metastases (3 percent) were radiologically confirmed. The neurological complaints of each of these patients necessitated imaging. Subcutaneous metastatic nodules were seen in 20% (n = 32) of patients with MPM who were not near any probable chest drain or biopsy site.

Distant intramuscular metastases was found in the muscles of seven individuals (4 percent), including the gluteal, psoas, and intercostal regions. Radiological scans of distant metastatic locations are shown. In comparison to biphasic/ sarcomatoid MPM, epithelioid MPM had a higher rate of peritoneal metastases (27.0 percent vs. 4.3 percent; P = 0.015) compared to biphasic/ sarcomatoid MPM. However, there was no statistically significant difference between the prevalence of bone metastases in the biphasic/sarcomatoid and epithelioid subtypes, with the former being 18.2% and the latter being 34.7 percent (p = 0.0936).

Survival of the patient

From the time a patient was first diagnosed with MPM until their deaths, the overall median survival time was 23.8 months (with a range of 1 month to 106 months). All except one patient had a documented death date; the rest were discharged to their primary oncology hospital and it was not known how they fared following their treatment at our Drug Development Unit. Although epithelioid and biphasic subtypes had a statistically significant superior overall survival (p 0.004), they were not statistically significant differences in overall survival.

Overall survival was not associated with the presence or absence of metatatic or locally invasive illness (Fig. 2c and d). There was no difference in overall survival between those with peritoneal or omental only metastases and those without (23.9 vs 22.0 months, HR 0.64, p = 0.54) among those with metastatic illness. Bone-only disease was associated with a 4-month survival difference, although this was not statistically significant (23.4 months vs 27.3, HR 0,72, p = 0,75). (Fig. 2e). There was a statistically significant difference in survival between those with and without visceral only metastases (18.9 months vs 25.7 months, HR 2.36, p = 0.07), however the difference was not statistically significant (Fig. 2g). Because of the small number of patients with brain-only metastases (HR 3.19, p = 0.12), the median overall survival for patients with brain metastases was only 14.1 months, compared to the median survival for all patients of 23.9 months (Fig. 2h).

a clinical experiment in its preliminary stages
Early-phase clinical trials were considered in 56% of the 164 patients referred for review, with 60% of those patients declared ineligible for enrollment and the remaining 7% unsure if they were eligible for participation in a clinical trial. Seventy percent of the 92 individuals who went through clinical trial screening ended up participating in an early phase trial, whereas 23 patients did not participate because of trial ineligibility, deterioration of health, or the patient’s own decision (5, 22 percent ). Some 39 (57 percent) patients who received an experimental agent had progression of radiological tumors, whereas 25 (36 percent) had stability and one confirmed complete response, and one confirmed partial response, respectively, were seen (1 percent respectively). Three individuals (4% of the total) were unable to be evaluated because they had prematurely terminated the experiment and could not be assessed radiologically.

Discussion

It was our goal to define the metastatic patterns of advanced MPM patients sent to our early phase clinical trial unit and to correlate these patterns with clinical outcomes. Small cohorts or autopsy series have been the primary source of evidence regarding the pattern of mesothelioma metastatic dissemination, reporting liver metastases in roughly 30 percent and nodal metastases in around 40 percent. Because we were able to include advanced MPM patients who had many and frequent imaging modalities as part of the clinical trial enrolment process, our study had the advantage of incorporating patients who would otherwise be excluded from such a clinical investigation.

Metastatic lesions were seen in 67 percent of the patients in this study. While brain metastases are still rare (only 3% of cases), bone and visceral metastasis are much more common (both 19% and 14%). Epithelioid subtypes were more likely to develop peritoneal metastases than other histological categories. The majority of the lesions in the bones were lytic in character. The incidence of bone metastases in MPM has never been documented to our knowledge. Due to the lack of imaging in prior studies, it is likely that our findings are more accurate than those based on case reports and autopsy series (in which bones are not routinely inspected with imaging). Proactive study and control of MPM spread sites necessitate comprehensive information of the disease’s potential spread locations. In this series, there was no association discovered between the occurrence of bone metastases and overall survival, but bone fractures have a significant morbidity. As a result of this occurrence, patients with advanced MPM should have more regular access to bone imaging as part of their treatment plan. Furthermore, if bone pain is reported, radiographic evaluation should be performed as soon as possible, and appropriate treatment should be initiated.

Overall survival was not associated with the prevalence of bone, visceral, or peritoneal/omental metastases in this cohort. MPM patients should be informed of this predictive data when they meet with their doctors to discuss their prognosis. We looked at a specific subset of patients with advanced MPM and found some interesting findings. The reported median overall survival time for patients in this category was 23.8 months, which is much longer than the documented typical survival time for patients with advanced MPM that has previously been studied. As treatment choices and prognosis for the MPM population continue to develop, the described cohort may be representative of future populations of individuals with this disease.

The retrospective nature of this study and the likelihood that some metastatic locations were not detected on the imaging platforms used are some of the study’s limitations. This group’s neurological complaints, for example, encouraged them to undergo brain imaging. Thus, it is possible that asymptomatic and unnoticed intracerebral metastases went unnoticed. This study found similar rates of brain metastases as a prior one.

Plain radiography was used more frequently a decade ago than CT thorax, which is now the preferred imaging technology in our review. Imaging modalities have also improved over the years, allowing for the discovery of previously unknown metastatic locations. As the referring center sent just one set of photos, it is unable to speculate on the timing of metastasis development throughout the course of the disease.

Conclusions

We offer a large cohort of mesothelioma patients and examine the occurrence of metastatic disease in these patients’ cancers. Considering that 67% of individuals with MPM have been shown to have metastatic illness, the disease should no longer be regarded as a local one without the potential to spread. In addition, because bone metastases account for about 20% of all cancer-related deaths, routine bone imaging or symptom-driven bone imaging should be considered. The presence of metastatic disease had no effect on survival.

Metastatic Pleural Mesothelioma

For many years, clinicians believed pleural mesothelioma a localized disease with minimal ability to spread to other areas of the body. However, a 2012 postmortem examination of 318 Australian and English mesothelioma patients found that 55.4% of them had metastases to distant places.

Only around 3% of postmortem instances involve cancer that has progressed to the brain or central nervous system.

More than 10% of patients with stage 4 pleural mesothelioma develop distant metastases. Other, uncommon areas may also be affected by cancer spread. A patient with pleural mesothelioma that has spread to the mouth was the subject of a study published in 2021.

Most mesothelioma patients have advanced cancer by the time they obtain a diagnosis. A palliative therapy approach is used when cancer has spread to other parts of the body, and the goal is to alleviate symptoms and provide comfort rather than treat the disease.

Mesothelioma that has spread to the peritoneum

At this stage, the disease usually does not extend beyond the peritoneum, which houses the spleen, liver and other digestive tract organs in addition to the stomach.

Progression of the disease causes tumors to invade other organs and distant regions of the body. Autopsies reveal distant metastases in around half of all instances of peritoneal mesothelioma.

Mesothelioma of the Pericardium
The pleura, lung, and mediastinum are frequently involved in the local spread of pericardial mesothelioma.

Pericardial mesothelioma spreads to the lymph nodes, lungs, and kidneys in roughly 25 to 45 percent of patients.

Mesothelioma of the Testicles with Metastasis

Tunica vaginalis to retroperitoneal lymph nodes then inguinal and iliac lymph nodes are common sites of dissemination for testicular mesothelioma.

It can spread to the thoracic and lumbar vertebrae, the omentum, the liver, and the lungs when it metastasizes, which is uncommon.

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