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A 28-year-old Black woman presents to an emergency department (ED) in Tampa, Florida, in March 2019 with persistent right upper quadrant abdominal pain, also noting that she has locally advanced breast cancer for which she has been receiving treatment at another hospital. She also has swelling of both feet and ankles.

Her medical history indicates that she has been diagnosed with clinical Stage III, T3N1M0, BRCA1/2-negative cancer of the left breast. The cancer is 90% estrogen receptor-positive, progesterone receptor-negative, and HER2-negative by immunohistochemistry. There is no other significant medical history or family history.

On presentation at the ED, she explains that in addition to continuing to have the persistent abdominal pain that was being treated at the other hospital, she is experiencing new left-side rib pain in the area of new osseous metastases.

Physical exam finds that her abdomen is distended, with tenderness to palpation in the right upper quadrant and epigastric area, with hepatomegaly and 2+ pitting edema in the bilateral lower extremities. Clinicians obtain her medical history, which covers the past several years of cancer treatment.

Cancer History

• Dec. 2016 to April 2017: The patient completes neoadjuvant chemotherapy with dose-dense doxorubicin/cyclophosphamide for four cycles (12/26/16 - 2/6/17) and paclitaxel for four cycles (2/27-4/10/17)

• May 2017: The patient undergoes bilateral mastectomy with left axillary lymph node dissection, right latissimus/implant reconstruction, and left tissue-expander placement

• Aug. 2017: Surgical pathology identifies residual isolated foci of invasive ductal carcinoma, comprising approximately 1% of a 6- to 7-cm tumor bed, presence of lymphovascular space invasion, and one lymph node with isolated tumor cells with chemotherapy-induced changes (0/18). The patient finishes radiation therapy to the chest wall following surgery

• Feb. 2019: Oncologists recommend adjuvant endocrine therapy, including ovarian function suppression with monthly goserelin and aromatase inhibitors. However, the patient is unable to tolerate the goserelin injections, so the team recommends further treatment with tamoxifen. The patient responds well, but she informs physicians that she is about 8 weeks pregnant. Tamoxifen is therefore discontinued

• March 2019: Two weeks after discontinuing tamoxifen, the patient is admitted to an outside hospital with complaints of right upper quadrant abdominal pain, abdominal distention, bilateral lower extremity edema, and nausea and vomiting

Notable lab findings include aspartate aminotransferase (AST) 208 U/L, alanine aminotransferase (ALT) 49 U/L, alkaline phosphatase (ALKP) 167 U/L, total bilirubin 1.1 mg/dL, and albumin 3.0 g/dL.

Clinicians perform limited abdominal ultrasound, which reveals hepatomegaly and possible acalculous cholecystitis. An early dating sonogram confirms an intrauterine pregnancy of 10 weeks and 5 days.

The patient undergoes a laparoscopy for possible cholecystectomy, but during the procedure, surgeons note that her liver is enlarged, cirrhotic-appearing, with areas of necrosis, and they then stop the procedure.

Subsequently, computed tomography (CT) of the abdomen and pelvis reveals a large, partially necrotic mass occupying the entire right hepatic lobe measuring 17×14×20 cm. The mass is found to invade and occlude the posterior branch of the right portal vein and exert an effect on the intrahepatic inferior vena cava (IVC) to near complete occlusion.

Necrotic nodularity is also found in the mesentery adjacent to the inferior liver tip, with invasion of the liver parenchyma; clinicians note extensive osseous metastatic disease.

The surgeons biopsy the liver during surgery, and intraoperative examination of the specimen identifies metastatic carcinoma. Microscopically, the entire available tissue is found to be composed of nests of neoplastic cells diffusely infiltrating the hepatic sinusoids, but without frank infiltration of the liver parenchyma.

The tumor compression of the hepatocytes has disrupted hepatic architecture, and clinicians note areas of hepatocyte atrophy and necrosis as well as desmoplasia around some of the involved sinusoids.

The team orders immunostaining for the endothelial marker CD31; this highlights the intrasinusoidal location of the tumor, which is confirmed by trichrome special stain, and additional immunostaining confirms the primary site of origin.

The tumor is positive for the GATA-3 transcription factor, ER, and CK-7, and negative for CK-20, PR, and HER2. Based on the clinical history of ER-positive breast carcinoma and the immunohistochemistry results, metastatic breast carcinoma is diagnosed. The patient is instructed to follow up with her oncologist and gynecologist, and is discharged home.

In March 2019, the patient undergoes an extensive workup, and MRI of the abdomen shows liver edema and necrosis.

The laboratory results are significant for AST 156 U/L, ALT 28 U/L, ALKP 174 U/L, total bilirubin 2.0 mg/dL, international normalized ratio 1.6, albumin 3.0 g/dL, lactate dehydrogenase (LDH) 953 U/L, and hemoglobin 8.4 g/dL. After consultation with the team, the patient elects to terminate the pregnancy.

Over the next 3 days, her liver failure rapidly progresses, with increasing AST (587 U/L), ALT (78 U/L), ALKP (145 U/L), total bilirubin (1.9 mg/dL), and albumin (2.8 g/dL). She develops a fever of T_max 38.6°C, tachycardia with a maximum heart rate of 149 bpm, and becomes increasingly lethargic.

She reports persistent pain and shortness of breath, and clinicians start empiric treatment with cefepime. CT chest angiogram rules out pulmonary embolism, but bilateral patchy ground-glass densities are found, which raises the possibility of early lung metastasis.

Abdominal CT demonstrates massive hepatomegaly with enlarging infarcts mostly in the peripheral right lobe, with focal capsular disruption and compression of the left portal vein and IVC.

Ultrasound of the liver shows no evidence of thrombus, with patent vasculature and appropriately directed flow. Portal pulsatility and loss of hepatic vein phasicity are noted, consistent with compression of the IVC. Results of viral hepatitis serologies, acetaminophen levels, and autoimmune and infectious workup are all negative.

Given the patient's worsening medical condition, the team discusses the goals of care with the patient and her family, and the decision is made to continue aggressive care. After an extensive review by the breast cancer tumor board, clinicians start palliative weekly low-dose doxorubicin. Within 3 days after the first cycle (20 mg/m² IV), the patient's bilirubin level decreased to 1.9 mg/dL, AST to 125 U/L, ALT to 51 U/L, and ALKP to 159 U/L.

After five cycles, the patient's symptoms resolve, her total bilirubin level has returned to normal range, and her performance status has returned to baseline.

Restaging CT scan of the abdomen reveals improved hepatomegaly and reduced compression of the intrahepatic IVC, with more organized hypoenhancement of the liver, which clinicians consider indicative of an improved infiltrative process with treatment response.

Lab measurements associated with poor liver function improve over the next 2 months, and the patient is switched to monthly liposomal doxorubicin, which is continued until Nov. 2019, with disease remaining stable. However, in Dec. 2019, in response to evidence of progressive bone metastatic disease, the patient's therapy is changed to abemaciclib and fulvestrant.

Discussion

Clinicians reporting this of a rare, aggressive form of diffuse intrasinusoidal hepatic metastasis in a pregnant patient presenting with acute liver failure note the importance of having a high index of suspicion in breast cancer patients who present with rapidly decompensating liver failure with no radiologic evidence of discrete hepatic lesions.

Metastatic disease can develop many years after initial diagnosis and treatment of early stage breast cancer, and liver metastasis is estimated to affect approximately 12-20% of breast cancer patients.

The most common is bone (51%), followed by lung (17%), brain (16%), and liver (6%). A more of approximately 300,000 patients with invasive breast cancer in the National Cancer Institute's Surveillance, Epidemiology, and End Results database found that 3.28%, 1.52%, 1.20%, and 0.35% of newly diagnosed breast cancers present with bone, lung, liver, and brain metastases at diagnosis, respectively.

The case authors explain that while x-ray usually reveals hepatic metastasis from breast cancer as discrete, easily distinguished mass lesions, in rare instances metastatic spread can be so diffuse that it is unidentifiable on imaging.

Breast cancer metastases that infiltrate the hepatic sinusoids usually result in clinical diagnosis when a patient presents with symptoms of hepatitis and rapidly progressive liver failure, and fulminant hepatic failure resulting from diffuse intrasinusoidal metastatic disease from breast cancer is an uncommon but known presentation of hepatic involvement.

This patient's case illustrates this , which often presents with rapid onset of ascites and marked elevation of bilirubin and hypoalbuminemia, and compromised liver function was accompanied by features typical of sinusoidal obstructive syndrome (SOS).

The patient had significant hepatomegaly associated with right upper quadrant pain, jaundice, and ascites, as well as evidence of compression of the intrahepatic IVC, which may also cause SOS.

The case authors explain that while elevations in liver enzymes and bilirubin may vary significantly depending on the area of the liver affected, the patient's lab test results were consistent with her presentation, with ischemic injury to the liver supported by an increase in LDH. The patient also had numerous small subsegmental infarcts in the periphery of the right hepatic lobe, which have been reported in SOS due to tumor infiltration.

While the causes of SOS may be multifactorial, in this patient the syndrome was likely related to decreased hepatic venous outflow caused by liver congestion from tumor infiltration and IVC compression/stenosis, the case authors speculate. Furthermore, the patient's quick response to chemotherapy suggests an improvement in liver function because of rapid reduction of tumor infiltration in the sinusoidal spaces, which in turn increased blood flow and decreased liver congestion.

The prognosis of breast cancer patients who have rapidly progressive liver failure is generally poor. Treatment is challenging since altered drug clearance makes it difficult to predict treatment-related toxicity. Bilirubin exceeding 5.0 mg/dL often is considered an absolute contraindication to the administration of chemotherapeutic agents metabolized through the liver.

Studies suggest that weekly low-dose doxorubicin is associated with less toxicity while maintaining dose intensity, and thus is a helpful alternative approach to treatment of patients with hepatic impairment. The choice of weekly doxorubicin to treat this patient was based on evidence of its efficacy in refractory advanced breast cancer.

The group notes that in a small randomized study of 43 breast cancer patients who had not responded to treatment with cyclophosphamide, methotrexate, and fluorouracil (i.e., CMF), weekly doxorubicin with a median cumulative dose of 240 mg/m² (range of 160-860) led to a complete plus partial response rate of 38%, median duration of response of 7 months, and median survival of 11 months.

In this patient's case, treatment resulted in a therapeutic partial response and improved quality of life.

Conclusion

The case authors conclude that although the liver is a known metastatic site in breast cancer, diffuse intrasinusoidal hepatic metastasis is a rare type of metastatic disease that should be considered when breast cancer patients present with rapidly decompensating liver failure and no discrete radiologic hepatic lesions.

Additionally, in patients with progressive liver failure and biopsy-confirmed metastatic carcinoma diffusely infiltrating the hepatic sinusoids, weekly doxorubicin should be considered as a first-line therapeutic option.

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