Spontaneous Tumor Lysis Syndrome in a Case of Hepatocellular Carcinoma with Sarcomatoid Differentiation

Abstract

Sarcomatoid hepatocellular carcinoma is a rare histologic variant of primary liver cancer comprising of malignant spindle cells and typical hepatocellular carcinoma (HCC). In terms of clinical presentation, they usually exhibit extensive tumor burden due to their larger size and a metastatic disease at the time of diagnosis as compared to conventional HCC. Tumor lysis syndrome is an oncological emergency, usually seen after cytotoxic chemotherapy in haematological malignancies. Here, we highlight a case of 76-year old male with no comorbidities, presenting with an excruciating backache and a paravertebral soft tissue mass and multiple osteolytic lesions, was clinically suspected to be a plasma cell neoplasm. On further evaluation, the patient was diagnosed of a sarcomatoid variant of hepatocellular carcinoma. This report showcases multiple rare findings by the presence of non-specific symptoms, non-cirrhotic liver, normal serum alpha protein levels and the occurrence of a spontaneous tumor lysis syndrome in a solid malignancy.

Introduction

Hepatocellular carcinoma (HCC) is the most frequent malignant lesion of liver, occurring in a cirrhotic background. The 5th edition of World Health Organization classification of digestive system tumors defines sarcomatoid HCC under the special HCC types including fibrolamellar carcinoma, scirrhous, undifferentiated carcinoma, and lymphoepithelioma-like carcinoma. Some of these variants are associated with a poor prognosis and a higher rate of recurrence and metastasis that significantly affect management in the era of precision medicine. The sarcomatoid variant of carcinoma is infrequent and can be seen in any organ where carcinomas tend to occur, such as lung, breast, skin, gastrointestinal and female genital tract. By definition, the sarcomatoid variant of carcinoma has to have both epithelial and mesenchymal differentiation in the same lesion. In recent years, the incidence of HCC with sarcomatoid change has increased markedly, the incidence is around 1.8–2.0% in surgical resected specimens and 3.9–9.4% of the autopsy cases [1, 2].

Case History

A 76-year old gentleman, with no comorbidities presented to the emergency department with an excruciating backache visual analog scale (VAS score 6/10) for the last 2 days. The pain started around a month back, initially was dull aching in nature, not well localized and radiating to the lower back. It has progressed to the present stage, intolerable in nature, not getting relieved with non-steroidal anti-inflammatory drugs. This was accompanied by decreased appetite, significant weight loss and yellowish discoloration of urine. There were no complaints of fever, abdominal pain, itching or any sensory, motor weakness, bladder and bowel symptoms. He gave no history of chronic medical illnesses; there was no drug or family history of note. Magnetic resonance imaging (MRI) of spine revealed paravertebral soft tissue mass impinging over thoracic vertebrae (D1-D9) with associated destructive changes. The first clinical suspicion was multiple myeloma; however, serum and urine protein electrophoresis were within the normal range. Patient underwent positron emission tomography (PET) scan for disease evaluation, which revealed fluorodeoxyglucose (FDG) avid destructive changes involving D1-D9 vertebrae along with a soft tissue component extending into the paravertebral region (Fig. 1a,b). This was associated with erosions along the left 3rd to 5th ribs and soft tissue thickening in posterior mediastinum along the pleura. Focal increased FDG uptake was also observed at anterior ends of right 4th, 8th rib with subtle lytic changes. FDG avid bilateral supraclavicular, cervical and left axillary lymph nodes were also seen. A hypodense mass measuring 5.8 × 5.7 cm, SUVmax 7.7 was noted involving segment IVB/V of liver (Fig. 1c). This was associated with multiple soft tissue lesions, likely nodal masses in peritoneum, periportal region encasing the portal vein and the aortocaval region infiltrating along crus of diaphragm. Few deposits were also seen in left paraspinal region in neck and right lower neck region. PET/CT scan findings favored a malignant lesion. Laboratory investigations revealed increased serum uric acid (0.76 mmol/l) (Normal range- 0.24–0.51 mmol/L), serum creatinine (424.2 mmol/l) (Normal range- (44.21—132.6 mmol/L), serum phosphorus (1.7 mmol/L) (Normal range-0.9 to 1.4 mmol/L), however, serum calcium (2.3 mmol/L) (Normal range-2.2 to 2.7 mmol/L) was in the normal range. Serology for viral hepatitis including HBsAg, HBcAb, and HCV-Ab was negative. The patient denied any past medical history and did not take any medication in the last one year. Coagulation profile was deranged (Prothrombin time 18.6 s and INR 2.3), suggestive of disseminated intravascular coagulation. Serum biomarkers (Prostate-specific antigen (PSA), Cancer antigen (CA) 19.9, carcinoembryonic antigen (CEA) were within normal limits. Surprisingly, serum Alpha-fetoprotein (AFP) level was within normal limits. The lab values were indicative of tumor lysis syndrome; thus, patient was initially started on iv hydration with febuxostat 40 mg twice daily. Since, the coagulation parameters were abnormal, tru-cut biopsy from the liver mass was aborted. PET-CT report was discussed with the multidisciplinary team consisting of medical oncologist, surgical oncologist, nuclear medicine physician and pathologist. In view of increased FDG avidity of supraclavicular nodes, it was decided to attempt biopsy from the same, after correction of coagulopathy with fresh frozen plasma transfusion and vitamin K. Ultrasound guided biopsy from right supraclavicular lymph node was obtained and sent for histopathological examination. Sections showed an effaced lymph nodal architecture with presence of tumor cells arranged in sheets and scattered singly. The malignant cells were large, round to polygonal and at many places exhibited spindled morphology (Fig. 2a). Tumor cells showed markedly pleomorphic nuclei and moderate to abundant eosinophilic cytoplasm. Few of the cells showed prominent nucleoli. Numerous bizarre cells along with atypical mitotic figures were observed (Fig. 2c). No heterologous element was seen. Morphological features were suggestive of a poorly differentiated malignant tumor. A panel of immunohistochemical stain was applied to know the primary. The tumor cells were positive for CK, Vimentin, Arginase and were negative for CK7, CK20, HepPar-1, S-100, HMB-45, CDX2, Synaptophysin, p63, CK19 and CD34 (Fig. 3a–d). Ki-67 proliferative index was 30–35% (Fig. 3e). Immunohistochemical findings favored a metastatic sarcomatoid carcinoma. In view of CK7/CK20 negativity, arginase positive, CK and vimentin positivity, a final diagnosis of metastatic sarcomatoid carcinoma of hepatic origin was proffered. The patient succumbed to illness during his 11th day of hospitalization.

Fig. 1.

a–b Coronal and sagittal PET scan view showing FDG avid destructive changes involving D1-D9 vertebrae along with a soft tissue component extending into the paravertebral region, associated with erosions along the left 3rd to 5th ribs and soft tissue thickening in posterior mediastinum along the pleura; c Hypodense mass involving segment IVB/V of liver

Fig. 2.

a Low power view showing an effaced lymph nodal architecture with tumor cells arranged in sheets and scattered singly (HE 40x); b High power view showing large, round to polygonal to spindled malignant cells with markedly pleomorphic nuclei, moderate to abundant eosinophilic cytoplasm. Occasional cell showing prominent nucleoli (HE 400x)

Fig. 3.

Immunohistochemical stain- (a) Cytokeratin: Positive (400x); b Vimentin: Positive (400x); c HepPar-1: Negative (400x); d Arginase: Positive (400x); e Ki67 proliferative index- 30–35% (400x)

Discussion

Hepatocellular carcinoma, although an aggressive tumor has a varied clinical presentation, ranging from asymptomatic disease to life-threatening illness. Most of the patients have established risk factors including chronic liver disease (hepatitis B/ C viral infection), heavy alcohol drinking and non-alcoholic fatty liver disease. Furthermore, majority of the symptoms and signs are often due to an underlying cirrhosis, for example jaundice, abdominal fullness or a palpable mass. They generally exhibit an elevated or rising trends of serum alpha-protein levels. Non-cirrhotic HCCs are relatively more advanced at the time of diagnosis and are usually detected due to the occurrence of cancer-related symptoms [3]. Sarcomatoid carcinoma, although a rare type of malignant tumor, is characterized by the morphological presence of both epithelial and mesenchymal elements. This variant has been described in a wide range of organs, most commonly being lung. The diagnosis of sarcomatoid hepatocellular carcinoma (SHC) requires a meticulous histopathological examination and an extensive immunohistochemical work up.

Although, the exact etiology is unknown, the previous published reports have elucidated the sarcomatous appearance to be an outcome of various anti-cancer therapies, including trans arterial chemoembolization (TACE), radiofrequency ablation (RFA), or percutaneous ethanol injection, advocating that recurrent therapies likely to promote sarcomatoid transformation of HCC [4, 5]. Interesting, some of HCV-associated neoplasms have also shown sarcomatous change by the phenomenon of epithelial-mesenchymal transition (EMT) [6].

The present case was non-alcoholic, with no typical signs and symptoms without any chronic liver disease. The other striking feature was the presence of normal serum AFP levels and a non-cirrhotic hepatic parenchyma. The story does not conclude here, unanticipatedly, laboratory investigations revealed markedly elevated serum uric acid, creatinine and serum phosphorus, alarming us to the possibility of tumor lysis. Tumor lysis syndrome (TLS) is an abnormal metabolic complication caused by the rapid breakdown of tumor cells, either spontaneously or after the initiation of chemotherapy, leading to dyselectrolytemia in the form of elevated potassium, uric acid and phosphate levels along with decreased serum calcium. The massive release of intracellular chemical substances (nucleic acids, potassium, phosphorus) cause severe impairment in the functioning of vital organs, commonly leading to acute kidney injury (due to uric acid obstructive uropathy), fatal arrhythmias, cardiac arrest and even death. The criteria to define “laboratory TLS” and “clinical TLS” was put forward by Cairo-Bishop in 2004 (Table 1)[7]. The current case fits into the above mentioned criteria of laboratory and clinical TLS.

Table 1.

Cairo–Bishop definition of laboratory and clinical tumour lysis syndrome

Laboratory tumour lysis syndrome	Clinical tumour lysis syndrome
Uric acid ≥ 8.0 mg/dl	Acute kidney injury (AKI) (defined as creatinine > 1.5 × the upper limit of normal for patient age and sex)
Potassium ≥ 6.0 mEq/dl	Cardiac arrhythmia
Phosphorous ≥ 4.6 mg/dl	Seizure, tetany, or other symptomatic hypocalcaemia
Calcium ≤ 7.0 mg/dl

Patients must meet more than two or four laboratory criteria in the same 24-h period within 3 days before to 7 days after chemotherapy initiation. A 25% increase from ‘baseline’ laboratory values is also acceptable. Other causes of AKI (e.g. nephrotoxic exposure, obstruction) should be excluded

The clinical presentation and radiological findings of mesenchymal lesions of liver often overlap, thus careful attention to histological and immunohistochemical clues can assist weeding out various congeners to arrive at an accurate diagnosis. SHC is a rapidly progressing tumor resulting in an enormous, solid-cystic mass showing mixed density on CT. A lower-density shadow is likely an outcome of ischemia and necrosis within the tumor due to high cell turnover. Similarly, enhanced CT shows reduced signal intensity in the central mass, while rest of the tumor parenchyma shows a relatively higher signal intensity. Such enhancements are also evident at the margins of the arterial and delayed phases. SHC exhibits weak signal intensity on T1W1 MRI, but high signal intensity on T2W1 [8]. Although the utility of FDG-PET in staging the disease is not defined, however, occasional studies in literature have shown some correlation of higher FDG uptake with poor tumor differentiation, size, microvascular invasion and AFP levels [9]. Although terminologies like sarcomatoid carcinoma and carcinosarcoma have been synonymously used in the published papers, the term sarcomatoid carcinoma is preferred when the spindle cell component has some amount of epithelial differentiation (confirmed by IHC for epithelial markers such as cytokeratin and non-specific mesenchymal lineage). When the spindle cells show specific lineages in the sarcoma group, like malignant fibrous histiocytoma, chondro, fibro or rhabdomyosarcoma and no epithelial differentiation, then carcinosarcoma is preferred. In one of the literature reviews of 92 cases of sarcomatoid carcinoma in the liver, around one-third of the cases did not show any specific sarcoma type, on the contrary 79% cases had HCC as the epithelial compartment along with osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma, chondrosarcoma and embryonal sarcoma as the accompanying sarcomatous components [10]. The prognosis is quite unfavourable as compared to HCCs with classic histology and are relatively more advanced at the time of diagnosis. These tumors are mostly detected at an advanced stage and typically show a higher incidence of extrahepatic disease (e.g., lymph nodes, bone and lungs) compared to conventional HCC [11, 12]. This is further supported bya study by Liao et al. which reported a decremental survival pattern (1-, 3- and 5-year survival of 45.0%, 17.5% and 10%, respectively), and an increased recurrence and extrahepatic metastasis in sarcomatoid HCC vs non-sarcomatoid HCC [1].

Conclusion

In summary, sarcomatoid variant is an unfavourable form of HCC with dismal prognosis. At present, there is no specific and effective therapies for sarcomatoid HCC. Future studies are urgently needed for exploring more effective therapies in order to extend the survival period and improve the quality of life of patients with SHC.

Author Contribution

Conceptualization: RC, AV, SR, JS, MAO.

Data curation: RC, JS.

Project administration: AV, SR, JS.

Writing-original draft: RC, MAO.

Writing-review & editing: RC, MAO.

Approval of final manuscript: RC, AV, SR, JS, MAO.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declarations

Ethical Standards

For this case report, formal consent from a local ethics committee is not required.

Patient Consent

The authors certify that they have obtained the appropriate consent from the patient. The patient has given his consent for the images and other clinical information to be reported in the journal. The patient understands that the name and initials will not be published, and due efforts have been made to conceal the same.

Conflict of Interests

The authors declare that they have no potential conflicts of interest to disclose.