Disseminated visceral Kaposi’s sarcoma after allogeneic hematopoietic stem cell transplantation: a case report

Abstract

Cases of disseminated visceral Kaposi’s sarcoma (KS) after allogenic hematopoietic stem cell transplantation (HSCT) are very rare worldwide, and disseminated visceral KS is often rapidly progressive and life-threatening, especially in paediatric patients. Here, the case of a 6-year-old female patient with disseminated visceral KS after allogeneic HSCT for treating severe aplastic anaemia is presented. The authors encountered difficulties in making the diagnosis due to lack of experience, but the diagnosis was achieved relatively quickly and accurately using metagenomic next-generation sequencing. After tapering and withdrawal of immunosuppressant drugs, the patient's condition was controlled. In conclusion, although HSCT-related KS is very rare, it should be considered during differential diagnosis.

Introduction

Kaposi's sarcoma (KS), an angioproliferative tumour that is characterized by the proliferation of mucosal skin and visceral blood vessels, was first discovered by Moritz Kaposi in 1872. ¹ KS is classified into four types, based on the clinical condition in which it develops: (1) sporadic or classic subtype, (2) endemic, (3) acquired immune deficiency syndrome-associated or epidemic KS, and (4) iatrogenic subtype in patients treated with immunosuppressive therapy medications, particularly in organ transplant recipients. ²

In 1994, KS-associated herpes virus (KSHV), also known as human herpes virus-8 (HHV-8), was discovered by Chang et al. ³ KS is more often reported in patients with solid organ transplantation, particularly kidney transplantation, than hematopoietic stem cell transplants (HSCT). In a study of patients who received HSCT, the incidence of KS between 2004 and 2017 was 0.17% in allogeneic transplantation, 0.05% in autologous transplantation, and 0.11% overall. ⁴

Although patients who have received myeloablative HSCT undergo prolonged periods of immunosuppression, there are few reports of KS after HSCT. KS usually affects the skin first, and the progression of cutaneous KS tends to be slow. In contrast, KS with visceral involvement is characterized by rapid progress, massive haemorrhage, and high mortality. ⁵

Herein, the case of a 6-year-old female Uyghur patient with severe aplastic anaemia (SAA), who was found to have disseminated KS (accumulated in the skin, gums, and bowel) after HSCT, is described. After tapering and withdrawal of immunosuppressant drugs, KS was controlled.

Case report

A 6-year-old female Uyghur patient was admitted to the People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China in January 2021 due to recurrent fever for 40 days and abnormal haemogram for 1 month. Results of a complete blood cell count were as follows: white blood cells, 2.06 × 10⁹/L; platelets, 10 × 10⁹/L; haemoglobin, 1 × 10⁹g/L; neutrophils, 0.24 × 10⁹/L; and lymphocytes, 1.34 × 10⁹/L. Bone marrow aspiration biopsy revealed hypoplastic bone marrow, a small number of trilineage hematopoietic cells in many adipose tissues, and a few lymphocytes and plasma cells distributed in the stroma. The patient was given a clear diagnosis of SAA, and scheduled for treatment by HSCT with her father as the donor, who was found to be human leucocyte antigen haploidentical (5/10). Both the patient and her father were seronegative for cytomegalovirus, Epstein-Barr virus, hepatitis B and C viruses, and human immunodeficiency virus. Their HHV-8 status was unclear because HHV-8 testing before transplantation was not routinely performed.

In January 2021, the patient underwent allogeneic haploidentical HSCT using the modified busulfan/ cyclophosphamide plus antithymocyte globulin (ATG) myeloablative conditioning regimen, comprising 0.8 mg/kg busulfan, every 6 h on days −7 and −6; 50 mg/kg cyclophosphamide, once daily on days −5 to −2; and 2.5 mg/kg rabbit ATG, once daily on days −5 to −2. A graft-versus-host disease (GVHD) prophylaxis regimen was administered, comprising cyclosporine A (1.25 mg/kg, i.v., every 12 h, then orally once intestinal function was restored, from day –9 to 1 year following HSCT), short-term methotrexate (15 mg/m², orally, on day +1 then 10 mg/m² on days +3, +5 and +11), and mycophenolate mofetil (15 mg, orally, every 12 h on days –9 until approximately day +30). The patient also received the antiviral ganciclovir (100 mg, i.v., every 12 h), the antifungal caspofungin (40 mg, i.v., once daily) or voriconazole (200 mg, orally, every 12 h), and the anti-pneumocystis drug sulfamethoxazole (one 400 mg/40 mg compound tablet, orally, twice daily).

The patient received bone marrow blood on day +1 and peripheral blood on day +2. A total of 7.61 × 10⁸ mononuclear cells and 3.18 × 10⁶ CD34+ cells were infused. All blood products were gamma irradiated to help prevent GVHD. The patient achieved granulocyte engraftment on day +12, and platelets were engrafted on day +14.

On day +17, the patient exhibited a scattered rash on the face, post-auricular region, both lower extremities, and back, and was diagnosed with acute skin GVHD (Grade II). The patient had recurrent diarrhoea and fever from day +58 to day +73, and positive faecal occult blood test. On day +74, she was diagnosed with acute gut GVHD (Grade I). After adequate glucocorticoid treatment (7.5 mg prednisolone, orally, once daily), acute GVHD was controlled on day +79. The patient continued to have recurrent diarrhoea and eventually acute gut GVHD developed into chronic gut GVHD (grade I).

The patient suddenly developed hyperspasmia during the night of day +176, with body temperature > 38°C, and toxic encephalopathy resulting from infection was considered. After anti-infective treatment with 280 mg meropenem (i.v., every 8 h) in combination with 140 mg linezolid (i.v., every 8 h), the patient's clinical symptoms disappeared and body temperature returned to normal on day +180.

On day +301, the patient complained of gingival swelling. Physical examination revealed two brown nodules of soybean-grain size above the skin surface in both lower extremities (Figure 1), and her absolute lymphocyte count was 1.59 × 10⁹/L. No special treatment was administered because there was no pain or itching at the nodule site. The patient had chronic gut GVHD (grade I) with recurrent symptoms of fever, abdominal pain, and diarrhoea (dusky red bloody stool), and these symptoms were observed to be gradually aggravated from day +321, at which time, her absolute lymphocyte count was 0.37 × 10⁹/L. Intestinal chronic GVHD was considered and corticosteroid treatment with 2 mg methylprednisolone (orally, twice daily) was initiated, however, the patient's symptoms did not ease, but worsened. The authors began to consider that the treatment approach was wrong. Previous studies have shown that patients often have acute or chronic GVHD when KS associated with HSCT is diagnosed.^4,6 At this point, KS was already suspected, but permission for a skin biopsy had been declined, making the diagnosis more difficult. As significantly contrasting treatments are administered for GVHD compared with KS, the gut lavage fluid was sent for metagenomic next-generation sequencing (mNGS) on day +330 to clarify the diagnosis. The results of mNGS suggested HHV-8 positivity, with evidence favouring the diagnosis of KS on day +332. On day +334, results from biopsy of skin nodules on the right lower extremity revealed cells that were positive for CD34 and HHV-8, which was consistent with KS. Intestinal biopsy pathology results were CD31(+), CD34(+), HHV-8(+), with ileocecal valve, transverse colon and descending colon tissue sections being consistent with KS (Figure 2). Treatment was initiated on day +334 by reducing the cyclosporine dose to control the progression of KS, and 5% topical imiquimod, once every other day, was applied to the skin nodules. After 1 month, the patient's KS was under control and her absolute lymphocyte count had increased to 1.21 × 10⁹/L. The patient's absolute lymphocyte count continued to gradually increase to 2.21 × 10⁹ by day +371, and she was completely off immunosuppressant medication by day +372. On day +422, the patient complained of a generalized rash with pruritus, without abdominal pain or diarrhoea. A drug-associated rash was diagnosed, which resolved with the administration of 5 mg desloratadine, orally, once daily. Pathological findings of biopsies obtained from the skin nodules on both lower extremities on day +429 suggested improvement of KS lesions. Results of colonoscopy conducted on day +435 were also encouraging, displaying smooth and unobstructed intestinal mucosa and clear submucosal texture. Retests for HHV-8 also returned negative results.

Figure 1.

Images showing dermatological lesions prior to treatment for Kaposi’s sarcoma in a 6-year-old female patient who had received hematopoietic stem cell transplantation for severe aplastic anaemia.

Figure 2.

Histologic sections from skin of the leg (upper images) and intestinal tract (lower images) prior to treatment for Kaposi’s sarcoma in a 6-year-old female patient who had received hematopoietic stem cell transplantation for severe aplastic anaemia. The tissue exhibited spindle cell proliferation in bundles and extravasated red blood cells; HE, haematoxylin and eosin; HHV8, human herpes virus-8; original magnification, × 20.

In June 2022, the patient's KS had stopped progressing, and her clinical symptoms had resolved, with significantly smaller skin nodules than before KS treatment, and normal gums.

Verbal informed consent was obtained from the patient's guardians before publication of this case report. Ethics committee approval was not required for publication of this case, and the reporting of this study conforms to CARE guidelines. ⁷

Discussion

Kaposi’s sarcoma associated with HSCT is extremely rare, with limited reports worldwide, particularly with regard to cases exhibiting multiple lesion sites. Here, a case of generalized KS associated with HHV-8 that developed 10 months after haploidentical allogeneic HSCT is reported. Pre-transplant HHV-8 status was unclear, as HHV-8 serology is not routinely performed as a pre-transplant test at the People's Hospital of Xinjiang Uygur Autonomous Region. In addition, a previous study did not recommend HHV-8 as a routine pre-transplant examination in non-high prevalence areas. ⁶

Treatment of transplant-associated KS is mainly through the reduction or discontinuation of immunosuppression, thus restoring host immunity. More studies are required to understand the effectiveness of antiviral treatments (cidofovir, phosphonates or ganciclovir) and to support their use in such cases. ⁸ Calcineurin inhibitors, such as cyclosporine and tacrolimus, are currently believed to promote the progression of KS by upregulating vascular endothelial growth factor (VEGF). Sirolimus may have anti-angiogenic properties by inhibition of the mammalian target of rapamycin, thereby treating renal transplant-related KS.^9,10 For lesions confined to the skin, surgical excision or electrochemotherapy are the preferable approaches, with radiotherapy not being chosen due to severe local side effects (oedema and ulcer). ¹¹

Patients face long-term immune deficiency after HSCT. In the present case, the intensity of immunosuppression of the haploidentical graft may have been the main reason for the development of KS. Difficulties were encountered in this diagnosis due to lack of experience, and HHV-8 was finally discovered through mNGS of gut lavage fluid. Zhou et al. ¹² showed that mNGS of blood samples rapidly and accurately identifies pathogens that may help assess the development of KS and dynamically guide treatment decisions. To the best of the authors’ knowledge, the present report is the first case study to present mNGS as a guide in the treatment of KS associated with HSCT. Post-transplant bacterial or viral infections have been one of the main threats affecting patients' lives. Traditional detection methods have some defects compared with mNGS, such as long detection period, low efficiency, and low sensitivity and specificity. In contrast, mNGS, as an emerging detection method, has the advantages of high detection sensitivity, short detection cycle, and wide application range. ¹³

The current patient's lesion was detected on day +301, at which time absolute lymphocyte count was 1.59 × 10⁹/L. A clear diagnosis was not made in a timely manner due to inexperience, which led to disease progression. On day +320, the patient was readmitted to hospital with abdominal pain and diarrhoea, and absolute lymphocyte count was detected to be 0.37 × 10⁹/L. Once the diagnosis was clear, the cyclosporine dose was gradually reduced, and the absolute lymphocyte count increased to 1.21 × 10⁹/L after 1 month. As cyclosporine was reduced, the patient's absolute lymphocyte count continued to gradually increase (2.21 × 10⁹/L on day +371). The patient's symptoms of fever, abdominal pain, diarrhoea, and swollen gums also subsided. The rise in absolute lymphocyte count was found to be consistent with the remission in clinical symptoms, which is in line with previous findings.^8,12

In conclusion, although HSCT-related KS is very rare, identification remains important and KS should be considered, particularly for visceral lesions, which are more fatal than KS lesions of the skin. Greater caution should be applied when dealing with haploidentical transplant patients because they face more intense immunosuppression.

Author contributions

Conception and design: TL. Drafted or revised the manuscript: RW. Analysis and interpretation of data: XL and YX. Acquisition of data: XL, YX, LZ, CW, and DZ. All authors contributed to the article and approved the submitted version.