A previously healthy, 36-year-old Chinese man presented with papulonodules on his face and hands that had emerged over an 8-month period, along with experiencing polyarthritis for half a year. He reported smoking half a pack per day for 17 years. His family history was significant for malignancy in that his mother had breast cancer.
On admission, a physical examination revealed multiple flesh-coloured to pinkish papules and nodules on his face ( Figure 1A ), distal interphalangeal and proximal interphalangeal areas, and papulonodular lesions arranged around the nail plica in a typical "coral bead" pattern ( Figures 1B, C ). The cutaneous lesions were tender but without pruritus. There was also significant tenderness noted in the bilateral interphalangeal joints, wrists, elbows, shoulders, ankles, knees and hips, with no signs of swelling.
Laboratory tests showed slightly elevated inflammatory markers, including a C-reactive protein (CRP) level of 23.4 mg/L (reference range, <5 mg/L), erythrocyte sedimentation rate (ESR) of 49 mm/h (reference range, <21 mm/h), interleukin-6 (IL-6) level of 9.69 pg/ml (reference range, 0-7 pg/ml) and tumour necrosis factor (TNF) level of 9.26 pg/ml (reference range, <7 pg/ml). Routine blood, biochemistry, urinalysis, C3 and C4 levels were normal. The levels of tumour markers (CEA, AFP, CA125, CA19-9, CA72-4, CA15-3, CYFRA21-1 and PSA) did not exceed the reference range. Further analysis revealed that the patient showed ANA (titer 1:320), LA (1.93, reference range, 0.8-1.2, LA performed with dilute Russell's viper venom time [dRVVT] screen/confirm), PPD test and tuberculosis interferon-gamma release assay positivity. The level of fibrinogen was 5.47g/L (reference range, 2.0-4.0 g/L). Tests for anti-dsDNA, anti-Smith, anticentromere, anti-ribonucleoprotein, anti-Jo1, anti-neutrophil cytoplasmic antibodies, rheumatoid factor (RF), anti-cyclic citrullinated peptide antibodies (ACPA), anticardiolipin antibodies (IgG, IgM and IgA), anti-beta2-glycoprotein I antibodies (IgG, IgM and IgA) and HbsAg were all negative. Radiographs of the joints revealed osteoporosis in both hands and wrists and a slightly narrowed space between the first and second metacarpophalangeal joints of both hands ( Supplementary Material 1 ). High-resolution computed tomography (HRCT) of the chest revealed emphysema and an inconspicuous mass of lymphoglandula within the posterior mediastinum ( Figure 1D ). The patient underwent endobronchial ultrasound (EBUS) puncture biopsy of the mediastinal lymphoglandula to exclude cancer after consultation with the Department of Respiratory Medicine. Contrast-enhanced CT imaging of the whole abdomen revealed calcified plaques in the abdominal aorta and its branches, with mural thrombosis. The above indicators led to a presumptive diagnosis of undifferentiated connective tissue disease and possible antiphospholipid syndrome. On day 7, the histopathologic features of the papulonodular skin lesions showed proliferation of abundant foamy macrophages and the presence of histocytes ( Figure 1E ). These lesions contained CD68-positive cells ( Figure 1F ) that were negative for S100, CD1a, Langerin, and Factor VIII markers ( Supplementary Material 2 ). Thus, a histological diagnosis of MRH was made.
The patient received methotrexate (15 mg once a week) accompanied by oral prednisone (10 mg twice a day) and was discharged after 20 days of treatment. He continued the above regimen after discharge according to his doctor's instructions. Approximately one month later, he was admitted again for assessment, which indicated that the papulonodular lesions had shrunk and that the inflammatory cytokines and molecules described above had returned to normal levels. Nonetheless, the patient's joint pain was not significantly relieved.
The results of EBUS puncture biopsy of the mediastinal lymphoglandula were available at the second hospital admission and showed a small number of abnormal cells ( Supplementary Material 3 ). Immunohistochemistry showed cells positive for PCK, EMA, CK5/6 (focal), GATA-3, Ki67 and MIB-1 (20% positive). CR, TTF-1, P63, D2-40 and CgA were negative, and a diagnosis of epithelial neoplasia was made. To identify the primary lesion, fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) was carried out, revealing increased glycometabolism in the soft tissue around the joints of the extremities and the mediastinal lymph nodes; the subcarinal lymph node findings confirmed the suspicion of malignancy ( Figure 2 ). However, the primary tumour was not found despite exhaustive tests. The patient discontinued methotrexate and prednisone according to the recommendations of the multidisciplinary treatment (MDT) team.
To further clarify the diagnosis and treatment approach, the patient received video-assisted thoracoscopic surgery (VATS) to excise the mediastinal mass (6x3.5x2.8 cm) for genetic analysis. Malignant cells were identified in the background of abundant lymphoid tissue in the mediastinal mass ( Supplementary Material 4 ). Histopathologic features of malignant cells were positive for P63 (focal), CK5/6 (focal), PCK, GATA-3, and Ki-67 (MIB-1, 50-60%) but not CR, PAX-8, CD5, CD117, WT-1, CgA, or EBER1/2, resulting in a diagnosis of poorly differentiated adenosquamous carcinoma. Genetic analyses revealed the presence of mutations in the SMARCA gene A4 (NM_003072.3:c.2438+1G>A IVS16, mutation rate 36.4%), amplification of EGFR, and a lack of PD-L1.
After discussion with oncologists, chemoradiotherapy was administered, namely, intravenous paclitaxel 210 mg for 1 day combined with intravenous carboplatin 450 mg for 1 day (once every 3 weeks) and radiotherapy for the mediastinal lymph nodes. After 6 months of follow-up from the diagnosis of malignancy (5 cycles of chemotherapy and 30 cycles of radiotherapy), the patient's joint pain was significantly reduced, and the papulonodular lesions had almost cleared, without any specific treatment. The latest re-examination on June 29, 2021, revealed that the patient was ANA negative and the LA level had decreased to 1.32, with no signs of tumour recurrence. The patient is still being followed-up. The changes to the lesions on the hands are presented in  Supplementary Material 5 . The patient's clinical course is shown in  Figure 3 .