|Year : 2017 | Volume
| Issue : 6 | Page : 989-993
Myeloid sarcoma: A clinicopathological study with emphasis on diagnostic difficulties
Ranjini Kudva, Vidya Monappa, Girish Solanke, Manna Valiathan, Anuradha C. K. Rao, V Geetha
Department of Pathology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India
|Date of Web Publication||13-Dec-2017|
Dr. Vidya Monappa
Department of Pathology, Kasturba Medical College, Basic Science Block, Manipal - 576 104, Karnataka
Source of Support: None, Conflict of Interest: None
Background: Myeloid sarcoma (MS) is a rare tumor composed of proliferation of myeloid precursors at extramedullary sites. They can arise de-novo or in association with hematological malignancies, most commonly acute myeloid leukemia. Clinically, it can masquerade as an abscess, cutaneous ulcer, or mass lesion. Morphologically, MS can mimic a variety of small round cell tumors including lymphomas and rhabdomyosarcoma.
Aims: (1) To study the clinical presentations and laboratory findings in patients with MS; (2) to revisit the histomorphological findings and the differential diagnosis of MS; (3) to evaluate the diagnostic role of immunohistochemistry (IHC) and determine the useful markers for accurate diagnosis of MS.
Materials and Methods: We reviewed cases of MS reported in our institution over a 10-year period from January 2004 to December 2013. The clinical presentations, laboratory data, and histopathological and immunohistochemical findings were studied.
Results: There were nine cases in our database, none of which were clinically suspected to be MS. Age ranged from 3 to 55 years, with a slight female preponderance. Cervical lymph nodes were the most common site involved. Histologically, the common finding was the presence of medium- to large-sized cells with fine granular chromatin, small nucleolus, and scant cytoplasm along with scattered eosinophil precursors. Myeloperoxidase was the most useful IHC marker. All cases were also positive for leukocyte common antigen contributing to the diagnostic confusion with lymphoma.
Conclusion: The possibility of MS should be considered when dealing with unusual lymphoma-like neoplasms that cannot be categorized as any of the Non-Hodgkin lymphoma subtypes.
Keywords: Chloroma, extramedullary myeloid tumor, myeloid sarcoma, myeloperoxidase
|How to cite this article:|
Kudva R, Monappa V, Solanke G, Valiathan M, Rao AC, Geetha V. Myeloid sarcoma: A clinicopathological study with emphasis on diagnostic difficulties. J Can Res Ther 2017;13:989-93
|How to cite this URL:|
Kudva R, Monappa V, Solanke G, Valiathan M, Rao AC, Geetha V. Myeloid sarcoma: A clinicopathological study with emphasis on diagnostic difficulties. J Can Res Ther [serial online] 2017 [cited 2020 Jan 23];13:989-93. Available from: http://www.cancerjournal.net/text.asp?2017/13/6/989/220418
| > Introduction|| |
Myeloid sarcoma (MS) also known as granulocytic sarcoma, extramedullary myeloid tumor, or chloroma is a rare neoplasm characterized by the occurrence of one or more tumor masses composed of immature myeloid cells at extramedullary sites. First described by Burns in 1811, the term “Chloroma” was coined by King in 1853 to describe this tumor based on its green color which is due to the enzyme myeloperoxidase (MPO) present in the myeloid cells. The new WHO classification describes this tumor as MS. It commonly occurs in bone, skin, or lymph node although any part of the body may be affected. It can arise de-novo, precede, or occur in association with any myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), or most commonly acute myeloid leukemia (AML). When the bone marrow (BM) biopsy does not demonstrate any hematological malignancy, the MS is described as nonleukemic or isolated. In patients without any preexisting hematological disorder, the diagnosis of MS is generally delayed due to the lack of suspicion. Morphologically, it can mimic “small round cell tumors” and lymphomas, thus contributing to the diagnostic difficulty.
| > Materials and Methods|| |
Searches of the pathology database in our tertiary care hospital identified nine patients diagnosed with MS over a 10-year period from January 2004 to December 2013. The clinical presentation and laboratory data of each case were documented. The original histopathology slides were retrieved and the histomorphology was reviewed. Immunohistochemistry (IHC) findings were obtained from the histopathology records; wherever necessary, additional markers were performed.
| > Results|| |
Nine cases were retrospectively identified for inclusion in this study. Summary of the cases is presented in [Table 1].
Clinical presentation showed a diverse picture with fever, weight loss, and easy fatigability being most common. Other symptoms were related to the site of involvement by tumors, such as proptosis (Case 4) and progressive weakness of lower limbs (Case 7). Clinical presentation, peripheral smear, and BM findings of each case are summarized in [Table 2]. None of the cases were clinically suspected to be MS. Even in the two cases with known hematological malignancy, possibility of MS was not clinically considered.
Other laboratory parameters (available in eight patients, excluding Case 9)
Hemoglobin was decreased in all patients (range: 4–10 g/dl); erythrocyte sedimentation rate was elevated in five patients; lactate dehydrogenase levels were done in two patients, both being elevated. Platelet count was decreased in four cases and was borderline in one case.
Histomorphologically, the common finding was the presence of myeloblasts. These cells appeared pale on hematoxylin and eosin stain, were medium to large in size, with enlarged irregular nucleus, few showing nuclear folds with fine granular chromatin, single small nucleolus, and scanty cytoplasm. The monoblasts seen in Case 5 and 8 were larger and showed moderate amount of cytoplasm. Fifty percent of the cases showed heterogeneous cell population with a mixture of myeloid precursors and lymphocytes. Eosinophil metamyelocytes with indented nucleus and moderate orangeophilic cytoplasm were seen in eight of the nine cases, proving to be a very useful morphological pointer. Mature eosinophils were seen in one- third of the cases. Other findings were the presence of increased mitosis, crush artifacts, and areas of necrosis [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d.
|Figure 1: (a) Section shows blastic variant of myeloid sarcoma with sheets of myeloblasts (H and E, ×400); (b) Section shows immature variant of myeloid sarcoma with myeloblasts and promyelocytes (more abundant cytoplasm and indented nucleus) (H and E, ×400); (c) Section shows monoblastic sarcoma showing sheets of large cells with cleaved nucleus (H and E, ×400), (d) Section shows eosinophil precursors with bright eosinophilic cytoplasm (H and E, ×400)|
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IHC findings were available only in eight cases, the remaining case being a slide review. MPO was strong, diffuse positive in 6/8 cases. The two cases associated with AML-M5a showed only scattered positive cells [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d. In one of these two cases, CD56 was negative. CD34 was done in four cases and showed diffuse positivity in two cases [Figure 3]a. CD117 was done only in one case where it showed occasional positive cells while MPO showed diffuse positivity [Figure 3]b. Leukocyte common antigen (LCA) was positive in all eight cases, the intensity varied from weak to moderate and focal to diffuse but was never strong [Figure 3]c. CD99 was done in two cases, wherein it showed diffuse membrane positivity [Figure 3]d. CD20 and CD3 were uniformly negative in all the cases. In Cases 3 and 4, desmin was negative ruling out possibility of rhabdomyosarcoma (RMS).
|Figure 2: (a and b) Diffuse, strong myeloperoxidase positivity in tumor cells (MPO, ×400 and ×200,) respectively, (c and d) scattered cells positive in monoblastic sarcoma (MPO, ×100)|
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|Figure 3: (a) Diffuse CD34 positivity in tumor cells (CD34, ×200); (b) Occasional CD117 positive tumor cells (CD117, ×400); (c) Diffuse, faint membranous leukocyte common antigen positivity in tumor cells (LCA, ×400); (d) Diffuse CD99 membranous positivity in tumor cells (CD99, ×400)|
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Treatment data were available only in seven cases. Cases associated with known or simultaneously detected hematological malignancy (Cases 1, 2, 3, 5, and 8) were treated as cases of AML with systemic chemotherapy. Case 4 was started on induction chemotherapy with daunorubicin and cytarabine. Within a span of 1 month, the patient developed multiple osteoblastic secondaries, peripheral blood neutropenia with paralytic ileus and expired. Case 7 underwent surgical laminectomy and was subsequently lost to follow-up. Cases 6 and 9 availed treatment at other centers.
Two patients developed multiple osteoblastic secondaries 1–2 months following histopathological diagnosis. One patient died and the other was lost to follow-up. Three patients are currently on follow-up and in remission. Other cases were lost to follow-up.
| > Discussion|| |
MS's are rare extramedullary myeloid tumors with an incidence between 3% and 4.7% of MPDs' and in 2–8% of patients with AML. The various clinical settings possible are as follows: (i) In association with AML, (ii) in nonleukemic patients with normal peripheral blood and BM findings but who in due course of time develop AML, (iii) in MDS with leukemic transformation, (iv) in association with MPDs, where it heralds the onset of blastic transformation. In this study, we found that most cases had simultaneously detected AML.
The capacity of the immature myeloid cells to invade extramedullary organs depends on several factors such as cellular surface markers and cytogenetic abnormalities. The expression of adhesion molecules such as CD56 may increase the ability of circulating blasts to home to the extramedullary sites. They have been commonly associated with FAB subtypes M5a, M5b, M4, and M2 AML.
MSs commonly occur in young patients or children with no sex predilection. In the present study, however, it was common in the fourth and fifth decades with a slight male preponderance. The organs frequently involved are bones and periosteum, probably due to the proximity to the BM. From the marrow, the tumor cells pass through the Haversian canals and reach the periosteum; later, they pass into the bloodstream and can reach any other organ. Reports in literature describe a lag period of 10–49 months between the diagnosis of MS and the development of AML.
The common sites involved by MS include soft tissue, periosteum, bone, lymph nodes, gastrointestinal tract, pericardium, bronchus, bladder, mediastinum, kidney, and lung. Uncommon sites include jaw, facial nerve, lips, nasal cavity, temporal bone, spine, parotid, cervix, and breast. In this study, cervical lymph nodes followed by skin were the common sites involved.
The clinical manifestations of MS are not specific and consist of local pain and mass effect. Most of our patients had history of easy fatigability, loss of appetite, fever. The blood-stained nasal discharge in Case 3 was probably due to tumor infiltration of nasal mucosa and tissue necrosis. Case 7 had weakness of lower limbs probably due to mass effect on the spinal cord. Radiological findings are also nonspecific; hence, the onus of diagnosing MS solely rests solely on the pathologist.
Histopathology has a central role in diagnosing MS, and this is further strengthened by the use of IHC. Diagnosis is comparatively easier when it arises in a setting of AML/MPS or MDS. However, in the absence of known hematological disorder, arriving at the diagnosis may be challenging. Routine histological examination of the tumors shows pleomorphic infiltrate of primitive cells of varying sizes and nuclear configuration with mononucleate and granulocytic cells of variable maturity along with scattered eosinophilic myelocytes. Eosinophilic myelocytes are a useful clue to the diagnosis; however, they may not always be present.
MS can be further subdivided into four groups based on the degree of maturation – blastic (predominantly myeloblasts), immature (myeloblasts and promyelocytes), differentiated (promyelocytes and mature neutrophils), and monoblastic sarcoma (monocytic precursors with large cells showing abundant cytoplasm). No prognostic significance is attributed to this categorization, and it has been omitted in the 2008 WHO classification of tumors of hematopoietic and lymphoid tissue. In the present study, there were five cases of blastic, two cases of immature, and two cases of monoblastic MS. Majority of our cases showed at least an occasional eosinophil precursor aiding in the diagnosis even in the absence of clinical suspicion or known hematological disorder. The authors noted cells with moderate amounts of cytoplasm, with enlarged folded nuclei in two cases wherein the BM showed AML - M5a leukemia (monoblastic sarcoma). Rarely, tumors with trilineage hematopoiesis or predominantly erythroid precursors or megakaryoblasts may occur in conjunction with transformation of MPDs'.
MS has to be differentiated from other morphologic mimickers which include non-Hodgkin lymphoma (NHL) (lymphoblastic lymphoma, diffuse large B-cell lymphoma, Burkitt lymphoma), poorly differentiated carcinoma, blastic plasmacytoid dendritic cell neoplasm (BPDCN), and small round blue cell tumors such as RMS and neuroblastoma. The differentials vary depending on the age of the patient and site of occurrence. IHC has an important role in this regard. CD68-KP1 is the most frequently expressed marker in MS, followed by MPO, CD117, CD99, CD68/PG-M1, lysozyme, CD34, terminal deoxynucleotidyl transferase, CD56, CD61/linker of activated T lymphocyte/factor VIII-related antigen, CD30, glycophorin A, and CD4. Monoblastic sarcoma is negative for MPO and positive for CD68 and lysozyme.
NHLs are positive for LCA and either T- or B-cell markers. MS may show weak LCA positivity but will be negative for B and T-cell markers. Carcinomas are generally cytokeratin positive. BPDCN shows cutaneous involvement and is positive with CD4, CD56, and CD123. CD99 positivity in MS can cause diagnostic confusion with small round blue cell tumors. Other specific markers such as desmin (RMS) are essential as observed in our cases.
Fluorescent in situ hybridization and/or cytogenetic studies can detect chromosomal aberrations such as monosomy 7, trisomy 8, MLL-rearrangement, inv (16), monosomy 16, 16q-, 5q-, 20q-, and trisomy 11 in around 55% of the cases. About 16% cases show evidence of (nucleophosmin) NPM1 mutation.
Owing to their rarity, there is no well-documented optimal treatment for MS. Literature describes treatment based on mostly case series; majority of which are retrospective studies. However, the consensus opinion suggests cytarabine-containing remission inducing systemic chemotherapy for isolated MS. It remains unclear whether consolidation therapies are required or not. Surgery could be an option for tumors causing organ dysfunction and/or obstruction. However, systemic therapy should be considered in all patients as soon as the diagnosis is confirmed to prevent or prolong relapse and progression to acute leukemia. Radiation therapy could be used for consolidation along with systemic chemotherapy. Hematopoietic stem cell transplantation can prove useful in patients in remission or relapse following chemotherapy.
Prognosis varies with the clinical situation. In MDS/MPD, the prognosis is bad as MS represents progression to blast crisis. Recurrence after BM transplantation suggests failure or resistance to therapy. In AML, prognosis is however not affected. The presence of MS in patients with the otherwise good-risk t (8;21) AML may be associated with a lower complete remission rate and decreased remission duration. Tsimberidou et al. demonstrated that isolated MS patients with chromosome 8 abnormalities had a worse prognosis and hence require intensive chemotherapy. In Case 4, the patient succumbed to complications secondary to chemotherapy. Necessary precautions to avoid this complication are thus recommended particularly so in pediatric patients.
| > Conclusion|| |
MSs are very rare tumors with an aggressive clinical course. Morphologically, they can mimic a variety of tumors which fall broadly under the category of small round cell tumors. This problem is further complicated by the lack of clinical suspicion in patients with no known hematological disorder. The presence of scattered eosinophilic myelocytes in tissue biopsy specimens is a very useful clue to the diagnosis. However, accurate diagnosis requires appropriate use of IHC markers, MPO being the most frequently expressed marker. The possibility of MS should be considered when dealing with unusual lymphoma-like neoplasms that cannot be categorized as any of the NHL subtypes. A diligent search for eosinophil precursors can be rewarding. A delay in the diagnosis may result in unwarranted fatality particularly so in pediatric patients.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]