Abstract

INTRODUCTION

Solitary plasmacytoma (SP) is a rare disease characterized by abnormal proliferation of monoclonal plasma cells, with a cumulative incidence of 0.15/100000[1,2]. Solitary bone plasmacytoma (SBP) is a subtype of SP that occurs primarily in the red-marrow-containing axial skeleton and long bones[3] and accounts for 70% of all SP cases[1]. SBP with minimal (< 10%) bone marrow plasma cells progresses to multiple myeloma (MM) within 3 years in approximately 60% of patients[2,4]. All SP are radiation-sensitive; therefore, radiotherapy (RT) is recommended as the first-line treatment strategy for the long-term disease control in these patients[3,5].

Unicentric Castleman disease (UCD) is a rare lymphoproliferative disorder with unknown prevalence and belongs to a heterogeneous group of conditions characterized by similar histopathological features but has distinct pathological etiologies, clinical symptoms, management, and outcomes[6,7]. For patients with resectable UCD, complete surgical excision is the optimal first-line treatment, with a 5-year overall survival of up to 90%; even after a 10-year follow-up, disease relapse is rare[6,8].

Here, we report the case of a 48-year-old man with SBP of the hyoid and UCD along with the clinical diagnosis, management process, and follow-up. Moreover, we reviewed the literature of related SBP cases to provide a comparative experience in guiding the management of this rare disease.

CASE PRESENTATION

Imaging examinations

Electronic laryngoscopy and plain computed tomography (CT) showed thickening of the left epiglottis (Figure ​(Figure1A1A and ​andC),C), arytenoid and aryepiglottic folds (Figure ​(Figure1B1B and ​andD),D), osteolytic lesions of the left hyoid (Figure ​(Figure1E),1E), and thyroid cartilage plate (Figure ​(Figure1F).1F). The left piriform fossa was occluded, and enlarged cervical and submandibular lymph nodes were observed bilaterally. The patient underwent selective neck dissection and partial hyoid resection to relieve neck compression, and a final diagnosis was made. ¹⁸F-FDG positron emission tomography (PET)/CT revealed focally increased radioactivity centered around the hyoid body and its left greater horn (SUV_max = 8.8) and the left submandibular and submental soft tissue (SUV_max = 4.8) exhibited on PET (Figure ​(Figure1G1G-​-I),I), CT (Figure ​(Figure1J1J-​-L),L), and PET/CT fusion (Figure ​(Figure1M1M-​-O).O). Osteolytic lesions were identified on the plain CT bone window. PET maximum-intensity projection image (Figure ​(Figure1P)1P) showed no other sites with abnormal ¹⁸F-FDG uptake, except for the perihyoid region. These findings were suggestive of a malignancy.

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Figure 1

Imaging findings during initial admission. A and C: Thickening of the left epiglottis; B and D: Arytenoid and aryepiglottic fold; E: Osteolytic lesions of the left hyoid; F: Thyroid cartilage plate; G-I: ¹⁸F-FDG centered around the hyoid body and its left greater horn (SUV_max = 8.8), and left submandibular and submental soft tissue (SUV_max = 4.8) exhibited on positron emission tomography (PET); J-L: Computed tomography (CT); M-O: PET/CT fusion; and P: PET maximum-intensity projection image demonstrated no other sites with abnormal ¹⁸F-FDG uptake.

Further diagnostic work-up

Histological results revealed angiofollicular lymph node hyperplasia of the hyaline-vascular type arranged in an onion-bulb appearance (Figure ​(Figure2A2A and ​andB,B, 200 × and 400 ×), and the presence of mature plasma cells characterized by an oval shape, abundant basophilic cytoplasm, perinuclear halo, round eccentric nuclei, and indiscernible nucleoli[6,7,9] (Figure ​(Figure2C2C and ​andD,D, 200 × and 400 ×). Histopathological results were positive for plasma cell markers [CD138 (Figure ​(Figure2E),2E), CD38 (Figure ​(Figure2F),2F), κ (Figure ​(Figure2G)2G) and λ (Figure ​(Figure2H)2H) light chains, CD79α (Figure ​(Figure2I),2I), IgG, IgM], and focal expression of T-cell markers [CD43 (Figure ​(Figure2J),2J), CD45], and CD56; however, deficiency of B-cell markers [CD20 (Figure ​(Figure2K),2K), CD19] was observed. The Ki-67 proliferation index was 3% (Figure ​(Figure2L).2L). No paraproteins and pathological elevation of κ and λ chains were detected by the serum protein electrophoresis and free light-chain assays[4,10]. Bone marrow biopsy indicated normal trilineage hematopoiesis with only 0.2% plasma cells in all leukocytes[4]. Additionally, polyneuropathy and other minor symptoms were absent.

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Figure 2

Histopathological and immunohistochemical analysis. A and B: Hematoxylin and eosin staining revealed angiofollicular lymph node hyperplasia (200 × and 400 ×); C and D: The presence of mature plasma cells (200 × and 400 ×); E-J: Positive immunohistochemical staining for plasma cell markers: CD138, CD38, κ light chains, λ light chains, CD79α, T-cell marker CD43; K: Negative staining for B-cell marker CD20; and L: The Ki-67 positive staining.

FINAL DIAGNOSIS

Systemic work-up ruled out the possibility of POEMS syndrome, lymphoma, and MM[4,11,12], thus leading to the diagnosis of SP of the hyoid, with UCD. Inflammatory factors, such as TNFα, IL-6, IL1β, TGFβ1, and VEGFα (Supplementary Figure 1), were increased, confirming the multiple cytokine-producing property of SBP[13,14].

TREATMENT

The patient underwent intensity-modulated RT[5] for the hyoid bone and high-risk subclinical areas, with a total dose of 50.4 Gy, divided into 28 fractions[10].

OUTCOME AND FOLLOW-UP

No acute toxicity was observed during RT. After 3 mo, contrast-enhanced CT revealed a slightly shrunken tumor boundary. The patient underwent CT and ¹⁸F-FDG PET/CT or 99mTc-MDP single-photon emission computed tomography (SPECT)/CT examinations at 6 and 12 mo, respectively. Recent 99mTc-MDP SPECT/CT reevaluation showed a slight increase in radioactivity around the hyoid, considering postoperative changes rather than local recurrence on SPECT (Figure ​(Figure3A),3A), CT (Figure ​(Figure3B),3B), and SPECT/CT fusion (Figure ​(Figure3C).3C). Focal bone destruction and secondary hyperosteogeny were also observed in the CT bone window (Figure ​(Figure3D).3D). Whole-body SPECT revealed no evidence of distant bone metastasis (Figure ​(Figure3E3E and ​andF).F). The patient was symptomatic and progression-free at the 40-mo follow-up visit.

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Figure 3

Molecular imaging in the evaluation of local recurrence and ectopic metastasis during follow-up. A-C: 99mTc-MDP radioactivity around the hyoid exhibited on single-photon emission computed tomography (SPECT), computed tomography (CT), and SPECT/CT fusion; D: Focal bone destruction and secondary hyperosteogeny exhibited on CT bone window; E and F: No evidence of distant bone metastasis on whole-body SPECT.

DISCUSSION

Plasma cell disease comprises a heterogeneous group of disorders characterized by an increase in the number of monoclonal plasma cells[4]. Abnormally proliferative cells can secrete a large quantity of monoclonal immunoglobulin and invade and damage various tissues or organs, such as the bones, bone marrow, kidneys, hearts, lungs, and immune system. Precision clinical intervention is needed for the accurate diagnosis of these diseases. In the present study, the histology of the neck mass showed Castleman’s lesion, such as vitreous degeneration with an "onion skin" appearance, and monoclonal proliferation of plasma cells, resembling the typical features of CD variant of POEMS syndrome. However, the patient did not meet the other major or minor criteria required for a definite diagnosis of POEMS syndrome or MM[4,11,12]; therefore, led to a final diagnosed with SBP of the hyoid and UCD. The National Comprehensive Cancer Network recommends using primary RT of a total dose of 40–50 Gy in 1.8–2.0 Gy per fraction over 4 wk, for patients with SP in whom the surgery is depended on clinical necessity[10]; in addition, for patients with UCD, excisional surgery is the optimal strategy with the benefit of long-term disease control[6,8]. The patient received intensity-modulated RT according to the guidelines after extended dissection of the neoplastic mass adjoining the primary lesion.

The hyoid bone is an atypical location and is extremely rare for the growth of SP; to the best of our knowledge, only three cases have been reported[15-17]. Goel et al[15] presented the first case treated with local RT followed by chemotherapy, and the hyoid swelling was significantly reduced in size during the 18-mo follow-up. Danaci et al[16] described the second case of a 60-year-old man. This patient underwent total excision of the hyoid mass but was not subsequently treated with RT or chemotherapy, and was alive and progression-free during the 24-mo follow-up period[16]. The third patient was diagnosed with non-secretory MM stage IIIA and presented with plasma cell infiltration into the hyoid bone. This patient received chemotherapy and anti-hypercalcemic therapy; however, the prognosis was not referred to in the report[17].

SP can be divided into SBP and solitary extramedullary plasmacytoma based on its origin from the bone marrow or soft tissue organs[4]. Abnormal monoclonal plasma cells and bone marrow stromal cells (BMSCs) in SBP strongly express multiple cytokines and their corresponding receptors that promote the growth and survival of tumor cells or angiogenesis through autocrine and paracrine mechanisms[13,14]. Plasma cell-derived matrix metalloproteinases participate in the degradation of the extracellular matrix and basement membrane, leading to chronic inflammation and bone-destructive lesions[18]. Abnormal plasma cells also induce local angiogenesis and stimulate neovascularization depending on secreted cytokines, such as ANG-1, CXCL12, and VEGFα, which supply nutrition for tumor cell growth[19-21]. Cytokine homeostasis, particularly that secreted by BMSCs, acts as a regulatory mechanism for tumor growth[22]. Some reports indicate that aberrant activation of gp130-dependent and Notch signaling may provide strong advantages for the growth of plasmacytomas[19,23-25]. CD and POEMS syndrome are also associated with the elevation of several classical cytokines in serum, such as IL-6, VEGFα, TNFα, IL1β, and TGFβ1 secreted by proinflammatory cells, as found in SBP. CD and SP can present independently, concurrently, or sequentially with POEMS[26-28]. Patients with CD and/or POEMS syndrome usually have an upregulation of serum VEGFα and IL-6 mediated cytokine storm, which might impair cerebral vessels, resulting in vasculopathy of the central nervous system and an increased risk of cerebral infarction[26,29,30].

Recently, with the development of high-throughput sequencing technology, genetic analyses have been broadly applied to reveal the molecular mechanisms of UCD and idiopathic multicentric Castleman disease (iMCD)[31-35]. Overall, two recurrent hotspot somatic mutations, PDGFRB (NM_002609.4, c.1997A > G, p.N666S) and NCOA4 (NM_005437.4, c.781 > T, p.L261F), were identified in 17% and 18% of the tested UCD and iMCD cases, respectively[33,34]. In a patient with iMCD accompanied by severe peripheral neuropathy, somatic alterations were identified in genes related to neuronal development, such as PDLIM5, SEC24B, ZFHX3, and PACRG[36]. Another patient harbored a somatic JAK1 missense mutation, but normal serum IL-6 had a complete response rate to the IL-6 antibody siltuximab, implicating the essential roles of the IL-6/IL-6R/JAK1/STAT pathway and its mutations in the pathogenesis of iMCD[37]. Somatic mutations were prone to enrichment in the mitogen-activated protein kinase and interleukin pathways in UCD and iMCD; however, genes affecting chromatin remodeling were solely enriched in iMCD[38]. Moreover, patients with iMCD have a high prevalence of germline MEFV variants that modify their clinical phenotypes and treatment responses[39,40]. Transcriptome profiling also revealed that UCD and MCD are involved in unique genes, pathways, and cell types[35].

¹⁸F-FDG PET/CT exhibits superior sensitivity and specificity for SBP lesions. It can detect minimal residual disease inside and outside the bone marrow at the same time in one examination, which cannot be identified by χ-ray and magnetic resonance imaging[41,42]. In the early stages of patients with SBP after RT, ¹⁸F-FDG PET/CT performs poorly in disease staging; however, a high SUV_max value is a regular prognostic indicator for progression[43]. 99mTc-MDP scintigraphy shows a relatively low sensitivity to detect bone lesions of SBP due to the suppressed differentiation of osteoblasts[44] and can be more applicable for evaluating the complications of SBP[45]. 99mTc-MIBI scintigraphy shows the same sensitivity and specificity as ¹⁸F-FDG PET/CT in the detection of SBP lesions[46] and even better performance in the detection of diffuse bone marrow involvement, but it is inefficient in the detection of focal lesions[47]. ¹⁸F-FDG PET/CT has the ability to simultaneously collect anatomical structure and metabolic information and can be used for the initial staging and response monitoring of CD[48]. It has high specificity and sensitivity for the identification of lymph node lesions in patients with CD[49] and is an important imaging marker for judging the severity and prognosis of the disease. A variety of metabolic parameters in ¹⁸F-FDG PET/CT, including SUV_max, SUV_mean, SUV_peak, metabolic tumor volume, and total lesion glycolysis, can be used for the differential diagnosis of UCD and other diseases[50].

CONCLUSION

To our knowledge, this is the first reported case presented with these two rare clinical entities (SP of the hyoid bone and UCD). In addition to comprehensive histopathological analysis, ¹⁸F-FDG PET/CT and 99mTc-MDP SPECT/CT are routinely used in the clinical practice of differential diagnosis, disease staging, and follow-up monitoring, highlighting the advantages of nuclear medical and other imaging techniques in the management of SP in the head and neck. In addition, the diagnostic and management processes provided valuable educational information to clinicians.

ACKNOWLEDGEMENTS

We sincerely thank Dr. Ya-Qiong Ren and Yu-Qi Shen at the Chinese Academy of Medical Sciences & Peking Union Medical College for staining of inflammatory factors of SBP and their independent figure combination and optimization.

Footnotes

Contributor Information

Yan-Hui Zhang, Department of Otolaryngology-Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.

Yi-Feng He, Department of Radiology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.

Hao Yue, Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai 200032, China.

Yue-Ni Zhang, NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150028, Heilongjiang Province, China.

Lei Shi, NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150028, Heilongjiang Province, China. moc.anis.piv@8230_ielihs.

Bin Jin, Department of Otolaryngology-Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.

Pin Dong, Department of Otolaryngology-Head and Neck Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai 200080, China.

References