Paraneoplastic Dermatomyositis in Patient with Primary Biliary Cirrhosis and Hepatocellular Carcinoma: A Case Report

Introduction

Dermatomyositis (DM) is an autoimmune disease characterized by distinctive skin eruptions, muscle involvement, and, in many cases, damage to various organs, as with interstitial lung disease, arthritis, and myocarditis. The prevalence of the disease varies between 1.97 and 21.5 cases per 100 000 population, depending on the geographic region [1,2], with peak morbidity occurring between the ages of 40 and 60 years. It presents 2.5 times more frequently in women than in men, with a female-to-male ratio of 2: 1 [3]. In the cases of paraneoplastic inflammatory myopathy, this ratio increases to 10: 1 in favor of women. In 15% to 30% of cases, DM is linked to an underlying neoplasm [4]. The risk of developing a carcinoma is highest within the first 3 years after the diagnosis of DM but remains elevated for more than 5 years thereafter [5]. The most frequently associated neoplasms affect the gastrointestinal tract, breast, lungs, and cervical canal of the uterus [6].

The most common symptom of DM is gradually progressive, painful, symmetrical proximal muscle weakness. It typically takes 3 to 6 months from the onset of the symptoms for patients to seek medical attention. In children and young adults, the disease can present with an acute onset, with symptoms developing over a few months, often accompanied by low-grade fever and asthenic syndrome. Other patients report mild muscle pain without significant muscle weakness. Amyopathic DM is a variant of the disease in which muscles are either unaffected or only mildly affected. This form is observed in about 20% of adult cases [7].

In idiopathic inflammatory myopathies, characteristic skin changes can be observed, which may precede muscle weakness by months. Pathognomonic for DM are Gottron papules, Gottron sign, and heliotrope face rash. Gottron papules are scaly, erythematous-livid papules and plaques localized over bony prominences, with a predilection for the extensor surfaces of the metacarpophalangeal joints, proximal interphalangeal joints, and distal interphalangeal joints of the hands [8]. Other researchers described these lesions as hyperkeratotic, flat, red papules with central atrophy [9]. Gottron sign refers to erythematous macular lesions in the same locations, as well as on the extensor surfaces of the elbows, knees, and ankles. These rashes are seen in 60% to 80% of patients with DM. The heliotrope rash is livid, edematous, or scaly, affecting the periocular areas and upper eyelids. Other characteristic skin manifestations include photosensitivity with diffuse erythema of the face, the “shawl sign” (rash on the nape, upper back, and shoulder areas), and the “V-sign” (photosensitive rash on the anterior chest, in the décolleté area, shaped like the letter V). The involvement of the nasolabial folds in the photosensitive erythema of the face in DM is important for differential diagnosis with the rash seen in systemic lupus erythematosus (SLE). The “holster sign”, located on the lateral surface of the hips and thighs, as well as “mechanic’s hands” (thickening and fissuring of the lateral and palmar surfaces of the hands) are other distinguishing skin manifestations of the disease [8]. Subclinical involvement of the heart is common in DM-polymyositis, but its frequency varies significantly depending on the diagnostic methods used. It manifests as arrhythmia, congestive heart failure, restrictive cardiomyopathy, and pericarditis/pericardial tamponade. Congestive heart failure is observed in 10% to 15% of patients with DM [10].

The exact pathogenesis of DM remains unknown. Growing evidence supports the role of interferon in idiopathic inflammatory myopathies. Increased expression of type I interferon is observed in the muscles, skin, and blood [11]. Antibodies specific to DM include anti-Mi2, anti-melanoma differentiation-associated protein 5 (anti-MDA5), anti-nuclear matrix protein 2 (anti-NXP2), anti-transcription intermediary factor 1 (anti-TIF1), and anti-small ubiquitin-like modifier activating enzyme (anti-SAE). In the antisynthetase syndrome, antibodies against transfer ribonucleic acid synthetases can be detected [12].

The frequent association between DM and cancer suggests a common pathogenetic mechanism, in which antigen mimicry between cancer cells and myocytes can trigger an inflammatory response, which is the basis for the development of the autoimmune disease [13].

Hepatocellular carcinoma (HCC) is one of the most common tumors, with an incidence of 1.4 to 3.0 cases per 100 000 population [14]. In Asia and Africa, the incidence of the disease reaches 30 cases per 100 000 [15]. The pathogenesis of the disease is not fully understood. There are several risk factors associated with the development of the disease, including chronic hepatitis C, chronic hepatitis B viral infection, alcoholic cirrhosis, advanced age, and male sex. The presence of cirrhosis is considered a major risk factor for the development of HCC, especially in advanced histological stages [16]. In the general population, the disease is often diagnosed late owing to the lack of pronounced and specific symptoms, as well as to the large functional reserve of the liver.

Primary biliary cirrhosis is a slowly progressive autoimmune disease characterized by a triad of chronic cholestasis, positive anti-mitochondrial antibodies, and a characteristic imaging or pathomorphological finding of non-suppurative destructive cholangitis and interlobular bile duct destruction. The incidence of primary biliary cirrhosis among women is 10 times higher than that in men [17]. The average age at diagnosis is 50 years [18].

Several authors report that primary biliary cirrhosis can be associated with HCC [19–21]. The data in the literature regarding the frequency of this comorbidity are contradictory, as primary biliary cirrhosis is a rare disease. Findor et al reported a frequency ranging between 1.4% and 4.9%, depending on patient sex [16]. Other researchers reported an incidence of HCC of 13 per 1000 person-years in patients with primary biliary cirrhosis [22].

We present a case involving a rare combination of these diseases, which often lack pronounced and specific symptoms. Increasing physicians’ familiarity with the clinical presentation of DM can facilitate earlier diagnosis, prompt appropriate investigations, and enable timely initiation of treatment, ultimately improving patient outcomes.

Case Report

We present the case of a 64-year-old woman. Her symptoms began in March 2023, with the appearance of rashes on the face and extremities, hair loss, generalized pruritus, and oral aphthae. She was treated for urticaria with antihistamines, but the symptoms did not improve. Following a pneumonia episode in January 2024, the skin eruptions were accompanied by generalized proximal muscle weakness, to the extent that she became unable to move independently, along with arthralgias. In April 2024, the patient was hospitalized consecutively in dermatology and rheumatology clinics, where, based on a facial erythematous rash, generalized pruritus, alopecia, arthralgias, and elevated rheumatoid factor of 42 (reference range <20), she received a diagnosis of SLE. The differential diagnosis considered an overlap between SLE and seropositive rheumatoid arthritis. Treatment with hydroxychloroquine 200 mg (1 tablet daily) and methylprednisolone 4 mg (2 tablets daily) was initiated, with good effect on the myopathic syndrome.

Owing to elevated cholestatic and cytolytic liver enzymes exceeding 3 times the upper reference limit (URL) during hospitalization, and negative markers for viral hepatitis, she was referred to a gastroenterological consultation. In May 2024, after hospitalization in the gastroenterology clinic, corticosteroid therapy was discontinued following computed tomography (CT) findings of newly diagnosed liver cirrhosis and a 3-cm hepatic lesion. Upper gastrointestinal endoscopy revealed grade III esophageal varices. Anti-mitochondrial antibodies were detected at a titer of 1: 1280. Considering a diagnosis of primary biliary cirrhosis, treatment with ursodeoxycholic acid (250 mg, 2 capsules twice daily) was initiated. The liver lesion was interpreted as a hepatic hemangioma, and a follow-up abdominal CT scan was recommended in 3 months. The patient’s comorbidities were ischemic heart disease, treated with trimetazidine dihydrochloride (35 mg, 1 tablet twice daily), and lumbar spine degenerative disc disease. No history of drug and alcohol abuse was recorded.

At the follow-up gastroenterology consultation 3 months later, further evaluation of a liver lesion suspicious for HCC was recommended. In September 2024, the patient was admitted to our gastroenterology clinic for a contrast-enhanced abdominal CT scan and an image-guided needle biopsy of the liver lesion.

On physical examination, the patient was afebrile and appeared to be alert and aware of place and time. Pulmonary auscultation revealed clear vesicular breathing without rales and a respiratory rate of 18 breaths per min. The cardiac rate was 72 beats per min, with regular rhythm; there were no murmurs, rubs, or clicks. The patient’s blood pressure was 110/70 mmHg. Skin examination revealed a livid heliotrope rash involving the periorbital area, upper eyelids, and scalp; Gottron papules on the extensor surfaces of the metacarpophalangeal, proximal interphalangeal, and distal interphalangeal joints (Figure 1); Gottron sign on the extensor surfaces of the elbows, knees, and ankles; and V-sign. Periungual capillary dilatation and cuticular hypertrophy was observed in the nailfold (Figure 2).

The abdomen was flat, soft, and non-tender, with physiological bowel sounds. The liver was palpable 2 cm below the costal margin, with a firm-elastic consistency and a sharp edge. The central nervous system and peripheral nervous system were functioning normally. Musculoskeletal assessment showed marked proximal muscle weakness, evidenced by a positive “chair test”, inability to lift the arms laterally from the sides of the body, and muscle hypotrophy in both upper and lower limbs. The remaining organ systems showed no abnormalities.

The laboratory test results revealed the following: aspartate aminotransferase of 126.0 U/L (reference range 5–40), alanine aminotransferase of 42.2 U/L (reference range 5–40), alkaline phosphatase (ALP) of 156 U/L (reference range 30–120), gamma-glutamyl transferase (GGT) of 72.8 U/L (reference range 10–40), and creatinine phosphokinase of 417.0 U/L. The tumor marker alpha-fetoprotein was slightly elevated, at 10.36 ng/mL (reference range 1.01–7.10). Serologic markers for hepatitis B and C were negative.

Abdominal contrast-enhanced CT showed a liver with a granular, hypodense structure with lobulated contours. In segment 7/8, a rounded lesion, which showed intense contrast enhancement in the arterial phase and demonstrated washout, with a diameter of 30 mm, was observed (Figure 3). There was no evidence of pathological dilation of the intrahepatic or extrahepatic bile ducts. The gallbladder was not enlarged, had thin walls, and contained a calcium-dense stone in the lumen, with a diameter of 8 mm. The portal vein measured 15 mm and was homogeneously contrast-enhanced. The pancreatic fat tissue appeared intact. The spleen was enlarged, with craniocaudal dimensions of 145 mm. An enlarged perihepatic lymph node with axial dimensions of 30×20 mm was noted. In conclusion, the CT findings were consistent with HCC, liver cirrhosis, and cholelithiasis.

The diagnosis of primary biliary cirrhosis was established based on the biochemical evidence of cholestasis (elevated ALP and GGT), contrast-enhanced CT scan showing a granular, hypodense liver with lobulated contours, exclusion of extrahepatic cholestasis, and the presence of anti-mitochondrial antibodies in the absence of serological evidence of viral hepatitis. According to the recommendations of the European Association for the Study of the Liver, invasive diagnostic procedures should be avoided in similar cases [23]. A percutaneous liver biopsy under ultrasound guidance was performed for further clarification of the tumor lesion. The pathomorphological examination of the biopsy specimen from the lesion showed large, polygonal cells with pale and finely granulated cytoplasm and a small, ovoid nuclei located in a sparse stroma with delicate vessels (Figure 4). A special Gomori stain was performed, revealing a loss of reticulin network and the formation of thick trabeculaes and pseudoglandular structures (Figure 5). The morphology was consistent with a well-differentiated hepatocellular carcinoma. A radiofrequency ablation was performed using 50 KJ of energy, with no complications observed.

Electromyography showed no spontaneous activity in the examined limb muscles. During voluntary activity, axonal potentials of short duration and low amplitude with myogenic characteristics were registered. Rapid recruitment was observed during maximal voluntary contraction. The patient was consulted by a rheumatologist, and a diagnosis of paraneoplastic DM was established. Therapy with methylprednisolone tablets (4 mg) was initiated at a daily dose equivalent to 30 mg of prednisone, resulting in rapid improvement of muscular symptoms, normalization of biochemical markers, fading of skin eruptions, and improvement in liver function from class B to class A, according to the Child-Pugh score.

Two months after the radiofrequency ablation (November 20, 2024), during which the patient was asymptomatic with improvement in muscle strength and functional capacity, she was admitted to the rheumatology clinic with a fever of up to 39°C, astheno-adynamia, and shortness of breath, with the symptoms persisting for 2 weeks. Physical examination revealed orthopnea, tachypnea, anasarca, and bilaterally diminished vesicular breath sounds, with abundant fine crackles paravertebrally and in both lung bases. Laboratory test results showed a constellation of findings consistent with an acute inflammatory process: C-reactive protein level of 188.61 mg/dL, B-type natriuretic peptide of 840 pg/mL, aspartate aminotransferase of 84.2, alanine aminotransferase of 44.9 U/L, ALP of 133.0 U/L, GGT of 46.2 U/L, creatinine phosphokinase of 72.0 U/L, and creatinine of 257 mg/dL.

Echocardiography was performed, revealing severe aortic insufficiency (pressure half-time 188 ms), tricuspid aortic valve with fibrotic changes, peak gradient of 18 mmHg, and preserved ejection fraction of 63%, with maintained left ventricular kinetics (left ventricle, 55/36 mm; wall thickness, 12 mm; end-diastolic volume, 146 mL; end-systolic volume, 55 mL; aortic annulus, 18 mm; ascending aorta, 33 mm; left atrium, 43 mm; mitral valve, fibrotic, moderate regurgitation; right ventricle, 33/32 mm; tricuspid annular plane systolic excursion, 22 mm; and tricuspid valve, moderate regurgitation). CT of the lungs showed bilateral inflammatory infiltrates and a right-sided pleural effusion, while abdominal CT revealed ascites. Etiologic treatment was administered, with antibiotics and diuretics.

The patient was discharged in stable condition, but 1 month later, the patient died due to severe, decompensated heart failure caused by a high-degree heart valve disease. The patient’s overall condition and associated comorbidities did not allow for surgical treatment or valve replacement.

Discussion

In the presented case, poor awareness of the symptoms of DM, combined with the absence of pronounced and specific signs of biliary cirrhosis and HCC, contributed to the late diagnosis and unfavorable patient outcome.

The association of DM with HCC is extremely rare [16,22]. The mechanism by which DM arises as a paraneoplastic syndrome remains unclear. The literature reports a link between anti-Mi2 antibodies, which are part of the nucleosomal remodeling and deacetylase complex, and DM (with a frequency of up to 31%) [24]. Some authors believe that anti-Mi2 antibodies may cross-react with HCC. Toshikuni et al reported a case of DM as a paraneoplastic syndrome in a 79-year-old woman with hepatitis C and primary HCC, in which there was an improvement in the clinical features of DM without steroid treatment of the inflammatory myopathy after resection of the neoplasm [25]. Myata et al reported the case of a patient with colorectal carcinoma, associated with DM [26]. Sumazaki et al described the role of antibodies against transcriptional intermediary factor 1γ, which are present in the serum of various cancer patients and are associated with paraneoplastic DM [27]. Apostolidis et al reported a case of DM and HCC in the context of alcoholic liver disease, treated with sorafenib [28]. Numerous case reports on the association between DM and neoplasms suggest that the presence of idiopathic inflammatory myopathy should serve as a red flag for an underlying malignancy. Patients must be thoroughly evaluated for carcinoma and closely monitored over time.

Another case was reported in which DM developed after starting D-penicillamine treatment for primary biliary cirrhosis [29], considered an autoimmune phenomenon induced by the drug. Several case reports in the literature describe DM induced by anti-neoplastic agents. The researchers suggest an immune-mediated mechanism, resulting from excessive autoimmune reactions by activated T cells, which can affect multiple organs, including the skin, lungs, thyroid gland, pituitary gland, and gastrointestinal system [30–33].

From 1995 to the present, 5 cases of DM in primary biliary cirrhosis have been reported [34–38]. While the cited authors report an overlap between the 2 diseases, we consider that, in our case, this was paraneoplastic DM in the context of HCC in a patient with primary biliary cirrhosis.

The diagnosis of primary biliary cirrhosis was based on CT data showing liver cirrhosis, positive anti-mitochondrial antibodies >3 URL and ALP >1.5 URL for a period longer than 24 weeks [23]. The tumor was staged as early Barcelona Clinic Liver Cancer (BCLC) A (single tumor up to 3 cm).

The BCLC system is the most widely used system for staging HCC, categorizing it into 5 clinical stages: very early stage (BCLC 0): single nodule under 2 cm, carcinoma in situ; early stage (BCLC A): single nodule or 3 nodules under 3 cm, performance status (PST) 0; intermediate stage (BCLC B): presence of multiple nodules, PST 0; advanced stage (BCLC C): portal invasion, N1, M1, PST 1–2; and terminal stage (BCLC D) [39].

The Child-Pugh scoring system is used as a predictive assessment of mortality in liver cirrhosis. Based on this system, patients are classified into 3 categories: class A, good liver function; class B, moderately impaired liver function; and class C, advanced liver dysfunction.

The system uses 5 clinical and laboratory parameters to categorize patients: serum bilirubin, serum albumin, ascites, encephalopathy, and prothrombin time/international normalized ratio (INR). These parameters are scored to assess the severity of liver disease and determine the prognosis [40].

The patient was assessed as class B according to Child-Pugh (7 points: ascites, 1 point; encephalopathy,1 point; hyperbilirubinemia >34, 2 points; hypoalbuminemia, 2 points; and low INR <1.7, 1 point). In October 2024, a radiofrequency ablation was performed for the treatment of HCC, according to the recommendations of the European Society for Medical Oncology [41].

The average life expectancy after diagnosis of HCC is less than a year. After therapeutic intervention, the survival rate for HCC is >5 years for stages 0 and A, 2.5 years for stage B, 2 years for stage C, and 3 months for stage D [42].

Each of the 3 diseases, along with their wide differential diagnoses, requires significant clinical expertise. In the differential diagnosis of skin lesions in DM, conditions to consider include discoid lupus erythematosus, subacute cutaneous lupus, psoriasis, rosacea, ocular cellulitis, lichen planus, cutaneous T-cell lymphoma, atopic dermatitis, and acute allergic contact dermatitis [43]. In the present case, the involvement of the nasolabial folds in the photosensitive erythema of the face in DM is important for differential diagnosis, with the rash seen in SLE. Not only the typical skin lesions, such as Gottron papule, Gottron sign, and V-sign, but also pronounced muscle weakness accompanied by extremity hypotrophy contribute to the differentiation between DM and SLE.

In the differential diagnosis of HCC, the following conditions should be considered: hepatic hemangioma, focal nodular hyperplasia, dysplastic nodules in cirrhosis, primary hepatic lymphoma, and focal steatosis. In the presence of atypical imaging appearances, it may not be easy to distinguish HCC from hepatic hemangioma and focal nodular hyperplasia [44].

The rapid deterioration of the patient’s general condition, as presented with severe congestive heart failure due to high-grade aortic insufficiency, along with the accompanying comorbidities, prevented surgical intervention and valve prosthesis placement.

Conclusions

This case report emphasized the rare combination of primary biliary cirrhosis, HCC, and DM, and highlights the importance of precise interpretation of pathogenetic findings by all specialists involved. Multiple diagnostic errors, coupled with the delayed detection of a high-grade valvular heart disease, reduced the likelihood of a favorable outcome.

In patients with multiple comorbidities, close collaboration between specialists and an interdisciplinary approach are necessary to improve the prognosis and outcome of the disease.