Pseudocirrhosis in Metastatic Breast Cancer in a Male Successfully Treated with Leuprorelin and Anastrozole Followed by Eribulin: A Case Report

doi:10.21203/rs.3.rs-1606874/v1

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Case Report

Pseudocirrhosis in Metastatic Breast Cancer in a Male Successfully Treated with Leuprorelin and Anastrozole Followed by Eribulin: A Case Report

https://doi.org/10.21203/rs.3.rs-1606874/v1

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Background

There are very few studies and cases in the literature describing metastatic breast cancer in the male population, accounting for less than 1% of all cases. Of those who have been reported, the vast majority fail to survive beyond 5 years from time of diagnosis. The lack of literature in this population makes it difficult for clinicians to foresee and prepare for upcoming complications in management. One of the more serious complications in managing metastatic breast cancer is the development of pseudocirrhosis, a frequent long-term side effect of chemotherapy and/or radiation typically seen in patients with malignancy in the liver.

Case Presentation

We report the case of a 48-year-old male with a completely unremarkable family, medical, and social history other than a homozygous mutation in his MTHFR gene who was diagnosed with stage IV ER/PR-positive, HER-2/neu negative, BRCA1 and BRCA2-negative breast cancer with metastasis to bone, lung, and liver who was successfully treated with a regimen consisting of radiation, Denosumab, Leuprorelin, and Anastrozole. 8 years later since initiation of treatments, he continues to survive and undergo symptomatic management of long-term side-effects of his treatments.

Conclusions

To our knowledge this is the only reported case of metastatic breast cancer with pseudocirrhosis in a male patient. It is imperative to report this unique case to help increase awareness for clinicians managing other males with breast cancer. What makes this case even more reportable is the good outcome overall as our patient remains alive and well 8 years since time of diagnosis, a relatively difficult and rare feat to achieve in end-stage breast cancer.

Pseudocirrhosis

Male Breast Cancer

Metastasis

Ascites

Anastrozole

Eribulin

Breast cancer in males is rare, representing roughly only 1% of all breast cancers worldwide.^[1] Cases of males with metastatic breast cancer who’ve successfully been treated and surpassed 5-year survivability are even less prevalent. A common complication of breast cancer with metastasis to the liver is pseudocirrhosis. However, to our knowledge we are the first to report such a case in a male. Pseudocirrhosis refers to changes in the liver that mimic cirrhosis, however the typical histological findings seen in cirrhosis are absent. ^[2,6,7,8] It is characterized by multifocal capsular retraction, enlargement of the caudate lobe, and nodularity of the liver. ^[2,9] Pseudocirrhosis commonly occurs in patients with metastatic breast cancer, although it has been reported in other malignancies, such as lung and gastric adenocarcinoma. ^[7,10,11] The mechanism and cause of pseudocirrhosis in relation to breast cancer remains unclear.^[3] The leading proposed mechanism is the conversion of previously viable tissue into scarred and physiologically dead tissue as a result of chemotherapy and/or radiation. Often the areas of damage are at the sites previously invaded by cancer cells.

Regarding metastatic breast cancer, the literature does have several cases of pseudocirrhosis in women undergoing chemotherapy; however, no cases of pseudocirrhosis have been previously reported in a male patient. Therefore, we are presenting a case of a male patient with metastatic breast cancer who subsequently developed pseudocirrhosis from chemotherapy.

We present the case of a 48-year-old male with a completely unremarkable family, medical, and social history other than a homozygous MTHFR A1298C gene mutation who initially presented with a constellation of symptoms including back pain, fatigue, unintentional weight loss, and increased dyspnea on exertion. Computed tomography (CT) of the chest with intravenous (IV) contrast revealed some diffusely scattered small subsegmental pulmonary emboli (Fig. 1A). However, a highly suspicious lesion was also visualized on the sternum as well as the liver which raised concerns for malignancy (Fig. 1A). Thus, a full body bone scintigraphy was obtained which revealed diffuse areas of increased nuclear activity compatible with metastatic disease in the spine, ribs, sternum, right scapula, and possibly the right shoulder (Fig. 2). A thorough physical exam revealed an abnormal area of hardened periareolar tissue. Subsequent excisional breast biopsy revealed the final diagnosis of metastatic breast cancer that was ER/PR-positive, HER-2/neu negative. Additional testing confirmed the cancer to be BRCA1 and BRCA2-negative.

He completed 5 treatments of palliative radiation to the lumbar spine and right shoulder and was placed on Tamoxifen which was discontinued after 1 year due to intolerable side-effects of thromboemboli. He developed multiple pulmonary emboli, deep vein thrombi, splenic vein thrombus, and hepatic vein thrombus. He was started on daily Enoxaparin injections and switched to a regimen consisting of Denosumab, Leuprorelin, and Anastrozole for the next 4 years. Serial positron emission tomography (PET) scans and down-trending tumor markers confirmed that he was responding well to this regimen. Upon 5-year completion of Anastrozole and Leuprorelin, he was then started on Eribulin and has been on this since. Overall, he had an excellent outcome, and we were able to provide him an increased quantity of life while preserving as much quality as possible.

Unfortunately, over the years he began to develop abdominal distention and ascites. Per previous CT images, patient had a relatively healthy liver. However, by year 5 post-diagnosis, he began to develop a nodular appearing liver along with grade I/II ascites requiring outpatient paracentesis as needed. Fluid analysis consistently reveals a yellow amber color, thin consistency, clear, with cytology showing rare, atypical single cells most likely being reactive histiocytes. Cell count with differential revealed total nucleated cell count of 54 cells/uL, minimal red blood cell count of < 2000 cells/uL, and fluid albumin 0.5 gm/dl. Fluid immunohistochemistry was performed for GATA3, ER, calretinin, and WT-1 with adequate controls. The atypical cells were negative for all the aforementioned tests. Additional testing revealed no evidence of hepatitis A, B, or C. Blood chemistry revealed the following: total protein 4.1 g/dL; albumin 2.4 g/dL; total bilirubin 1.4 mg/dL; aspartate aminotransferase (AST) 25 IU/L; alanine aminotransferase (ALT) 18 IU/L; alkaline phosphatase (ALP), 86 IU/L.

The decision was made to drain his ascites as needed and initiate furosemide and spironolactone. Additionally, he was placed on a low sodium diet with fluid restriction of 1.5 L. Over the years he underwent multiple upper endoscopies that revealed esophageal varices and portal hypertensive gastropathy that gradually worsened with time. We continued symptomatic management as needed. Today, he is 8 years post-diagnosis of metastatic breast cancer and 4 years since onset of his ascites and is still relatively doing well overall, but his ascites has progressed to grade III. His Model for End-Stage Liver Disease (MELD) score has been typically ranging 18–24 with chronic hypoalbuminemia, chronic mild hyponatremia, portal hypertension with occasional variceal bleed requiring banding, and recurrent ascites requiring aggressive paracentesis biweekly with removal of 5–7 L of fluid per session.

Because our patient’s metastatic breast cancer was hormone receptor positive, the decision was made to place him on a regimen that consisted of denosumab, leuprorelin, and anastrozole. Systemic chemotherapy is usually the treatment of choice for individuals with metastatic breast cancer, however complications such as pseudocirrhosis of the liver may occur post-treatment. ^[2,3,4,5,6] Pseudocirrhosis is a serious complication in patients with metastatic breast cancer undergoing treatment and is associated with increased mortality. While pseudocirrhosis has been described in multiple different malignancies, breast cancer is the most common. Nearly two-thirds of breast cancer patients with metastasis to the liver will eventually develop pseudocirrhosis. In pseudocirrhosis, one or more of the stages of progression to a true cirrhotic state are bypassed (see Fig. 4). In the case of our patient, he previously only had mild-moderate fatty liver disease at most (Fig. 1B). However, upon his metastasis, he received radiation therapy followed by chemotherapy with 5 years of hormone therapy followed by 3 more years of Eribulin while gradually developing pseudocirrhosis (Fig. 3).

The pathophysiology is believed to be multifactorial. The leading hypothesis is that it is a combination of drug-induced fibrosis, sinusoidal scarring and obstruction, and microthrombi throughout the vasculature of the liver due to the hypercoagulability of the metastatic state resulting in chronic ischemic nodular hyperplasia. ^{[6, 12]} For these reasons, we believe our patient was especially at high risk for developing pseudocirrhosis because of his MTHFR mutation resulting in increased thrombi and hepatic occlusive disease. After all, he did end up suffering from multiple thrombi. His occlusive disease was exacerbated by his malignancy which is why he was indefinitely placed on daily Enoxaparin injections. Additionally, he received five sessions of radiation to his lumbar spine and left shoulder which may have led to an extent of fibrosis and sinusoidal collapse. Over time, the addition of Eribulin likely added to insult of liver injury via mechanisms discussed above. There are many chemotherapeutic agents known to cause pseudocirrhosis and other forms of liver injury. However, Eribulin is not one of the typically listed agents. The very first reported case of Eribulin-induced pseudocirrhosis was by Akdeniz et al in 2018 where they reported two cases of pseudocirrhosis in patients taking Eribulin.^[13] Oddly enough, our patient’s onset of abdominal distention and ascites coincided with the 5 months after initiation of Eribulin. We cannot rule out Eribulin as a major culprit of his pseudocirrhosis.

Unfortunately, his state of metastasis precludes such patients from being able to qualify for liver transplants as the immunosuppressants would likely result in relapse and recurrence of malignancy. Thus, conservative symptomatic management remains to be the mainstay approach in patients with pseudocirrhosis. A transjugular intrahepatic portosystemic shunt (TIPS) may be an option for such patients. However, such procedures are very high-risk and recent literature is showing mixed results in success. Although associated with increased risk of morbidity and mortality, our patient has been living with pseudocirrhosis for roughly four years now. Our patient was provided the option for TIPS, but it was refused at the time. As of today, our patient has completed over 150 paracenteses since initial onset of his pseudocirrhosis 4 years ago but continues to perform activities of daily living with minimal difficult. Additional cases will need to be reported to better understand and manage male breast cancer patients who are prone to similar complications as their female counterparts.

Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal Growth Factor Receptor 2 (HER-2), Intravenous (IV), computerized tomography (CT), positron emission tomography (PET), Model for End-Stage Liver Disease (MELD), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP)

Ethics Approval and Consent to Participate: Ethical approval and informed consent (to participate and for publication) is completed.

Consent for Publication: Consent for publication has been obtained to the best of our ability in line with the COPE best practices guidelines and directly from the patient.

Availability of Data & Materials: All data generated or analyzed during this study are included in this article. Additionally, the datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing Interests: There are no conflicts of interest with respect to this manuscript.

Funding: No funding was involved in the production of this clinical case report

Authors’ Contributions: HG and MT were the primary contributors to writing this manuscript. AM and SS analyzed and interpreted the patient data regarding the metastatic breast cancer and pseudocirrhosis. SH and BP were primary providers during majority of patient’s hospitalizations and helped obtain medical records from all participating hospitals and clinics our patient participated in. CH and RA compiled the data and created the figures below. RA also assisted with final edits of the paper. JS was the mentor on the case and provided pathological analysis of the patient’s presentation. All authors read and approved the final manuscript.

Acknowledgements: Please note that this manuscript is original, not under consideration elsewhere, and none of the manuscript’s contents have been previously published. All listed authors above contributed to the design, analysis, interpretation, literature search, drafting, writing, and revising the manuscript. All authors provide approval of the version of the manuscript to be published

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No competing interests reported.

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Pseudocirrhosis in Metastatic Breast Cancer in a Male Successfully Treated with Leuprorelin and Anastrozole Followed by Eribulin: A Case Report

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Case Presentation

Discussion And Conclusion

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