A case of diffuse hepatocellular carcinoma

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Introduction

According to V.V. Breder et al. [1], hepatocellular carcinoma (HCC) is the most common malignant liver tumor, and in most cases, liver cancer develops against the background of chronic viral hepatitis and liver cirrhosis (about 85 % of cases)¹. Quite rarely does HCC affect healthy liver tissue.

In 2020, HCC ranked sixth among all malignant tumors worldwide, and its mortality rate is third, which necessitates the development of prevention measures, early diagnosis, and improved treatment methods. Annually, more than 6,000 patients with a HCC diagnosis are identified in Russia [2–4].

The tumor can take three forms: nodular, massive and diffuse, the latter is more common in the West [5–7]. Timely diagnosis of the diffuse type of HCC presents great difficulties for medical practitioners. Here is a clinical case study.

Clinical case

Patient X. was urgently admitted to the gastroenterology department of a city hospital with complaints of weakness, right upper quadrant pain, shortness of breath during moderate physical exertion, heartburn, air burping, jaundice of the skin and sclera, abdominal distension, loss of appetite and nausea. She had been suffering from psoriatic polyarthritis for over 10 years and had been taking methotrexate for a long time. Over the past few months, she began to notice increased pain in the right upper quadrant, weakness, shortness of breath, swelling of the lower legs and feet, and abdominal distention; she denied alcohol consumption and did not have a history of viral hepatitis.

An outpatient examination revealed a slight increase in the level of transaminases (ALT and AST), as well as hyperbilirubinemia. A blood test showed leukocytosis with a stab shift. An ultrasound examination of the abdomen showed diffuse changes in the liver, marked hepatosplenomegaly and splenic vein dilatation.

Due to the lack of effect from outpatient treatment and the worsening of symptoms, the patient was hospitalized for diagnosis verification. Additional examinations were performed to confirm the diagnosis and rule out chronic hepatitis, liver polycystosis, liver abscess, and malignant liver disease.

On admission, the patient's condition was assessed as moderate. Jaundice of the skin and mucous membranes was noted, as well as multiple telangiectasias. Auscultation of the lungs revealed vesicular breathing, but it was weakened in the lower parts on the right. The pulse was satisfactory, and blood pressure was normal. Signs of a bulging liver and an enlarged venous network on the abdomen were found. Palpation of the abdomen revealed an enlarged liver that occupied the entire abdominal cavity to the navel, and the spleen could be palpated with difficulty.

The results of laboratory and instrumental tests conducted in the hospital showed the following: a mild normochromic anemia, leukocytosis up to 27 000, without a stab shift, were detected in the blood test. Proteinuria up to 0.35 g/l and bacteriuria caused by E. coli growth were found in the urinalysis. A biochemical blood test showed minimal cytolysis, pronounced cholestasis (alkaline phosphatase – 1202 U/L, gamma-glutamyl transpeptidase – 1634 U/L), hyperbilirubinemia – up to 101 μmol/L, mainly due to direct bilirubin, as well as an increase in C-reactive protein level up to 299 mg/L. Viral hepatitis markers are negative. Prothrombin index and fibrinogen are within normal limits. Alpha-fetoprotein level is normal (7.04 ng/mL), antibodies to Echinococcus granulosus IgG – 0.08 CU. Blood culture for sterility was performed three times and no growth was detected.

The patient did not show an increase in alpha-fetoprotein levels. In 20 % of cases with hepatocellular carcinoma, the level of this marker is significantly elevated (more than 400 ng/ml), and in almost half of cases it does not exceed 20 ng/ml. Alpha-fetoprotein level can also rise in other liver diseases, including viral hepatitis, as well as some other cancers (germ cell tumors), and during pregnancy [8; 9].

During the patient’s stay in the hospital, there was an increase in cytolysis (especially due to AST exceeding 10 norms) and bilirubin levels up to 151 μmol/L (mainly due to indirect bilirubin up to 101 μmol/L). High levels of alkaline phosphatase and gamma-glutamyl transpeptidase persisted, while there was a slight decrease in C-reactive protein level to 173 mg/L.

Chest X-ray examination revealed a small amount of fluid in the lateral sinuses on both sides. An ultrasound examination of the abdominal cavity organs showed an enlarged liver (oblique vertical size is 255 mm) with uneven contours and medium-grained with homogeneous echo structure. Diffuse changes in the pancreas and lymph nodes of the hepatic hilum were found, ascites was absent. Fibrogastroduodenoscopy revealed signs of grade 1–2 Candida esophagitis according to Kodsi and erosions of the antrum of the stomach. Varicose veins were not detected. To differentiate between liver cirrhosis and malignant liver tumor, multislice computed tomography of the abdominal organs, retroperitoneal space and small pelvis with contrast enhancement was performed.

In the multislice computed tomography series, the liver is located in a typical position and is enlarged: anteroposterior size is up to 8.9 cm, oblique caudal size is up to 16.2 cm for the left lobe, and for the right lobe anteroposterior size is up to 21.4 cm and oblique caudal size is up to 25.0 cm. The contours are clear, uneven, and the edges are rounded. The structure of the parenchyma is heterogeneous due to diffuse lesions with hypodense multi-sized foci. Some of them merge, forming partitions of various thicknesses. Most of the formations have clear even contours. Hyperdense inclusions are noted in single formations. Contrast agent accumulation in the unaffected part of the parenchyma is uniform, but contrast does not accumulate in hypodense foci. Bile ducts and veins are dilated normally. The spleen is located regularly and sized within normal limits. Portal and splenic veins are not dilated. Free fluid was found in the abdominal cavity in the form of a thin strip parahepatically along the lateral surface and in the Douglas space.

Multislice computed tomography shows an enlarged liver with diffuse formation of cysts, which probably corresponds to liver polycystosis. Several of these cysts have complications such as hemorrhages into the walls and contour contrasting. There is also an increase in lymph nodes at the hepatic hilum, a small amount of fluid in the abdominal cavity, and pleural effusion on both sides of the chest (Fig. 1).

 

Fig. 1. MSCT image of liver damage

 

Despite the intensive therapy, there was a rapidly progressive deterioration of the patient's condition, which led to her death.

The following is the result of a postmortem histological examination of liver tissue: «The tumor is represented by fields of large cells that do not form ordered trabecular structures, with large nuclei. Many cells contain mitotic figures, including atypical ones. The cell nuclei are characterrized by pronounced polymorphism, many of them contain large eosinophilic nucleoli. Along with atypia and high mitotic activity, there is a high nuclear-cytoplasmic ratio (ratio of nucleus area to cytoplasm). Cells are located both in groups and isolated, separated by narrow layers of stroma (Fig. 2). Tumor tissue with abundant vascularization (Fig. 3). In many vessels, tumor emboli are found (Fig. 4). Histological conclusion: poorly differentiated hepatocellular carcinoma (G3), multifocal tumor growth».

 

Fig. 2. Pronounced cellular and nuclear polymorphism, high nuclear-cytoplasmic ratio. Stained with hematoxylin and eosin, magnification 400x

 

Fig. 3. Abundance of full-blooded vessels in the layers of connective tissue. Stained with hematoxylin and eosin, magnification 400x

 

Fig. 4. Tumor emboli in the vessels among the tumor tissue. Stained with hematoxylin and eosin, magnification 400x

 

Results and discussion

Diagnosing the diffuse form of HCC with multifocal growth presents significant challenges due to the lack of a specific clinical picture of the disease. As a rule, at the beginning of development, the tumor is asymptomatic due to the high compensatory response of liver tissue. It is known that even in the presence of large metastases in the liver, clinical and laboratory indicators may differ little from normal, and the pain syndrome is absent for a long time [8; 9]. This leads to patients not paying attention to mild manifestations of dyspepsia and not seeking medical help. Over time, symptoms become more pronounced and noticeable: pains most often occur due to tumor invasion into anatomical structures, including large vessels, formation of tumor thromboemboli, and metastases in organs. The main complaints in the late stages of the disease are general weakness, lethargy, rapid fatigue, jaundice, increased abdominal volume, discomfort and pain in the right upper quadrant, as well as fever and lower limb edema. HCC is most often detected in advanced stages. The range of manifestations may be due to underlying liver diseases such as chronic hepatitis, cirrhosis, taking medications, as well as complications of the tumor process. In this case, the patient did not have any underlying liver diseases.

Perhaps, long-term use of methotrexate was a triggering factor for the development and rapid progression of the tumor process.

Diffuse tumor growth in the liver made ultrasound verification difficult, MSCT is a more informative method of instrumental diagnostics, but strict adherence to the contrasting technique is very important. In this case, the lack of CT verification may be due to a violation of the contrasting technique. The MSCT series do not show early and late arterial phases or venous phase, which is unacceptable when differentiating malignant processes in parenchymal organs. Strict adherence to the contrast protocol in most cases facilitates visualization of tumors and differential diagnosis of benign and malignant liver lesions.

Conclusions

The diffuse form of HCC presents great difficulties for timely clinical diagnosis due to a prolonged asymptomatic period, the absence of specific clinical and biochemical manifestations, as well as not always obvious signs during CT imaging. Late tumor diagnosis is also due to rapid progression and low life expectancy rates in patients [10–14].

 

¹ Clinical guidelines Liver cancer. Association of Oncologists of Russia, Interdisciplinary Society of Liver Tumor Specialists, All-Russian Public Organization «Russian Society of Clinical Oncology», All-Russian Public Organization for the Promotion of the Development of Radiation Diagnostics and Therapy «Russian Society of Radiologists and Radiologists». Moscow. 2022 (published on 07/22/2022 by the Ministry of Health of the Russian Federation).

About the authors

E. I. Voronova

E.A. Vagner Perm State Medical University

Author for correspondence.
Email: lizikvoronova@mail.ru
ORCID iD: 0000-0002-4156-9610

PhD (Medicine), Associate Professor of the Department of Internal Medicine and Family Medicine

Russian Federation, Perm

G. G. Friend

E.A. Vagner Perm State Medical University

Email: lizikvoronova@mail.ru
ORCID iD: 0000-0002-2861-4878

DSc (Medicine), Professor, Head of the Department of Pathologic Anatomy with a Section Course

Russian Federation, Perm

A. D. Pastuchov

E.A. Vagner Perm State Medical University

Email: lizikvoronova@mail.ru

PhD (Medicine), Associate Professor of the Department of Oncology, Radiodiagnosis and Radiotherapy with the Course of Radiology

Russian Federation, Perm

D. Yu. Sosnin

E.A. Vagner Perm State Medical University

Email: lizikvoronova@mail.ru
ORCID iD: 0000-0002-1232-8826

DSc (Medicine), Professor of the Department of Faculty Therapy № 2, Occupational Pathology and Clinical Laboratory Diagnostics

Russian Federation, Perm

Ya. B. Khovaeva

E.A. Vagner Perm State Medical University

Email: lizikvoronova@mail.ru
ORCID iD: 0000-0003-1186-3867

DSc (Medicine), Professor, Head of the Department of Internal Medicine and Family Medicine

Russian Federation, Perm

E. N. Kazachenko

City Clinical Hospital No. 2 named after F.H. Gral

Email: lizikvoronova@mail.ru
ORCID iD: 0009-0000-7105-8224

PhD (Medicine), Head of the Department of Gastroenterology

Russian Federation, Perm

N. P. Moiseenko

E.A. Vagner Perm State Medical University

Email: lizikvoronova@mail.ru
ORCID iD: 0000-0002-9836-9548

PhD (Medicine), Associate Professor of the Department of Internal Medicine and Family Medicine

Russian Federation, Perm

References

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