• Users Online: 604
  • Print this page
  • Email this page


 
 
Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 1  |  Page : 1-7

Central nervous system manifestations of hematological malignancies: Our spectrum over 3 years


1 Department of Laboratory Medicine, Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, Telangana 500034, India
2 Department of Neurosurgery, Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, Telangana 500034, India
3 Department of Medical Oncology, Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, Telangana 500034, India

Date of Submission02-Jan-2021
Date of Acceptance16-Feb-2022
Date of Web Publication12-Apr-2022

Correspondence Address:
Dr. Rachna Khera
Department of Laboratory Medicine, Basavatarakam Indo-American Cancer Hospital and Research Institute, Hyderabad, Telangana.
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_1_21

Rights and Permissions
  Abstract 

Objective: Hematological malignancy presenting primarily with central nervous system (CNS) manifestations is rare and often portends a worse prognosis. The aim of this study is to report the spectrum of hematological malignancies presenting primarily with CNS symptoms. Materials and Methods: All histologically verified hematological malignancies involving CNS from January 2016 to December 2018 were included. The presence of lymphadenopathy, organomegaly, and bone marrow (BM) examination results was recorded to rule out a spread from systemic disease. The diagnosis was aided by special stains (reticulin) and immunohistochemistry (IHC) as appropriate. Antibodies used were CD20, CD3, CD10, Bcl 2, Bcl 6, MUM 1, CD138, CD68, MPO, PCK, and Ki67. The Hans algorithm was used to classify diffuse large B cell lymphoma (DLBCL) into germinal center B-cell (GCB) and non-GCB types. Results: During the study period, 18 DLBCLs, 4 plasmacytomas, and 3 myeloid sarcomas (MSs) were diagnosed. DLBCLs included 16 primary central nervous system lymphomas (PCNSLs) and 2 systemic lymphomas with evidence of lymphadenopathy. PCNSLs had male predominance and a mean of 46 (14–67) years. Frontal lobe was the most common location. Seven (70%) PCNSLs were non-GCB type and 3 (30%) were GCB type. One was a primary spinal T cell/histiocyte-rich large B cell lymphoma (a variant of DLBCL). Two were diagnosed as corticoid-mitigated lymphoma. One of the three MS cases had acute myeloid leukemia on BM examination and the rest two were isolated spinal masses with normal BM study. There were four spinal plasmacytomas, presenting with cord compression. Conclusion: Primary CNS presentation of hematological malignancies requires a high index of suspicion clinically and radiologically, and diagnosis requires IHC for proper classification.

Keywords: GCB, myeloid sarcoma, non-GCB, PCNSL, plasmacytoma


How to cite this article:
Khera R, Ahmed F, Mundada MC, Kommu VR, Murthy SS, Challa S, Rajappa SJ, Mallavarapu KM, Santa A, Kumar PB. Central nervous system manifestations of hematological malignancies: Our spectrum over 3 years. Int J Neurooncol 2021;4:1-7

How to cite this URL:
Khera R, Ahmed F, Mundada MC, Kommu VR, Murthy SS, Challa S, Rajappa SJ, Mallavarapu KM, Santa A, Kumar PB. Central nervous system manifestations of hematological malignancies: Our spectrum over 3 years. Int J Neurooncol [serial online] 2021 [cited 2022 Jun 27];4:1-7. Available from: https://www.Internationaljneurooncology.com/text.asp?2021/4/1/1/342817




  Introduction Top


Hematological malignancy presenting in the central nervous system (CNS) as the initial manifestation is a rare phenomenon. It can pose a diagnostic challenge and often portends a worse prognosis.[1] Hence, accurate diagnosis at the earliest is important for the proper management of the patients. Most common hematological malignancy affecting CNS is primary central nervous system lymphoma (PCNSL), defined as diffuse large B cell lymphoma (DLBCL) confined to brain, leptomeninges, or spinal cord without evidence of systemic lymphoma. It represents 2.4–3% of all brain tumors and 4–6% of all extranodal lymphomas.[2] CNS involvement by systemic DLBCL at presentation accounts for less than 5% of systemic non-Hodgkin’s lymphoma (NHL).[3] CNS involvement can be seen in leukemia either by direct infiltration of brain and/or spinal cord by leukemic cells as primary manifestation or as a complication of treatment (secondary manifestation). Myeloid sarcoma (MS), also known as granulocytic sarcoma or chloroma, is an extramedullary myeloid tumor, most frequently affecting skin, lymph nodes, gastrointestinal tract, bone, soft tissue, and testes.[2] Spinal epidural MS is not common, and spinal cord compression caused by a granulocytic sarcoma is even rarer.[4] Plasma cell myeloma is a hematological disorder with bone marrow (BM)-based proliferation of plasma cells. Spinal involvement presenting with cord compression has been reported in 11–24% of the patients with myeloma.[5] We, in this study, aim to report spectrum of hematological malignancies which presented primarily with CNS symptoms at our institute over 3 years.


  Materials and methods Top


All histologically verified cases of hematological malignancies involving CNS from January 2016 to December 2018 were included. The presence of lymphadenopathy and organomegaly and BM examination results were recorded to rule out a spread from systemic disease.

The slides and blocks were retrieved from archives of pathology department. Hematoxylin and Eosin (H&E)-stained sections were reviewed, and diagnosis was made by histopathology aided by special stains (reticulin) and immunohistochemistry (IHC) as appropriate. Reticulin staining was done to highlight the perivascular framework of tumor cells. For IHC, streptavidin biotin conjugate immunoperoxidase method[6] was used. Antibodies used were CD20 (Dako, clone L26, ready to use), CD3 (Cell Marque, clone MRQ-39, dilution, 1:100), CD10 (Dako, clone 56C6, ready to use), B-cell lymphoma-2 (Bcl-2) (Dako, clone124, ready to use), Bcl-6 (Dako, clone PG-B6P, ready to use), multiple myeloma oncogene 1 (MUM-1) (Cell Marque, clone MRQ-43, dilution, 1:100), CD138 (Cell Marque, clone B-A38, dilution, 1:25), CD68 (Cell Marque, clone KP1, dilution, 1:100), MPO (Dako, polyclonal, ready to use), Pan-cytokeratin (PCK) (Dako, clone AE1/AE3, dilution, 1:50), and Ki67 (Dako, clone MIB1, dilution, 1:100). The Hans algorithm was used to classify DLBCL into germinal center B-cell (GCB) and non-GCB types.[7]


  Results Top


During the study period, a total of 505 CNS tumors were diagnosed including spinal tumors. Hematological malignancies presenting primarily with CNS manifestations constituted 25 (25/505, 4.9%). There was male predominance (male: female 3:1) with age ranging from 14 to 67 (mean 46) years in our cohort. All the patients were immunocompetent. Frontal lobe was the most common location. Based on the pathology and IHC, patients were diagnosed with DLBCL in 18, MS in 3, and plasmacytoma in 4 cases.

Diffuse large B cell lymphoma (n = 18)

The tumor was composed of large cells with vesicular nuclei and prominent nucleoli with some interspersed small lymphocytes. Reticulin stain revealed perivascular cuffing by tumor cells and prominent network in majority of the cases. On further work up, two cases were found to have systemic diseases, and so, they were considered secondary CNS involvement by systemic DLBCL. Sixteen cases were labeled as PCNSL, which constituted 3.2% of all CNS tumors diagnosed over this period.

Out of the 16 cases labeled as PCNSL, IHC for CD10, Bcl6, and MUM1 was not performed in three cases. Large cells were seen only focally, dominated by infiltration of foamy macrophages and small mature lymphocytes in two cases [Figure 1]. A diagnosis of PCNSL (corticoid-mitigated lymphoma) was made in these two cases as there was a history of administration of steroids pre-operatively. One case was diagnosed as primary spinal T cell/histiocyte-rich large B cell lymphoma (a variant of DLBCL characterized by only scattered large cells in the T-cell and histiocyte-rich background).[8] Hence, the Hans algorithm could not be applied in these six cases. Ten out of 16 cases were further subtyped as per Hans algorithm, seven of which (70%) belonged to the non-GCB group [Figure 2] and three (30%) to the GCB group [Figure 3]. CD20 was positive in all the cases. CD10 was positive in the three cases (GCB group). Bcl-2 expression was seen in 7/9 (77%), Bcl-6 in 12/16 (75%), and MUM1 in 11/16 (69%) cases. Co-expression of BCL-6 and MUM1 was noted in 69% (11/16) of the cases.
Figure 1: Microscopic features of PCNSL (corticoid mitigated lymphoma). (A) Tumor predominantly shows foamy histiocytes (H&E ×400). (B) Scattered foci of large lymphoid cells seen (H&E ×400). (C) These cells are positive for CD20 (IHC ×100). (D) Background CD3-positive T lymphocytes are seen admixed with histiocytes (IHC ×100). (E) Histiocytes positive for CD68 immunostain (IHC ×100)

Click here to view
Figure 2: Imaging and microscopic features of DLBCL—non-GCB. (A and B) MRI brain T2W sagittal and coronal views show hypointense lesion with extensive perilesional edema in the left frontoparietal region. (C) Diffuse sheets of large lymphoid cells with high N/C ratio, vesicular nucleus, and prominent nucleolus. Few multinucleate cells are seen (H&E ×400). (D)–(I) show immunohistochemical features. (D) Tumor cells positive for CD20 (IHC ×400). (E) Tumor cells negative for CD3 (IHC ×400). (F) Ki67 labeling index in the tumor cells is 80%. (G) Tumor cells negative for CD10 (IHC X400). (H) Tumor cells positive for BCL6 (IHC ×400). (I) Tumor cells positive for MUM1 (IHC ×400)

Click here to view
Figure 3: Imaging and microscopic features of DLBCL—GCB. (A) MRI brain T2W coronal image shows isointense mass lesion in the left capsuloganglionic area with perilesional edema and mass effect over supratentorial ventricular system. (B) Intraoperative squash smears show large lymphoid cells in a granular background (H&E ×400). (C) Diffuse sheets of large lymphoid cells with high N/C ratio, vesicular nucleus, and prominent nucleolus (H&E ×400). (D) to (I) show immunohistochemical features. (D) Tumor cells positive for CD 20 (IHC × 400). (E) Tumor cells negative for CD 3 (IHC ×400). (F) Ki67 labeling index in the tumor cells is 65%. (G) Tumor cells positive for CD 10 (IHC ×400). (H) Tumor cells positive for BCL6 (IHC ×400). (I) Tumor cells negative for MUM1 (IHC ×400)

Click here to view


IHC results of PCNSL cases are provided in [Table 1].
Table 1: Immunohistochemistry results in PCNSL cases

Click here to view


Myeloid sarcoma (n = 3)

All the patients presented as extradural spinal masses with cord compression. Morphologically, the cells revealed high nucleocytoplasmic ratio, with vesicular nucleus having round-to-mildly irregular nuclear contours and scant-to-moderate amount of eosinophilic cytoplasm. One patient had concomitant acute myeloid leukemia on BM examination, whereas the other two cases had normal BM study. All three cases of MSs were immunopositive for CD117 and MPO, but were negative for PCK, CD34, CD20, and CD3 [Figure 4].
Figure 4: Microscopic features of myeloid sarcoma. (A) Tumor shows sheets of round cells with high N/C ratio (H&E ×100). (B) MPO immunostain positivity in the tumor cells (IHC ×400). These cells are negative for (C) pan keratin and (D) CD34 (IHC ×100). (E) CD117 positivity in the tumor cells (IHC ×100)

Click here to view


Plasmacytoma (n = 4)

All patients presented with extradural spinal masses with cord compression. Histopathology examination revealed sheets of cells with moderate eosinophilic cytoplasm, round central to eccentric nucleus, and coarse chromatin. On IHC, tumor cells expressed CD138 in all the four cases. IHC for CD20, CD3, and CD56 yielded negative results [Figure 5]. BM examination was carried out in only one case and revealed 7% of the plasma cells.
Figure 5: Microscopic features of plasma cell neoplasm. (A) Tumor shows sheets of plasma cells (H&E ×100). (B) CD138 immunostain positivity in the tumor cells (IHC ×400). These cells are negative for (C) CD20, (D) CD3, (E) CD56 (IHC ×100)

Click here to view



  Discussion Top


Hematological malignancy presenting primarily with CNS features is relatively rare. In our study, hematological malignancies constituted 4.9% and PCNSL constituted 3.2% of all the CNS tumors diagnosed over 3 years which is comparable to other studies in the literature.[9],[10],[11]

PCNSL is a distinct form of extranodal lymphoma, accounting for approximately 4–6% of extranodal lymphomas. (1) It is commonly seen in immunocompromised patients; however, increased incidence has been reported in both immunocompetent and immunocompromised patients over the past two decades.[10] Immunodeficiency is known to play a major role for the development of PCNSL, but in our study, none of the PCNSL patients was immunodeficient.

Age range for PCNSL is wide with a peak incidence reported in the sixth or seventh decades in the immunocompetent patients, and younger age in the immunocompromised individuals.[11] The age of onset was 46 years in our study, which is in agreement with other series in Indian patients who were immunocompetent.[12],[13],[14]

According to the Hans algorithm, PCNSL commonly belongs to non-GCB subtype as CD10 expression is reported in less than 10% of the cases.[15] Camilleri-Broët et al.[16] reported a series of 83 patients of DLBCL of brain and found that non-GCB subtype constituted 96.3% of the total cases and attributed poor prognosis to this subtype. Bhagavathi et al.,[17] Mahadevan et al.,[18] and Sharma et al.[19] reported similar results, 95.2%, 91.6%, and 79.6%, respectively. Our findings are in agreement with the existing literature that PCNSL is predominantly of non-GCB subtype. Systemic DLBCL has heterogeneous clinical and molecular profile. Non-GCB subtype portends a worse prognosis when compared with GCB subtype in systemic DLBCL. PCNSL has worse overall prognosis than the systemic DLBCL and behaves aggressively.[17],[18] We could not analyze treatment outcome of the patients in our study.

[Table 2] shows the comparison of the present study with other similar studies on PCNSL.
Table 2: Comparison of the present study with other Indian studies

Click here to view


Our study included three patients with MS: one with concomitant BM involvement and two with normal BM study. MS as a cause of cord compression is very rare; however, it is an important cause of morbidity and mortality.[20] Widely accepted management guidelines are not available due to the rarity. Current literature suggests variable treatment modalities including radiotherapy and systemic chemotherapy. Surgery is sometimes used upfront for cases who need immediate debulking and rapid relief.[21] Hence, a high index of suspicion and accurate diagnosis is important in such cases to aid in proper management of the patients.

Four patients with plasmacytoma presented with cord compression due to epidural mass as the initial manifestation. All the patients underwent surgery upfront for decompression. Although the exact incidence of spinal cord compression by epidural myeloma has not been reported, extraosseous involvement of MM is an uncommon condition and is found in <5% of the patients with MM.[22] Extraosseous myeloma involvement at diagnosis or during the course of the disease is considered a poor prognosis. Hence, early intervention is critical for the management of cord compression.[23] Histopathological examination along with IHC workup clinched the diagnosis in all the cases and aided in appropriate treatment of the patients.


  Conclusion Top


Primary CNS presentation of hematological malignancies is rare and poses a diagnostic challenge. A high index of suspicion clinically, radiologically, and diagnostically is needed for accurate diagnosis and appropriate treatment of the patients.

Financial support and sponsorship

Nil.

Conflicts of interest

The authors declare that they have no conflicts of interest.



 
  References Top

1.
Nagpal S, Recht L Treatment and prophylaxis of hematologic malignancy in the central nervous system. Curr Treat Options Neurol 2011;13:400-12.  Back to cited text no. 1
    
2.
Kluin PM, Deckert M, Ferry JA. Primary diffuse large B-cell lymphoma of the CNS. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. editors.WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. Lyon: IARC Press; 2017. p. 167-8.  Back to cited text no. 2
    
3.
Gleissner B, Chamberlain M Treatment of CNS dissemination in systemic lymphoma. J Neurooncol 2007;84:107-17.  Back to cited text no. 3
    
4.
Antic D, Verstovsek S, Elezovic I, Grujicic D, Gotic M, Bila J, et al. Spinal epidural granulocytic sarcoma in non-leukemic patient. Int J Hematol 2009;89:95-7.  Back to cited text no. 4
    
5.
Wallington M, Mendis S, Premawardhana U, Sanders P, Shahsavar-Haghighi K Local control and survival in spinal cord compression from lymphoma and myeloma. Radiother Oncol 1997;42:43-7.  Back to cited text no. 5
    
6.
Hsu SM, Raine L, Fanger H Use of avidin–biotin–peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 1981;29:577-80.  Back to cited text no. 6
    
7.
Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 2004;103:275-82.  Back to cited text no. 7
    
8.
Khera R, Ahmed F, Murthy SS, Rao V, Mallavarapu KM, Challa S Primary spinal T cell/histiocyte-rich large B cell lymphoma (THRLBCL)—A rare diagnosis at a rare site.J Hematopathol2018;11:115-8.  Back to cited text no. 8
    
9.
Sarkar C, Sharma MC, Deb P, Singh R, Santosh V, Shankar SK Primary central nervous system lymphoma—A hospital based study of incidence and clinicopathological features from India (1980–2003). J Neurooncol 2005;71:199-204.  Back to cited text no. 9
    
10.
Villano JL, Koshy M, Shaikh H, Dolecek TA, McCarthy BJ Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. Br J Cancer 2011;105:1414-8.  Back to cited text no. 10
    
11.
Deckert M, Paulus W Malignant lymphomas. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WB, editors. WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon, France: International Agency for Research on Cancer; 2007. p. 188-92.  Back to cited text no. 11
    
12.
Tandon A, Challa S, Shanmugam M, Gopalan S, Paul RT, Digumarthi R Epstein–Barr virus as a possible etiologic agent in primary central nervous system lymphoma in immunocompetent individuals. Neurol India 2009;57:36-40.  Back to cited text no. 12
    
13.
Paul T, Challa S, Tandon A, Panigrahi M, Purohit A Primary central nervous system lymphomas: Indian experience, and review of literature. Indian J Cancer 2008;45:112-8.  Back to cited text no. 13
    
14.
Pasricha S, Gupta A, Gawande J, Trivedi P, Patel D Primary central nervous system lymphoma: A study of clinicopathological features and trend in western India. Indian J Cancer 2011;48:199-203.  Back to cited text no. 14
    
15.
Deckert M, Brunn A, Montesinos-Rongen M, Terreni MR, Ponzoni M Primary lymphoma of the central nervous system—A diagnostic challenge. Hematol Oncol 2014;32:57-67.  Back to cited text no. 15
    
16.
Camilleri-Broët S, Crinière E, Broët P, Delwail V, Mokhtari K, Moreau A, et al. A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: Analysis of 83 cases. Blood 2006;107:190-6.  Back to cited text no. 16
    
17.
Bhagavathi S, Sharathkumar A, Hunter S, Sung L, Kanhere R, Venturina MD, et al. Activated B-cell immunophenotype might be associated with poor prognosis of primary central nervous system lymphomas. Clin Neuropathol 2008;27:13-20.  Back to cited text no. 17
    
18.
Mahadevan A, Rao CR, Shanmugham M, Shankar SK Primary central nervous system diffuse large B-cell lymphoma in the immunocompetent: Immunophenotypic subtypes and Epstein–Barr virus association. J Neurosci Rural Pract 2015;6:8-14.  Back to cited text no. 18
    
19.
Sharma MC, Gupta RK, Kaushal S, Suri V, Sarkar C, Singh M, et al. A clinicopathological study of primary central nervous system lymphomas & their association with Epstein–Barr virus. Indian J Med Res 2016;143:605-15.  Back to cited text no. 19
[PUBMED]  [Full text]  
20.
Seok JH, Park J, Kim SK, Choi JE, Kim CC Granulocytic sarcoma of the spine: MRI and clinical review. AJR Am J Roentgenol 2010;194:485-9.  Back to cited text no. 20
    
21.
Bakst RL, Tallman MS, Douer D, Yahalom J How I treat extramedullary acute myeloid leukemia. Blood 2011;118:3785-93.  Back to cited text no. 21
    
22.
Innes J, Newall J Myelomatosis. Lancet 1961;1:239-45.  Back to cited text no. 22
    
23.
Damaj G, Mohty M, Vey N, Dincan E, Bouabdallah R, Faucher C, et al. Features of extramedullary and extraosseous multiple myeloma: A report of 19 patients from a single center. Eur J Haematol 2004;73:402-6.  Back to cited text no. 23
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Materials and me...
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed674    
    Printed0    
    Emailed0    
    PDF Downloaded81    
    Comments [Add]    

Recommend this journal