A 45-year-old man (body weight of 47.5 kg, height of 158 cm and body surface area of 1.46 m2) was initially admitted to our hospital on July 31, 2021 due to recurrent fever with a maximal body temperature of 40 C for over two months and generalized rashes with uneven surface and pruritus. The patient had previously been diagnosed with a "drug rash" at the local hospital and was given anti-allergy therapy, yet without amelioration. One week previously, the patient developed an obvious shortness of breath, accompanied by a more frequent outbreaks of rash.
Upon admission, the patient was observed with clinical manifestations of pale complexion, poor spirit, cachexia, hepatosplenomegaly, dark erythema, and papules of varying sizes on both palms. Multiple enlarged lymph nodes could be palpated on both sides of his neck, supraclavicular and inguinal regions; with the largest node of 2.0 cm x 2.0 cm in size on the right side of his neck. Initial laboratory data on July 31, 2021, showed complete hemocytopenia, worsening inflammatory indicators, and elevated lactate dehydrogenase (LDH). In addition, serum ferritin was increased to 1519.25ng/mL (reference range, 21.80-274.66 ng/mL) on 21 August ( Table 1 ). Subsequent hybrid imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT) revealed generalized and multiple enlargements of the lymph nodes, hepatosplenomegaly, and bilateral tonsillomegaly:with augmented glucose metabolism throughout the body ( Figure 1 ). The patient was therefore first considered to have lymphoma possibly, with a requisite for lymph node biopsy.
Supportive therapy was promptly started with anti-infective and anti-allergic medications, etc. However, the patient had no improvement in hematologic parameters ( Table 1 ), and in fact showed deterioration (Hb of 44 g/L, PLT count of 19 x 109/L, and beta2-microglobulin [BMG] of 4.47 mg/L compared with normal prior value). CRP and PCT were also assessed for severe acute inflammation and were found to be elevated. Lymph node aspiration, bone marrow (BM) cytology, and biopsy were then performed to exclude the possibility of malignancies.
To investigate the potential complication of this patient, we further examined the soluble interleukin-2 receptor sIL-2R/sCD25 (ELISA instructions were followed: the anti-sIL-2R antibody was reacted with the serum as tested and the final A450 value was measured using an enzyme marker to analyze sIL-2R expression. [Kindstar Diagnostics, Wuhan, Hubei, China]) and NK cell activity (Peripheral blood was drawn on an empty stomach and NK cell activity (CD16+56 +) is detected using a test kit and flow cytometry.). Laboratory results showed an increase in sIL-2R to 11,340 U/mL, and NK cell activity of 3.0%, indicating diminished NK cell activity. A diagnosis of HLH was confirmed combined with the patient's medical history ( Table 2 ). Hence, the patient was provided with a revised HLH-1994 regimen (etoposide at 100 mg qw and dexamethasone at 10 mg/m2 qd). However, a joint consultation regarding the sampled pathologic specimen (i.e., tissues collected by aspiration from the right inguinal lymph node) showed predominantly follicular dendritic cells (FDC) hyperplasia, with insignificant cellular anisotropy and fair proliferative activity, making it difficult to diagnose malignancy at that time; and the result of BM biopsy was consistent with chronic inflammation, with no definite evidence of neoplasm. Owing to the undetermined pathologic diagnosis and inconspicuous treatment efficacy, the treatment regimen of HLH-1994 was suspended on September 2.
Biopsy of the right supraclavicular lymph node was ultimately performed on September 3 after a general surgery consultation, and the final pathologic diagnosis was consistent with primary HS ( Figure 2 ). The sections for hematoxylin-eosin (H&E) staining ( Figures 2A, B ) revealed structural disruption of the lymph nodes with patches of large neoplastic cells that were markedly atypical cytologically, proliferation of small vessels, and diffusely distributed cells with slightly larger nuclei and abundant cytoplasm. Extensive immunohistochemical studies ( Figures 2C-E ) showed that the tumor cells were positive for CD163, CD68, S100, Lys, and CD34; and negative for CD1a, CD207, HMB45, MPO, and CD30. The Ki-67 proliferation index was 30%. Further immunostaining for PD-L1 was positive as over 80% of the tumor cell membranes were stained ( Figure 2F ). The patient unfortunately had a recurrent high fever on September 8 during supportive therapy, with generalized and scattered punctate rashes that were bright red in color and faded upon pressure; and the patient also exhibited splenomegaly that was assessed as progressive disease (PD). These attributes suggested highly malignant behaviors of this tumor.
There is presently no uniform standard therapeutic regimen for HS. Importantly, PD-L1 was also highly expressed in this patient. A combination chemotherapeutic regimen of PD-1 inhibitor + AEVD (epirubicin/etoposide/vincristine/dexamethasone) was implemented on September 15 ( Figure 3 ) that consisted primarily of sintilimab (200 mg on d 0), epirubicin (50 mg on d 1), etoposide (100 mg on d 1), vincristine (3 mg on d 1), and dexamethasone (15 mg on d 1) in a 21-d course:supplemented by supportive treatment. The patient was fortunately found to improve after 2 days of the combination chemotherapy. On September 17, 2021, the patient was observed with an improvement in the general symptoms, showing alleviation in generalized rashes, and no fever, coughing, or expectoration. Multiple lymph nodes shrank and the levels of inflammatory indicators also decreased. In addition, Hb was improved to 58 g/L, PLT to 26x109/L, PCT to 0.575 ng/mL, CRP to 38.12 mg/L, and ferritin to 1196.83 ng/mL ( Table 1 ). The patient was discharged on September 18.
However, one week after discharge, the patient developed a rapid growth of the lymph nodes after a reduction in size previously. The largest one was now 3.0 cm x 3.0 cm in size on the right side of the neck, and was tough and poorly mobile. The patient also had persistent fever (37-40.5 C). The patient was admitted to our hospital for the second time on September 29, 2021 for chemotherapy. Physical examination of the patient after admission showed recurrent rashes. Emergency hematologic evaluation revealed triglyceride level of 3.07 mmol/L, BMG of 4.40 mg/L, IL-6 of 111.00 pg/mL, PCT of 69.00 ng/mL, whole blood CRP of 112.11 mg/L, LDH of 536.9 mu/L, and a significantly elevated ferritin of 10,692.38 ng/mL; accompanied by a dramatic deterioration in the condition of the patient ( Table 1 ). The patient exhibited an intermittent fever (Tmax of 40.5 C), coughing and expectoration. The patient was provided with antibiotic treatment on admission, and a second chemotherapy was initiated on September 30.
In order to seek for better treatment choices, next-generation gene sequencing (NGS) of the pathological biopsy samples from our patient was ordered subsequently. Using NGS technology, the first puncture biopsy of cervical lymph nodes detected mutations in IDH2, RHOA, TET2, ECT2L, PLCG1, PTPN11, BIRC6, CROCC, MUC4, PIK3CB, PRKAG2, ARID1A, and PCSK9 genes:with primary variants of IDH2, RHOA, and TET2 ( Figure 4 ). A novel missense mutation [c.50G>T, p.Gly17Val (NM_001664)] was also found in RHOA gene; non-synonymous mutation [c.515G>A, p.Arg172Lys (NM_002168)] in IDH2 gene; and c.3344delC, p. Pro1115fs (NM_001127208) in TET2 gene, with a frame-shift deletion mutation and a splicing mutation at c.3501-2A>C (NM_001127208). These mutations are known to be damaging mutations associated with high response to drugs classified in the epigenetic modification category, i.e., histone deacetylase inhibitors (HDACis).
The HDACis chidamide was consequently administered in this case and the specific regimen of chemotherapy was changed to sintilimab at 200 mg on d 0, dexamethasone at 10 mg on d 0-14, etoposide at 100 mg on d 1-2 and d 8, and chidamide at 20 mg (biw, every Wednesday and Saturday). After 4 days of treatment, review of the patient indicated a marked remission of inflammatory indicators, and after 10 days of targeted therapy, PCT was recovered to 0.212 ng/mL, LDH to 100 mu/L, and ferritin to 1686.97 ng/mL ( Table 1 ). Moreover, the fever disappeared and the infection was controlled in the patient. The enlarged lymph nodes were also markedly diminished to the size of a soybean. The patient was discharged with instruction of chidamide at 20 mg biw and was asked to be back for next cycle in one week.
However, the patient discontinued chemotherapy due to financial problem and survived for another month.