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Radiographically Occult Carcinomatous Spread of Breast Cancer to the Liver: A Challenging Case

Radiographically Occult Carcinomatous Spread of Breast Cancer to the Liver: A Challenging Case Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 4935615, 5 pages https://doi.org/10.1155/2019/4935615 Case Report Radiographically Occult Carcinomatous Spread of Breast Cancer to the Liver: A Challenging Case 1 2 1 1 1 Trish Millard, Akriti Gupta, Christiana Brenin, Paul Marshall, and Patrick Dillon Division of Hematology/Oncology, University of Virginia, 1215 Lee St, Charlottesville, VA 22908, USA Department of Pathology, University of Virginia, 1215 Lee St, Charlottesville, VA 22908, USA Correspondence should be addressed to Patrick Dillon; pmd5b@hscmail.mcc.virginia.edu Received 10 May 2019; Revised 16 October 2019; Accepted 8 November 2019; Published 6 December 2019 Academic Editor: Mauro Cives Copyright © 2019 Trish Millard et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Metastatic carcinomatosis to the liver is a pattern of malignant infiltration that tends to provoke hepatic fibrosis. It is a rare complication of multiple solid tumor types and often seen in the absence of discrete tumor mass in the liver. We report a case of a 69-year-old woman with metastatic ductal carcinoma of the breast who presented with rising serum tumor markers and mildly cirrhotic contour of the liver on a CT scan. An early diagnosis of occult spread to the liver was made by means of a percutaneous liver biopsy showing desmoplastic response to invasive breast cancer cells found diffusely in the liver. This case highlights a rare pattern of metastatic spread of breast cancer as well as predisposing and prognostic features. for HER2. She attempted first-line therapy with palbociclib 1. Case Presentation and letrozole; however, this was stopped for neutropenic fever and osteomyelitis. She was then treated sequentially We present a 69-year-old Caucasian woman who had a his- tory of metastatic, estrogen receptor-positive, and human with letrozole and Faslodex for 35 months, until February 2019 with serial stability on CT scans every 3 months. epidermal growth factor receptor 2/neu (HER2) nonampli- She received bone strengthening therapy with denosumab fied, invasive ductal breast cancer, and she went on to throughout her course. develop occult liver involvement. The patient originally Then, at the nine-year mark from her original breast can- underwent left modified radical mastectomy in 2010 for a 3.1 cm mass, and she had an axillary nodal dissection which cer (2/2019), a routine follow-up CT scan (Figure 1) revealed a mildly nodular liver surface contour suggestive of cirrhotic found one of seventeen lymph nodes involved. She was changes, but no focal hepatic lesion. The physical examina- treated with adjuvant Taxotere and Cytoxan chemotherapy tion revealed no icterus, hepatomegaly, or splenomegaly. for 6 cycles and then completed adjuvant external beam radi- There were no stigmata of chronic liver disease and no aster- ation therapy to the chest wall and axilla in 25 fractions. The patient took two years of adjuvant aromatase inhibitor ther- ixis. The chest portion of the CT revealed a few small peri- bronchovascular nodules in the inferior left lower lobe and apy and stopped due to arthralgia. stable vertebral body bone lesions. The laboratory data at The patient presented to her oncologist with new pain in the same time revealed that the serum bilirubin rose to the pelvis 5 years after the initial diagnosis (March 2015). A 2.5 mg/dL from a baseline of 1.0 mg/dL two months prior. bone scan and CT scan revealed widespread metastatic dis- ease limited to the bones. A biopsy of the left iliac crest con- The alkaline phosphatase rose to 343 U/L from 180; the aspartate aminotransferase (AST) and alanine aminotrans- firmed metastatic ductal adenocarcinoma of breast origin ferase (ALT) remained within normal limits at 40 and 21, which remained 100% positive for the estrogen receptor respectively. The albumin was 3.0 g/dL, the PT was 14.6 s and 100% positive for the progesterone receptor and negative 2 Case Reports in Oncological Medicine Figure 2: MRI demonstrating course texture (VIBE axial image post gadolinium). Figure 1: CT demonstrating ascites and mildly nodular liver surface tic tissue response that was diffusely infiltrated by nests of contour (oral and IV contrast present). intermediate grade ductal adenocarcinoma with multiple intracytoplasmic lumens which recapitulated breast tissue appearance. Immunohistochemical stains for estrogen recep- (normal is 9-13), the PTT was 39.1 (normal is 27.8-37.6), and the conjugated bilirubin was 1.0 (0-0.5 mg/dL). The serum tor and progesterone receptor demonstrated positivity in level of cancer antigen (CA 15-3) rose from 285 to 100% and 90% of tumor cells, respectively (Figure 3). An 381 U/mL. Alpha fetoprotein was 7 and CA-125 was 4. Other additional immunohistochemical (IHC) stain with mamma- tumor markers were not checked at the time of the evaluation. globin (not shown) was 1+ positive, further supporting a breast origin for the malignant cells. HER2 was not amplified Upon finding evidence of a suddenly cirrhotic appear- ance of the liver in the absence of known liver disease, the by FISH. The morphology and IHC stains were completely patient underwent evaluation for primary and secondary concordant with the original tumor morphology and recep- causes of cirrhosis. She had a negative workup for hepatitis tors. Ascites fluid at the same time was cytologically negative A, B, C and HIV. She had normal iron studies, except for for malignant cells. Serial scans did not detect other primary cancer aside from the breast cancer. an elevated ferritin of 1,102 ng/mL. She was a nondrinker and nonsmoker who did not use herbal medications or drugs The patient was treated with paracentesis for symptom and had not received hepatotoxic agents. She had no interna- control. She was offered palliative chemotherapy, but ulti- tional travel, chemical exposures, or farm work. She did not mately declined additional therapies in order to pursue a report any insect or animal exposures and she had no sick comfort-based approach. Given her preference for palliative care, the patient did not undergo esophagogastroduodeno- contacts. She had no family history of liver disease, hemo- chromatosis, Wilson’s disease, or alpha-1 antitrypsin. She scopy (EGD) screening for varices. was seen by a hepatologist who tested immunoglobulins, erythrocyte sedimentation rate (ESR), and antinuclear anti- 2. Discussion body to rule out autoimmune hepatitis. The autoimmune panel was only notable for a mildly elevated ESR of 50 (nor- The liver is a common location of metastatic disease in solid mal 0-30), but that finding was blamed on known metastatic tumor oncology. Hepatic metastases usually demonstrate cancer to bones. The hepatologist did not deem her likely to discrete mass lesions and are sometimes painful when they have CMV, EBV, or other viral etiology given lack of extrahe- involve the capsule of the liver [1]. On the other hand, patic findings on CT and lack of symptoms/fevers/weight descriptions of occult metastatic carcinomatosis of the liver loss/lymphadenopathy and lack of immunosuppression. An such as characterized in this case report have not been widely ultrasound of the liver was performed and failed to detect a reported (see Table 1 for literature review). A few published focal liver lesion, gallstones, biliary obstruction, or abnormal cases have described a diffuse infiltration of the liver by duc- blood flow. She next had gadolinium-enhanced magnetic tal or lobular breast cancer but often not found until the time resonance imaging (MRI) of the liver (Figure 2), which dem- of an autopsy [2–6]. The first report of occult, diffuse liver onstrated a nodular liver surface contour and a fibrotic invasion of any histology was described by Watson in 1955 appearance of the hepatic parenchyma. No masses were involving several cases of disseminated bronchogenic carci- detected within the liver. The abdominal vasculature was noma leading to fulminant liver failure [7]. Since that time, normal in caliber and all the arteries, veins, and portal vessels carcinomatosis or sinusoidal infiltration of the liver (also were patent. New ascites was seen. termed hepar lobatum carcinomatosum) has been reported Given the lack of a mass in the liver and lack of intrinsic due to primary tumors of the colon, pancreas, lung, stomach, liver disease found by any serology or lab testing, there was kidney, adrenal, ovary, breast, and lymphomas [8]. Occult concern for radiographically occult metastasis to the liver. involvement of the liver due breast cancer has been described Thus, the patient next underwent a random percutaneous only in case reports and has been too rare to formally study liver biopsy under ultrasound guidance. The random liver [2,3,5, 6,9–18]. Unfortunately, no authors have been able biopsy revealed liver parenchyma disrupted by a desmoplas- to elucidate common risk factors nor common shared Case Reports in Oncological Medicine 3 (a) (b) (c) (d) Figure 3: Diffusely infiltrating nests of intermediate-grade ductal adenocarcinoma with disrupted hepatic parenchyma (H&E) ((a) 100x and (b) 400x). Tumor cell nests staining for estrogen (c) and progesterone (d) receptors. biologic features (Table 1). Loss of E-cadherin appears com- itive radiographic evidence and perhaps also due to the indo- mon, but our case like others had histologic evidence of the lent rate of progression of some estrogen-driven breast breast cancer cells attempting to recapitulate round ductal cancers [4]. Detection of liver metastases may also be delayed structures which is not typically seen in breast cancer which in the modern era of CDK4/6 therapy whereby the interval of is lacking E-cadherin [9, 16]. It is believed that breast cancers cross-sectional imaging may be extended beyond the historic three-month timeframe. We recommend performing MRI of downregulate (or lose) E-cadherin as cells from the primary tumor gain access to the angiolymphatic system in the pro- the liver when breast cancer patients first demonstrate inex- cess of epithelial to mesenchymal transition (EMT). Cancer- plicable rises in liver function tests or any other abnormality ous cells may then reexpress E-cadherin at the metastatic of the liver on standard CT imaging. The MRI may be niche by mesenchymal to epithelial transition (MET) [19]. followed by liver biopsy whenever liver enzymes remain ele- We hypothesize that this is the process that we observed in vated in the setting of inexplicable liver contour changes in a the liver of our patient. We also point out that other adhesion metastatic breast cancer patient. molecules (VCAM-1, P-cadherin, and ICAMs and selectins Our literature review suggests that extensive liver involvement is sometimes seen in breast cancer patients such as E-selectin and integrins such as LFA-a and VLA-4) and chemokine receptors (CXCR4, CCR6, and CCR7) have after prolonged intervals without overt disease progression. been speculated to be involved in the homing of breast cancer Subtle signs of liver involvement may include weight cells to the liver and warrant additional research. changes, subclinical bleeding from varices, slow accumula- This case report highlights the challenging clinical diag- tion of ascites, jaundice, and even slowly progressive hepatic encephalopathy [13, 20]. In retrospect, there is suspicion nosis of occult liver involvement by breast cancer when radiographic imaging fails to detect any mass forming lesions that our case of occult liver infiltration may have developed in the liver. It should be pointed out that rapidly progressive subtly over 6-12 months with the only indicator being subtle liver failure in estrogen receptor-positive breast cancer is increases in bilirubin and alkaline phosphatase values to less atypical and warrants a thorough diagnostic workup. Com- than one time the upper limit of normal. It is worth pointing out that there are also existing reports of de novo diagnosis monly, the cross-sectional imaging done for metastatic breast cancer demonstrates either discrete lesions within the liver or of breast cancer made upon finding occult hepatic involve- occasionally the sequelae of regressed hepatic lesions with ment [11, 14]. capsular retraction and decrease in the liver size. Indeed, liver Regardless of whether metastatic liver carcinomatosis is involvement by breast cancer has often only been able to be an early or late complication of breast cancer, the prognosis is currently deemed to be quite poor and is generally less than identified postmortem owing to the occasional lack of defin- 4 Case Reports in Oncological Medicine Table 1: Summary of literature reports of diffuse and/or occult liver involvement by metastatic breast cancer. Time E-cad Authors Age Receptors Concurrent diagnoses/presentation/notes Imaging from 1 Histology Ref loss Dx Cirrhosis on MRI, no focal Jungst et al., 2013 70 NA Diabetes, variceal bleeding NA 7 yr Ductal+lobular [13] lesion Poorly Allison et al., 2004 42 ER-, PR- Tobacco abuse, thrombocytopenia Yes Not performed 0 yr [9] differentiated Poorly Allison et al., 2004 54 NA Ascites, jaundice, hematochezia Yes Multiple masses on CT 9 yr [9] differentiated Poorly Allison et al., 2004 36 NA Nausea/vomiting/abd pain and jaundice Yes Small masses on CT 9 mo [9] differentiated Hanamornroongruang 49 ER+, PR+ Weight loss, jaundice, abd pain Yes CT without mass 10 yr Ductal, stage I [2] and Sangchay, 2013 Martelli et al., 2000 53 ER+, PR+ Dyspnea, fever NA Hepatomegaly on US 4 yr Ductal [3] Fatigue, weakness, abdominal distention/jaundice, Mogrovejo et al., 2014 67 ER+, PR-, HER2- No CT ascites 21 yr Ductal+lobular [4] lower extremity edema Poorly Borja et al., 1975 46 NA Jaundice, ascites, spider angiomata NA CT cirrhosis 3 mo [5] differentiated Hyperthyroid, ascites, thrombocytopenia, CT/US w/o mass, heterogeneous Graber et al., 2010 57 ER+, PR+, HER2+ Yes 0 yr Lobular [6] hyperbilirubinemia parenchyma CT with ascites, splenomegaly, Fournier et al., 2010 52 ER+, PR-, HER2- Bone mets from breast cancer, abdominal fullness NA 5 yr Ductal, stage II [10] but no liver abnormality CT hepatomegaly, periportal Goswami et al., 2011 38 ER-, PR+, HER2+ Malaise, lethargy, sore throat, dyspnea NA 0 yr Ductal, grade 2 [11] nodes Morrison and 57 NA Rapid fulminant hepatic failure NA NA 0 yr Carcinoma NOS [14] Pennington, 1984 Drowsiness, disorientation, lymphangitic cancer CT normal liver, laparoscopic Nakajima et al., 2005 68 NA NA 8 mo Ductal, stage I [15] spread to lungs slight cirrhosis US w/o mass, reversal of portal Nascimento et al., 2001 62 NA Ascites, edema NA 13 yr NA [16] flow, MRI w cirrhosis Nausea, vomiting, abdominal girth increase, CT neg for lesions, MRI w Mucinous, poorly Nascimento et al., 2001 46 NA NA 5yr [16] disseminated intravascular coagulopathy cirrhosis differentiated Jaundice, dark urine, acholic stool, and abdominal CT nodular contour c/w Sass et al., 2007 55 ER+, PR-, HER2- NA 4 yr Ductal, stage I [17] distension cirrhosis, no focal lesion Shivashankar and 66 ER+, PR+ Abdominal distention, hepatomegaly NA CT with cirrhosis, but no mass 8 yr NA [18] Sweetser, 2012 Bone mets from breast cancer, no presenting Current case 69 ER+, PR+, HER2- Yes Cirrhosis on CT, US and MRI 9 yr Ductal symptom, eventual leptomeningeal metastases NA: not available; E-cad: E-cadherin; ER: estrogen receptor; PR: progesterone receptor; Ref: reference number; NOS: not otherwise specified; CT: computerized tomography; MRI: magnetic resonance imaging. Case Reports in Oncological Medicine 5 [8] P. Jha, L. Poder, Z. J. Wang, A. C. Westphalen, B. M. Yeh, and 6 months overall and less than 3 months when evidence of F. V. Coakley, “Radiologic mimics of cirrhosis,” American hepatic failure is present [6, 9, 12]. Treatment options are Journal of Roentgenology, vol. 194, no. 4, pp. 993–999, 2010. limited due to the fact that most cytotoxic chemotherapy is [9] K. H. Allison, C. L. Fligner, and W. T. Parks, “Radiographically difficult to administer in the setting of hepatic impairment. occult, diffuse intrasinusoidal hepatic metastases from primary Likewise, the CDK4/6 inhibitors and the mTOR inhibitors breast carcinomas: a clinicopathologic study of 3 autopsy cases,” are not recommended in Child-Pugh class C hepatic impair- Archives of Pathology & Laboratory Medicine,vol. 128,no.12, ment. Liver transplant is currently not indicated for patients pp. 1418–1423, 2004. with diffuse metastatic disease. [10] C. Fournier, G. Tisman, R. Kleinman, Y. Park, and W. D. Macdonald, “Clinical evidence for overcoming capecitabine 3. Conclusion resistance in a woman with breast cancer terminating in radiologically occult micronodular pseudo-cirrhosis with Liver metastases of breast cancer usually present as discrete portal hypertension: a case report,” Journal of Medical Case metastatic nodules and diagnosis is often straightforward Reports, vol. 4, p. 112, 2010. on cross-sectional imaging, but can occasionally present as [11] R. Goswami, M. Babich, and K. F. Farah, “Occult breast malig- radiographically occult disease. Unfortunately, the diagnosis nancy masquerading as acute hepatic failure,” Gastroenterol- of carcinomatous spread within the liver is difficult to make ogy & hepatology, vol. 7, no. 1, pp. 62–65, 2011. and is often delayed. In cases of cirrhotic-appearing liver [12] S. Gulia, S. Khurana, T. Shet, and S. Gupta, “Radiographically such as the one described here, a high level of suspicion is occult intrasinusoidal liver metastases leading to hepatic fail- required and a liver biopsy is essential to making the diagno- ure in a case of breast cancer,” BMJ Case Reports, vol. 2016, article bcr2015214120, 2016. sis. We have not been able to discern specific predisposing features for this pattern of metastatic spread. Both ductal [13] C. Jungst, J. Kramer, G. Schneider, F. Lammert, and and lobular histologies have been observed to follow this V. Zimmer, “Subacute liver failure by pseudocirrhotic metasta- tic breast cancer infiltration,” Annals of Hepatology, vol. 12, pattern. Neither receptor status nor E-cadherin status has no. 5, pp. 834–836, 2013. correlated with the risk of diffuse liver invasion. Unfortu- nately, this phenotypic pattern of metastatic breast cancer [14] W. L. Morrison and C. R. Pennington, “Liver metastases from an occult breast carcinoma presenting as acute fulminant has been poorly studied to date. The treatment options are hepatic failure,” The British Journal of Clinical Practice, limited and the prognosis is currently viewed as poor. vol. 38, no. 7-8, pp. 273-274, 1984. [15] T. Nakajima, S. Sekoguchi, T. Nishikawa et al., “Multifocal Conflicts of Interest intraportal invasion of breast carcinoma diagnosed by laparoscopy-assisted liver biopsy,” World Journal of Gastroen- The authors declare that they have no conflicts of interest. terology, vol. 11, no. 15, pp. 2360–2363, 2005. [16] A. B. Nascimento, D. G. Mitchell, R. Rubin, and E. Weaver, “Diffuse desmoplastic breast carcinoma metastases to the liver References simulating cirrhosis at MR imaging: report of two cases,” Radi- ology, vol. 221, no. 1, pp. 117–121, 2001. [1] M. Koenigsberg and L. M. Freeman, “Multinuclide evaluation of hepatic mass lesions,” CRC Critical Reviews in Clinical Radi- [17] D. A. Sass, K. Clark, D. Grzybicki, M. Rabinovitz, and T. A. ology and Nuclear Medicine, vol. 6, no. 2, pp. 113–152, 1975. Shaw-Stiffel, “Diffuse desmoplastic metastatic breast cancer simulating cirrhosis with severe portal hypertension: a case [2] S. Hanamornroongruang and N. Sangchay, “Acute liver failure of “pseudocirrhosis”,” Digestive Diseases and Sciences, vol. 52, associated with diffuse liver infiltration by metastatic breast no. 3, pp. 749–752, 2007. carcinoma: a case report,” Oncology Letters, vol. 5, no. 4, pp. 1250–1252, 2013. [18] R. Shivashankar and S. Sweetser, “A woman with ascites, [3] O. Martelli, L. Coppola, A. L. de Quarto, M. Palma, nodular liver contour, and splenomegaly,” Gastroenterology, vol. 143, no. 3, pp. 541–871, 2012. R. Sarmiento, and C. M. Foggi, “Fulminant hepatic failure caused by diffuse intrasinusoidal metastatic liver disease: a case [19] K. Palen, J. Weber, M. B. Dwinell, B. D. Johnson, report,” Tumori Journal, vol. 86, no. 5, pp. 424–427, 2000. R. Ramchandran, and J. A. Gershan, “E-cadherin re-expression [4] E. Mogrovejo, P. Manickam, M. Amin, and M. S. Cappell, shows in vivo evidence for mesenchymal to epithelial transi- “Characterization of the syndrome of acute liver failure caused tion in clonal metastatic breast tumor cells,” Oncotarget, by metastases from breast carcinoma,” Digestive Diseases and vol. 7, no. 28, pp. 43363–43375, 2016. Sciences, vol. 59, no. 4, pp. 724–736, 2014. [20] P. Knouse, C. Hancock, S. Iwaz, and P. Kaiser, “Metastatic car- [5] E. R. Borja, J. M. Hori, and R. P. Pugh, “Metastatic carcinoma- cinomatosis cirrhosis: a rare pattern of metastasis,” Cureus, tosis of the liver mimicking cirrhosis: case report and review of vol. 11, no. 1, article e3876, 2019. the literature,” Cancer, vol. 35, no. 2, pp. 445–449, 1975. [6] I. Graber, J. Dumortier, G. Poncet, P. E. Queneau, P. Mathevet, and J. Y. Scoazec, “Hepar lobatum carcinomatosum revealing an occult metastatic lobular carcinoma of the breast,” Annals of Diagnostic Pathology, vol. 14, no. 6, pp. 438–442, 2010. [7] A. J. Watson, “Diffuse intra-sinusoidal metastatic carcinoma of the liver,” The Journal of Pathology and Bacteriology, vol. 69, no. 1, pp. 207–217, 1955. 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Radiographically Occult Carcinomatous Spread of Breast Cancer to the Liver: A Challenging Case

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Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 4935615, 5 pages https://doi.org/10.1155/2019/4935615 Case Report Radiographically Occult Carcinomatous Spread of Breast Cancer to the Liver: A Challenging Case 1 2 1 1 1 Trish Millard, Akriti Gupta, Christiana Brenin, Paul Marshall, and Patrick Dillon Division of Hematology/Oncology, University of Virginia, 1215 Lee St, Charlottesville, VA 22908, USA Department of Pathology, University of Virginia, 1215 Lee St, Charlottesville, VA 22908, USA Correspondence should be addressed to Patrick Dillon; pmd5b@hscmail.mcc.virginia.edu Received 10 May 2019; Revised 16 October 2019; Accepted 8 November 2019; Published 6 December 2019 Academic Editor: Mauro Cives Copyright © 2019 Trish Millard et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Metastatic carcinomatosis to the liver is a pattern of malignant infiltration that tends to provoke hepatic fibrosis. It is a rare complication of multiple solid tumor types and often seen in the absence of discrete tumor mass in the liver. We report a case of a 69-year-old woman with metastatic ductal carcinoma of the breast who presented with rising serum tumor markers and mildly cirrhotic contour of the liver on a CT scan. An early diagnosis of occult spread to the liver was made by means of a percutaneous liver biopsy showing desmoplastic response to invasive breast cancer cells found diffusely in the liver. This case highlights a rare pattern of metastatic spread of breast cancer as well as predisposing and prognostic features. for HER2. She attempted first-line therapy with palbociclib 1. Case Presentation and letrozole; however, this was stopped for neutropenic fever and osteomyelitis. She was then treated sequentially We present a 69-year-old Caucasian woman who had a his- tory of metastatic, estrogen receptor-positive, and human with letrozole and Faslodex for 35 months, until February 2019 with serial stability on CT scans every 3 months. epidermal growth factor receptor 2/neu (HER2) nonampli- She received bone strengthening therapy with denosumab fied, invasive ductal breast cancer, and she went on to throughout her course. develop occult liver involvement. The patient originally Then, at the nine-year mark from her original breast can- underwent left modified radical mastectomy in 2010 for a 3.1 cm mass, and she had an axillary nodal dissection which cer (2/2019), a routine follow-up CT scan (Figure 1) revealed a mildly nodular liver surface contour suggestive of cirrhotic found one of seventeen lymph nodes involved. She was changes, but no focal hepatic lesion. The physical examina- treated with adjuvant Taxotere and Cytoxan chemotherapy tion revealed no icterus, hepatomegaly, or splenomegaly. for 6 cycles and then completed adjuvant external beam radi- There were no stigmata of chronic liver disease and no aster- ation therapy to the chest wall and axilla in 25 fractions. The patient took two years of adjuvant aromatase inhibitor ther- ixis. The chest portion of the CT revealed a few small peri- bronchovascular nodules in the inferior left lower lobe and apy and stopped due to arthralgia. stable vertebral body bone lesions. The laboratory data at The patient presented to her oncologist with new pain in the same time revealed that the serum bilirubin rose to the pelvis 5 years after the initial diagnosis (March 2015). A 2.5 mg/dL from a baseline of 1.0 mg/dL two months prior. bone scan and CT scan revealed widespread metastatic dis- ease limited to the bones. A biopsy of the left iliac crest con- The alkaline phosphatase rose to 343 U/L from 180; the aspartate aminotransferase (AST) and alanine aminotrans- firmed metastatic ductal adenocarcinoma of breast origin ferase (ALT) remained within normal limits at 40 and 21, which remained 100% positive for the estrogen receptor respectively. The albumin was 3.0 g/dL, the PT was 14.6 s and 100% positive for the progesterone receptor and negative 2 Case Reports in Oncological Medicine Figure 2: MRI demonstrating course texture (VIBE axial image post gadolinium). Figure 1: CT demonstrating ascites and mildly nodular liver surface tic tissue response that was diffusely infiltrated by nests of contour (oral and IV contrast present). intermediate grade ductal adenocarcinoma with multiple intracytoplasmic lumens which recapitulated breast tissue appearance. Immunohistochemical stains for estrogen recep- (normal is 9-13), the PTT was 39.1 (normal is 27.8-37.6), and the conjugated bilirubin was 1.0 (0-0.5 mg/dL). The serum tor and progesterone receptor demonstrated positivity in level of cancer antigen (CA 15-3) rose from 285 to 100% and 90% of tumor cells, respectively (Figure 3). An 381 U/mL. Alpha fetoprotein was 7 and CA-125 was 4. Other additional immunohistochemical (IHC) stain with mamma- tumor markers were not checked at the time of the evaluation. globin (not shown) was 1+ positive, further supporting a breast origin for the malignant cells. HER2 was not amplified Upon finding evidence of a suddenly cirrhotic appear- ance of the liver in the absence of known liver disease, the by FISH. The morphology and IHC stains were completely patient underwent evaluation for primary and secondary concordant with the original tumor morphology and recep- causes of cirrhosis. She had a negative workup for hepatitis tors. Ascites fluid at the same time was cytologically negative A, B, C and HIV. She had normal iron studies, except for for malignant cells. Serial scans did not detect other primary cancer aside from the breast cancer. an elevated ferritin of 1,102 ng/mL. She was a nondrinker and nonsmoker who did not use herbal medications or drugs The patient was treated with paracentesis for symptom and had not received hepatotoxic agents. She had no interna- control. She was offered palliative chemotherapy, but ulti- tional travel, chemical exposures, or farm work. She did not mately declined additional therapies in order to pursue a report any insect or animal exposures and she had no sick comfort-based approach. Given her preference for palliative care, the patient did not undergo esophagogastroduodeno- contacts. She had no family history of liver disease, hemo- chromatosis, Wilson’s disease, or alpha-1 antitrypsin. She scopy (EGD) screening for varices. was seen by a hepatologist who tested immunoglobulins, erythrocyte sedimentation rate (ESR), and antinuclear anti- 2. Discussion body to rule out autoimmune hepatitis. The autoimmune panel was only notable for a mildly elevated ESR of 50 (nor- The liver is a common location of metastatic disease in solid mal 0-30), but that finding was blamed on known metastatic tumor oncology. Hepatic metastases usually demonstrate cancer to bones. The hepatologist did not deem her likely to discrete mass lesions and are sometimes painful when they have CMV, EBV, or other viral etiology given lack of extrahe- involve the capsule of the liver [1]. On the other hand, patic findings on CT and lack of symptoms/fevers/weight descriptions of occult metastatic carcinomatosis of the liver loss/lymphadenopathy and lack of immunosuppression. An such as characterized in this case report have not been widely ultrasound of the liver was performed and failed to detect a reported (see Table 1 for literature review). A few published focal liver lesion, gallstones, biliary obstruction, or abnormal cases have described a diffuse infiltration of the liver by duc- blood flow. She next had gadolinium-enhanced magnetic tal or lobular breast cancer but often not found until the time resonance imaging (MRI) of the liver (Figure 2), which dem- of an autopsy [2–6]. The first report of occult, diffuse liver onstrated a nodular liver surface contour and a fibrotic invasion of any histology was described by Watson in 1955 appearance of the hepatic parenchyma. No masses were involving several cases of disseminated bronchogenic carci- detected within the liver. The abdominal vasculature was noma leading to fulminant liver failure [7]. Since that time, normal in caliber and all the arteries, veins, and portal vessels carcinomatosis or sinusoidal infiltration of the liver (also were patent. New ascites was seen. termed hepar lobatum carcinomatosum) has been reported Given the lack of a mass in the liver and lack of intrinsic due to primary tumors of the colon, pancreas, lung, stomach, liver disease found by any serology or lab testing, there was kidney, adrenal, ovary, breast, and lymphomas [8]. Occult concern for radiographically occult metastasis to the liver. involvement of the liver due breast cancer has been described Thus, the patient next underwent a random percutaneous only in case reports and has been too rare to formally study liver biopsy under ultrasound guidance. The random liver [2,3,5, 6,9–18]. Unfortunately, no authors have been able biopsy revealed liver parenchyma disrupted by a desmoplas- to elucidate common risk factors nor common shared Case Reports in Oncological Medicine 3 (a) (b) (c) (d) Figure 3: Diffusely infiltrating nests of intermediate-grade ductal adenocarcinoma with disrupted hepatic parenchyma (H&E) ((a) 100x and (b) 400x). Tumor cell nests staining for estrogen (c) and progesterone (d) receptors. biologic features (Table 1). Loss of E-cadherin appears com- itive radiographic evidence and perhaps also due to the indo- mon, but our case like others had histologic evidence of the lent rate of progression of some estrogen-driven breast breast cancer cells attempting to recapitulate round ductal cancers [4]. Detection of liver metastases may also be delayed structures which is not typically seen in breast cancer which in the modern era of CDK4/6 therapy whereby the interval of is lacking E-cadherin [9, 16]. It is believed that breast cancers cross-sectional imaging may be extended beyond the historic three-month timeframe. We recommend performing MRI of downregulate (or lose) E-cadherin as cells from the primary tumor gain access to the angiolymphatic system in the pro- the liver when breast cancer patients first demonstrate inex- cess of epithelial to mesenchymal transition (EMT). Cancer- plicable rises in liver function tests or any other abnormality ous cells may then reexpress E-cadherin at the metastatic of the liver on standard CT imaging. The MRI may be niche by mesenchymal to epithelial transition (MET) [19]. followed by liver biopsy whenever liver enzymes remain ele- We hypothesize that this is the process that we observed in vated in the setting of inexplicable liver contour changes in a the liver of our patient. We also point out that other adhesion metastatic breast cancer patient. molecules (VCAM-1, P-cadherin, and ICAMs and selectins Our literature review suggests that extensive liver involvement is sometimes seen in breast cancer patients such as E-selectin and integrins such as LFA-a and VLA-4) and chemokine receptors (CXCR4, CCR6, and CCR7) have after prolonged intervals without overt disease progression. been speculated to be involved in the homing of breast cancer Subtle signs of liver involvement may include weight cells to the liver and warrant additional research. changes, subclinical bleeding from varices, slow accumula- This case report highlights the challenging clinical diag- tion of ascites, jaundice, and even slowly progressive hepatic encephalopathy [13, 20]. In retrospect, there is suspicion nosis of occult liver involvement by breast cancer when radiographic imaging fails to detect any mass forming lesions that our case of occult liver infiltration may have developed in the liver. It should be pointed out that rapidly progressive subtly over 6-12 months with the only indicator being subtle liver failure in estrogen receptor-positive breast cancer is increases in bilirubin and alkaline phosphatase values to less atypical and warrants a thorough diagnostic workup. Com- than one time the upper limit of normal. It is worth pointing out that there are also existing reports of de novo diagnosis monly, the cross-sectional imaging done for metastatic breast cancer demonstrates either discrete lesions within the liver or of breast cancer made upon finding occult hepatic involve- occasionally the sequelae of regressed hepatic lesions with ment [11, 14]. capsular retraction and decrease in the liver size. Indeed, liver Regardless of whether metastatic liver carcinomatosis is involvement by breast cancer has often only been able to be an early or late complication of breast cancer, the prognosis is currently deemed to be quite poor and is generally less than identified postmortem owing to the occasional lack of defin- 4 Case Reports in Oncological Medicine Table 1: Summary of literature reports of diffuse and/or occult liver involvement by metastatic breast cancer. Time E-cad Authors Age Receptors Concurrent diagnoses/presentation/notes Imaging from 1 Histology Ref loss Dx Cirrhosis on MRI, no focal Jungst et al., 2013 70 NA Diabetes, variceal bleeding NA 7 yr Ductal+lobular [13] lesion Poorly Allison et al., 2004 42 ER-, PR- Tobacco abuse, thrombocytopenia Yes Not performed 0 yr [9] differentiated Poorly Allison et al., 2004 54 NA Ascites, jaundice, hematochezia Yes Multiple masses on CT 9 yr [9] differentiated Poorly Allison et al., 2004 36 NA Nausea/vomiting/abd pain and jaundice Yes Small masses on CT 9 mo [9] differentiated Hanamornroongruang 49 ER+, PR+ Weight loss, jaundice, abd pain Yes CT without mass 10 yr Ductal, stage I [2] and Sangchay, 2013 Martelli et al., 2000 53 ER+, PR+ Dyspnea, fever NA Hepatomegaly on US 4 yr Ductal [3] Fatigue, weakness, abdominal distention/jaundice, Mogrovejo et al., 2014 67 ER+, PR-, HER2- No CT ascites 21 yr Ductal+lobular [4] lower extremity edema Poorly Borja et al., 1975 46 NA Jaundice, ascites, spider angiomata NA CT cirrhosis 3 mo [5] differentiated Hyperthyroid, ascites, thrombocytopenia, CT/US w/o mass, heterogeneous Graber et al., 2010 57 ER+, PR+, HER2+ Yes 0 yr Lobular [6] hyperbilirubinemia parenchyma CT with ascites, splenomegaly, Fournier et al., 2010 52 ER+, PR-, HER2- Bone mets from breast cancer, abdominal fullness NA 5 yr Ductal, stage II [10] but no liver abnormality CT hepatomegaly, periportal Goswami et al., 2011 38 ER-, PR+, HER2+ Malaise, lethargy, sore throat, dyspnea NA 0 yr Ductal, grade 2 [11] nodes Morrison and 57 NA Rapid fulminant hepatic failure NA NA 0 yr Carcinoma NOS [14] Pennington, 1984 Drowsiness, disorientation, lymphangitic cancer CT normal liver, laparoscopic Nakajima et al., 2005 68 NA NA 8 mo Ductal, stage I [15] spread to lungs slight cirrhosis US w/o mass, reversal of portal Nascimento et al., 2001 62 NA Ascites, edema NA 13 yr NA [16] flow, MRI w cirrhosis Nausea, vomiting, abdominal girth increase, CT neg for lesions, MRI w Mucinous, poorly Nascimento et al., 2001 46 NA NA 5yr [16] disseminated intravascular coagulopathy cirrhosis differentiated Jaundice, dark urine, acholic stool, and abdominal CT nodular contour c/w Sass et al., 2007 55 ER+, PR-, HER2- NA 4 yr Ductal, stage I [17] distension cirrhosis, no focal lesion Shivashankar and 66 ER+, PR+ Abdominal distention, hepatomegaly NA CT with cirrhosis, but no mass 8 yr NA [18] Sweetser, 2012 Bone mets from breast cancer, no presenting Current case 69 ER+, PR+, HER2- Yes Cirrhosis on CT, US and MRI 9 yr Ductal symptom, eventual leptomeningeal metastases NA: not available; E-cad: E-cadherin; ER: estrogen receptor; PR: progesterone receptor; Ref: reference number; NOS: not otherwise specified; CT: computerized tomography; MRI: magnetic resonance imaging. Case Reports in Oncological Medicine 5 [8] P. Jha, L. Poder, Z. J. Wang, A. C. Westphalen, B. M. Yeh, and 6 months overall and less than 3 months when evidence of F. V. Coakley, “Radiologic mimics of cirrhosis,” American hepatic failure is present [6, 9, 12]. Treatment options are Journal of Roentgenology, vol. 194, no. 4, pp. 993–999, 2010. limited due to the fact that most cytotoxic chemotherapy is [9] K. H. Allison, C. L. Fligner, and W. T. Parks, “Radiographically difficult to administer in the setting of hepatic impairment. occult, diffuse intrasinusoidal hepatic metastases from primary Likewise, the CDK4/6 inhibitors and the mTOR inhibitors breast carcinomas: a clinicopathologic study of 3 autopsy cases,” are not recommended in Child-Pugh class C hepatic impair- Archives of Pathology & Laboratory Medicine,vol. 128,no.12, ment. Liver transplant is currently not indicated for patients pp. 1418–1423, 2004. with diffuse metastatic disease. [10] C. Fournier, G. Tisman, R. 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