Myeloid sarcoma with maxillary gingival swelling as the initial symptom: A case report and review of literature

Abstract

BACKGROUND

Myeloid sarcoma (MS), also referred to as granulocytic sarcoma or chloroma, is a rare type of extramedullary malignant tumor. MS comprises primitive granulocytic precursor cells that play a key role in the early stages of white blood cell development. Notably, the occurrence of this tumor in the gingiva is rare.

CASE SUMMARY

The present study reported the case of MS with gingival swelling in the maxillary region, with aleukemic presentation in a 32-year-old male patient. Following two courses of chemotherapy, computed tomography of the region demonstrated complete clearance of the tumor. At the 12-month follow-up appointment, the patient was in a stable condition with the absence of progression. The etiology, clinical features, diagnosis, and relevant treatment of MS are discussed in the present study.

CONCLUSION

Diagnosis of MS may be confirmed following histological and immunohistochemical examinations.

Key Words: Acute myeloid leukemia, Biopsy, Gingival, Myeloid sarcoma, Immunohistochemistry, Case report

Core Tip: We report a rare case of myeloid sarcoma (MS) with maxillary gingival swelling as the initial symptom. In this case, histopathological and immunohistochemical analyses showed diffuse infiltration of myeloperoxidase-positive neoplastic cells with 80% Ki-67 staining, indicating MS. Flow cytometry revealed a predominance of granulocytes without distinct B-cell or T-cell markers, supporting the diagnosis. Absence of CD20 and CD3 markers lessened lymphoma likelihood, confirming the lesion's hematopoietic nature.

INTRODUCTION

Myeloid sarcoma (MS), also referred to as granulocytic sarcoma or chloroma[1], is a solid malignant tumor associated with the infiltration of immature myeloid cells which occurs at extramedullary site[2,3]. The term chloroma is derived from the green color observed in some cases[4,5]. MS often occurs during myeloproliferative disorders or acute myeloid leukemia (AML)[6,7], and in some cases, may precede bone marrow or peripheral blood involvement[2]. Primary, isolated or aleukemic MS are used to describe a condition with no signs of leukemia or other hematological disease, despite the presence of a specific myeloid mutation. Notably, this form of myelodysplastic syndrome may progress to AML in some patients[8].

To the best of our knowledge, there are few intra-oral cases of MS[9-11]. A literature search using MS and oral cavity produced a total of 66 previous studies. Moreover, there are few cases of MS in the gums[10,12,13]. A literature search using MS and gingival produced a total of 49 previous studies; however, gum swelling was only described as the first symptom of MS in 21 of these cases. Thus, the occurrence of this tumor in the gingiva is not often described. The present study reported a case of gingival MS with gingival swelling comparable to periodontal disease in the posterior area.

Notably, the biopsy performed on the maxillary mass of the patient and the subsequent histologic examination demonstrated the diffuse infiltration of abnormal cells. High levels of the tumor marker, Ki-67, revealed that the tumor exhibited a high potential for metastasis.

CASE PRESENTATION

Chief complaints

One-month history of indolent and stable swelling in the left maxillary molar buccal gingival region.

History of present illness

A 32-year-old male presented to Qingdao University Affiliated Hospital on August 31, 2015, with a one-month history of indolent and stable swelling in the left maxillary molar buccal gingival region. The patient did not present with prodrome symptoms, and the size of the mass was stable.

History of past illness

There was no history of systemic or hereditary disease, such as hematological disorders, and no history of previous medication.

Personal and family history

Deny family genetic history.

Physical examination upon admission

Based on an extra-oral examination, results of the present study revealed that the face of the patient was symmetrical, despite the presence of swelling on the left side of the molar buccal gingival region. This indicated that the swelling was localized to a specific area and did not cause any notable facial asymmetry. The left submandibular lymph nodes were not palpable. Intra-oral examination revealed a firm mass with tenderness that was gray-white in color with regular surfaces, a swelling mass in the left molar gingival area, and the largest dimension was 2 cm. Thus, results of these examinations demonstrated that the swelling or involvement of the gingiva extended from the distal aspect of the left maxillary first molar to the distal aspect of the left maxillary second molar. The observed swelling affected a specific area of the gingiva in the posterior region of the upper jaw (Figure 1). Notably, the probing depth was 4 mm and the probe bleeding degree was 2. In the periodontal pocket, subgingival plaques and attachment loss was observed.

Figure 1  Initial intra-oral examination demonstrated swelling in the left maxillary molar buccal gingival region.

Laboratory examinations

Notably, results of laboratory tests revealed that the complete blood count of the patient was normal.

To further investigate the nature of the gray-white infiltrating mass, an incisional biopsy was performed using an intra-oral approach. After specimen collection, tissues were fixed in 10% PFA for 24 h and subsequently embedded in paraffin. Histological sections were obtained, dehydrated, and subjected to hematoxylin and eosin staining. Simultaneously, each section was incubated overnight at 4 °C in the presence of primary antibodies against myeloperoxidase-positive (MPO), Ki-67, CD3, CD34, CD56, CD10, CD7, CD20, CD21, TIA1, and Mum-1 (Maixin, China), followed by secondary immunohistochemistry labeling. After overnight hybridization with Eber probes (VENTANA, United States), the sections were washed and incubated at 37 °C for 30 min with the appropriate horseradish peroxidase-conjugated secondary antibodies. Finally, all sections were subjected to microscopic examination and histopathological diagnosis.

During the histological examination of the gingival biopsy specimen, diffuse infiltration of abnormal cells was observed throughout the tissue (Figure 2). Moreover, an immunohistochemical analysis was performed to characterize the type of neoplastic cells present. Results of this analysis indicated that the neoplastic cells were MPO, and the Ki-67 staining rate was 80% (Figure 3). Moreover, results of the present study demonstrated that cells were negative for CD3, CD34, CD56, CD10, CD7, CD20, CD21, TIA1, Mum-1 and Eber (Figure 4). Collectively, results of the histopathological and immunohistochemical analyses led to a diagnosis of MS. The patient was referred to a hematologist, who confirmed the initial diagnosis of leukemia.

Figure 2 A photomicrograph demonstrated the presence of diffuse neoplastic infiltration in the gingiva, indicating the involvement of abnormal cells that invaded the tissue in a scattered manner. These neoplastic cells are described as intermediate-sized immature blast-like cells with thin cytoplasm, finely-dispersed chromatin, and rounded or indented nuclei. Magnification, × 300.

Figure 3 Neoplastic cells stained positive for myeloperoxidase-positive and Ki-67. Magnification, × 200. MPO: Myeloperoxidase-positive.

Figure 4 Cells were negative for CD3, CD34, CD56, CD10, CD7, CD20, CD21, TIA1, Mum-1 and Eber. Magnification, × 200.

In the pathological bone marrow biopsy results of this case, the ratio of red blood cells to granulocytes is consistent with the expected values, and various stages of red blood cells and granulocytes are observed. The predominant cell population in the red blood cell lineage consists of mature cells. Megakaryocytes are visible, and their nuclei exhibit segmentation. Plasma cells are rarely observed in the lymphocytic lineage. Both fe and reticular fibers were positive staining pattern. There is no diffuse infiltration of abnormal leukemia cells in the bone marrow, indicating that the bone marrow is not involved. Alternatively, it is possible that the disease has not progressed to involve the bone marrow, and there is no cytological evidence of acute leukemia (Figure 5). Notably, granulocytes observed in the bone marrow slices demonstrated high levels of proliferation. Each stage of the granulocyte was visible, and 3% of the original granulocytes were in the late stage (Figure 6). In addition, eosinophilic granulocytes were visible.

Figure 5 The proportion of red blood cells and granulocytes was as expected. A: Various stages of red blood cells; B: Various stages of granulocytes. Red cell stages were dominated by mature cells. Megakaryocytes were visible with lobulated nuclei. Few plasma cells of lymphocytes were observed. Both fe and reticular fibers were positive. Magnification, × 300.

Figure 6 Immunophenotyping using flow cytometry. A: A 63.7% of the cells were granulocytes, 17.8% of the cells were lymphocytes, 2.6% of the cells were monocytes, 1.7% of the cells were immature cells and 9.9% of the cells were CD45-negative; B-H: Flow cytometry was performed using myeloperoxidase-positive (MPO), CD79a, CD7, CD33, CD11b, CD13, CD16, CD19 and CD3 antibodies. The MPO/CD79a, CD7/CD33, CD11b/CD13, CD11b/CD16, CD16/CD13, CD19/CD33 and CD3/CD79a gate helps distinguish granulocytes morphology. The results showed that granulocytes morphology were generally within normal parameters; I-K: Flow cytometry was performed using CD4, CD56 and CD123 antibodies. The CD4/CD56, CD4/CD123 and CD56/CD123 gate helps distinguish B-cell. No distinct expressing CD4, CD56, and CD123 were observed within the B-cell group in the present study. FITC: Fluorescein isothiocyanate; ECD: Extracellular domain; ADC: Apparent diffusion coefficient.

Flow cytometry was employed for the immunophenotypic analysis of the whole blood samples obtained to characterize immune cell subpopulations. After red blood cell lysis and washing, cells were centrifuged at 300 ×g for 10 min, the supernatant was completely aspirated, and a pre-mixture of antibodies against CD45, MPO, CD33, CD11b, CD13, CD16, CD19, CD3, CD4, CD56, and CD123 was added to the cells. The cells were resuspended and incubated in the dark at 4 °C for 10 min. After incubation, cells were centrifuged, and the cell pellet was resuspended and washed in PBS containing 1% BSA. Flow cytometric analysis was performed immediately.

Immunophenotyping using flow cytometry revealed that 63.7% of the cells were granulocytes, 17.8% of the cells were lymphocytes, 2.6% of the cells were monocytes, 1.7% of the cells were immature cells, and 9.9% of the cells were CD45-negative (Figure 6A). The granulocyte morphology of CD45, MPO, CD33, CD11b-CD13-CD16 is generally within normal parameters (Figure 6B-F). No distinct expressing CD4, CD56, and CD123 were observed within the B-cell group in the present study (Figure 6I-K).

The presence of the CD45 marker ruled out the potential for other tumors, and indicated that the lesion was a result of a hematopoietic disorder. Based on the absence of CD20 and CD3 markers, the patient was evaluated for potential lymphomas. Notably, these markers are commonly used in immunophenotyping to identify specific types of lymphocytes, and the absence of CD20 and CD3 markers are indicative that B-cell and T-cell lymphomas are less likely to be present. The lesion observed in the present case was confirmed as MS due to high MPO expression levels[14].

Imaging examinations

Radiological examination revealed no extensive bone loss (Figure 7). The gray-white color of the mass was indicative of localized chronic periodontal disease. The patient was referred to a hematologist, who confirmed the initial diagnosis of leukemia.

Figure 7  Radiological examination demonstrated left maxillary second molar in the absence of bone destruction.

FINAL DIAGNOSIS

The lesion observed in the present case was confirmed as MS.

TREATMENT

The patient initially received the idarubicin (IDA) regimen (IDA hydrochloride 10 mg/1 d-3 d, Cytarabine 100 mg/1 d-7 d) treatment, supplemented with gastric protection and antiemetic therapy. After one course of chemotherapy, the patient was switched to the Mitoxantrone (MA) regimen (MA 8 mg/1 d-3 d, Cytarabine 100 mg/1 d-7 d), with additional measures for gastric protection and antiemetic therapy.

OUTCOME AND FOLLOW-UP

After the two courses of chemotherapy, results of the computed tomography scan demonstrated complete clearance of the tumor. On days 7-14 after discontinuing chemotherapy, a bone marrow and blood sample examination indicated remission. On days 21-28 after discontinuing chemotherapy, a follow-up bone marrow and blood cell count showed complete disease remission. At the 12-month follow-up appointment, the patient was in a stable condition with the absence of MS progression, but long-term follow-up is still required in the later stages.

DISCUSSION

MS is a rare type of cancer that involves the growth of myeloid cells outside of the bone marrow. Notably, MS occurs as an extramedullary tumor mass in various parts of the body. This tumor is often associated with AML, and is estimated to develop in 2%-8% of patients with AML[2]. However, the specific pathogenesis of MS is not yet fully understood. Results of a previous study demonstrated that MS originates in the bone marrow and travels via the Haversian canals to reach the subperiosteal bone region[15].

Results of previous studies described increases in tissues with intact mucosa that varied in color, including brown, black, red and pale-gray. MS is often associated with other hematological disorders, such as myeloid leukemia and other myeloproliferative disorders. Previous studies described the presence of MS in the gingiva, palate, extraction sockets and buccal mucosa, despite the rare occurrence of MS in the oral cavity[16-18]. Notably, symptoms may be comparable with those of periodontitis, periodontal abscesses, pyogenic granuloma, carcinoma or lymphomas[10,19,20].

MS is not an aggressive tumor, and the lesion described in the present study demonstrated no extensive bone loss. Notably, the lesion described in the present study was gray-white in color, compared with the dark red color of the majority of periodontal diseases. As malignant, infectious and inflammatory lesions may exhibit overlapping clinical features, accurate diagnoses are challenging. Thus, the selection of appropriate histological and immunohistochemical analyses is required for the accurate clinical diagnosis of MS[11].

Histological examination carried out in a previous study revealed an infiltrate of primitive, poorly differentiated cells with round to oval nuclei, granular chromatin, well-defined nuclear membranes and variably prominent nucleoli[15]. Notably, granulocytic sarcomas are histologically comparable with lymphomas. Thus, immunohistochemical studies are ineffective in establishing an accurate diagnosis[21].

In the present study, an immunohistochemical examination was performed to exclude malignant lymphoma in the case of extramedullary myeloid cell infiltration. Myeloid cell markers were observed in the present study, including MPO and lysozyme, as well as B lineage markers and T lineage markers. The absence of these markers suggested that neoplastic cells involved in infiltration were not of lymphoid origin. Although lymphoid markers, such as CD3 and CD20, were used for differential diagnosis, the history of concurrent leukemia may have played a notable role in the final diagnosis of oral MS[22]. In addition, the presence of B-cell and T-cell lymphomas were excluded following negative staining for CD3 and CD20. However, a concise immunohistochemical panel, including markers such as CD20, CD43, CD68 and MPO are often used to identify the majority of extramedullary myeloid tumors. These markers are commonly used in the evaluation of myeloid neoplasms and may aid in distinguishing them from other types of tumors, including lymphomas[23]. The expression of these markers in conjunction with clinical history and histopathological features support the diagnosis of extramedullary myeloid tumors. Immunohistochemical staining may also aid in the final diagnosis of MS, as bone marrow cells respond to antibodies against lysozyme, MPO and chloroacetate esterase. Bone marrow mother cells in MS typically express antigens associated with bone marrow, such as CD43; however, these do not respond to lymphoid antigens[24].

A high Ki-67 staining rate of 80%-90% indicates a high proliferation rate of malignant cells in the tissue sample. Ki-67 is a protein marker that is often used to assess the proliferation or growth rate of cells in a tissue sample, particularly in the context of cancer[2]. The Ki-67 staining rate observed in the present study was 80%, indicative of malignant cells. MPO is an enzyme located in myeloid cells that is often used as an immunohistochemical marker for the identification of myeloid cells in tissue samples. MPO is used in the diagnosis of myeloid leukemia and other myeloproliferative disorders. MPO may be detected using various staining techniques, including Sudan Black B and peroxidase or diaminobenzidine[16]. Results of the present study indicated positive MPO staining, and negative CD3 and CD20 staining, indicative of a myeloid neoplasm.

The treatment of MS and AML are similar, as MS may develop into AML. Results of a previous study highlighted the slow progression to leukemia in patients with chloroma treated with chemotherapy. However, results of an additional previous study demonstrated that there was no association between the aforementioned treatment and the survival rates of patients[25]. Notably, the presence of MS in myelodysplastic syndromes is indicative of progression to a more aggressive disease stage[26,27]. At present, systemic chemotherapy and local radiotherapy are commonly used treatment options for patients with MS[28]. Notably, high-dose therapies are recommended as a front-line approach for patients with MS, in order to achieve complete remission. High-doses are used as aggressive treatment strategies[29]. Results of a previous study outlined positive outcomes in patients who received chemotherapy at the time of chloroma diagnosis. Specifically, these patients exhibited a lower rate of progression to leukemia, highlighting the potential benefits of early intervention[30]. During the remission period of hematological diseases, such as MS, allogeneic bone marrow or peripheral stem cell transplantation may be considered as treatment options. However, the efficacy of these methods remains unclear. Notably, the overall course of MS is acute, with the majority of MS-related deaths occurring within the first year following diagnosis. This highlights the aggressive nature of the disease, and the requirement for effective treatment strategies[25]. Moreover, there was no significant association between a specific treatment modality and survival.

Prognostic factors for MS may include patient age and genetic factors. Elderly individuals exhibit a higher risk of developing certain types of AML. The presence of AML in a patient with MS may indicate a poor prognosis[12,15]. Specific chromosomal alterations are associated with a more favorable prognosis. In addition, specific chromosomal alterations in patients with MS may be associated with either a more favorable or unfavorable prognosis. Thus, additional assessments of patients may improve the subsequent prognosis. Notably, patients with single lesion involvement exhibited a prolonged survival time compared with patients with multiple organ involvement. These results indicated that metastasis may play a role in determining the prognosis of the patient[2]. Moreover, patients with MS exhibit a poor prognosis, and MS disease progression is closely associated with the clinical course of AML. Thus, MS may significantly impact the progression and outcomes of AML in certain patients.

Following two courses of intensive chemotherapy without radiotherapy in the present case, complete clearance of MS was observed. Thus, early aggressive treatment may prevent or delay subsequent progression to AML; however, additional clinical observations are required in other cases. The overall survival rate of patients with MS remains unclear, as there are a small number of cases. Adequate diagnosis is required for the selection of appropriate treatment options, and the prevention of serious complications.

Mutation gene testing plays a crucial role in the treatment of MS and serves as important diagnostic and therapeutic evidence. Unfortunately, due to the relatively rare occurrence of such cases in the oral cavity, our lack of experience led us to not conduct these gene mutation tests in the initial sample cohort, including ASXL1, NPM1, DNMT3A, FLT3, TET2, IDH2, TP53, EZH2, and STAG2, among others. It is highly necessary to consider these gene tests as potential avenues for future research, thereby enhancing the quality and significance of our work.

In conclusion, the occurrence of MS in the oral cavity is rare. A diagnosis of MS should be considered in patients that present with atypical clinical features. Diagnosis of MS may be confirmed following histological and immunohistochemical examinations.

CONCLUSION

The present study reported the case of MS with gingival swelling in the maxillary region, with aleukemic presentation in a 32-year-old male patient. Diagnosis of MS may be confirmed following histological and immunohistochemical examinations.