xml Dr.Madhusudan Astekar 2013-10-21T00:28:20+05:30 Microsoft® Word 2010 2013-10-21T00:28:20+05:30 ijomp Microsoft® Word 2010

Review Article

Small Round Cell Tumor of the Head and Neck Region: A Review

Reshma V, Kavita Rao, Priya NS, Umadevi HS, Mohsin G, Sreelatha Hosthor


Small round cell tumors configure a heterogeneous group of malignant neoplasms that present clinical predominance in children and young adults. It encompasses a wide variety of undifferentiated primitive neoplasms which have in common the ability, with varying frequency, to present as a nondescript proliferation of round cells with high nuclear cytoplasmic ratio and hyperchromatic nuclei by light microscopy. Their differential diagnosis is influenced by the age of the patient, their site of occurrence, and slight degrees of differentiation exemplified by minor architectural and cytoplasmic features. All tumour types have special treatment modalities and the prognosis is dependent on the exact histological diagnosis confirmed by adjuvants like immunohistochemistry and cytogenetics. This article reviews some of the most common small round cell tumors involving the head and neck region which includes Ewing’s sarcoma, rhabdomyosarcoma, neuroblastoma, and lymphomas.

Keywords: Cytogenetics; Head Neck; Immunohistochemistry; Small Round Cell; Undifferentiated Tumors.

Reshma V, Kavita Rao, Priya NS, Umadevi HS, Mohsin G, Sreelatha Hosthor. Small Round Cell Tumor of the Head and Neck Region: A Review. International Journal of Oral & Maxillofacial Pathology; 2013:4(2):24-33. ©International Journal of Oral and Maxillofacial Pathology. Published by Publishing Division, Celesta Software Private Limited. All Rights Reserved.

Received on: 27/04/2013 Accepted on: 09/08/2013


Small-round-cell tumors (SRCTs) are a group of cytomorphologically similar neoplasms with varied origin. The neoplastic elements include undifferentiated, uniform, small round to oval closely packed cells with a solitary hyperchromatic nucleus and a high nuclear cytoplasmic ratio. The nucleoli may or may not be prominent.1,2

They lack any particular morphological features that would allow precise identification and represent a diagnostic challenge when examined by light microscopy alone. Thus their diagnosis requires an integrated approach which includes immunophenotypic and genetic analysis.3 Immunohistochemistry is now successfully integrated into the diagnostic routine, as they give valuable complementary information.4 SRCTs occur mostly in children and young adults. They tend to involve the skeletal system or soft tissue.3

The most common neoplasms capable of presenting as a SRCT are Ewing's family of tumors, rhabdomyosarcoma, neuroblastoma, lymphomas, and desmoplastic small round cell tumor (DSRCT).2,5,6,7 DSRCT is predominantly an intra-abdominal tumor which sometimes includes pleura and tunica vaginalis.3 The present article selectively reviews the salient histopathological, immunohistochemical and cytogenetic features of small round cell tumors in the head and neck region.

Ewing’s sarcoma Family of Tumors (ESFTs)

ESFTs are those group of highly malignant SRCTs which are characterized by phenotyphic heterogeneity i.e. lack of overt differentiation along a single pathway, non-specific histotypic markers or complex patterns of multi-lineage differentiation with co-expression of neural, mesenchymal and epithelial traits.8 ESFTs comprise osseous and extra osseous Ewing’s sarcoma (ES), peripheral primitive neuroectodermal tumor (pPNET), and Askin tumor of the thorax. Roessner et al classified them into three subgroups, namely typical Ewing’s sarcoma (TES), atypical Ewing’s sarcoma and peripheral neuroectodermal tumor (PNET).9 ES and PNET are closely related tumors with the same t(11:22)(q24;q12) translocation. They represent opposite ends of ES family of tumors that ranges from undifferentiated neoplasms (ES) to morphological evidence of neural differentiation (PNET).10 In the Intergroup Ewing’s Sarcoma Study (IESS) approximately 4% of the primary bone tumors arose in the bones of the head and neck.11 Bone and soft tissue EFTs in the

head and neck have been reported to represent anywhere from 1–7% of EFTs in some studies.13

Histopathology: Conventional: The bone marrow is filled with monotonous population of round blue cells that acquire a nested, sheet-like or solid pattern without any intervening stroma (Fig 1). As the tumour invades soft tissues or periosteum, the stroma consists of reticular network and abundant vasculature and presents a filigree pattern (lace-like rest of tumoral cells enveloped in a dense fibrillar matrix). It shows three types of cells with transitional forms between them:

  • a) Principal / tumoral cells: small blue round cells, cell contours are less defined with scarce cytoplasm.
  • b) Dark cells: condensed chromatin and scarce cytoplasm conforming apoptotic figures.
  • c) Clear cells with poorly defined cytoplasmic borders filled with abundant amounts of glycogen which is considered a specific marker.14,15
  • Vessels with hyalinised walls, surrounded by a rim of neoplastic cells are associated with necrosis which may be focal or extensive. Inflammatory cells are usually absent. Parallel rims of reactive bone consisting of osteoblasts, chondroblasts and giant osteoclasts are seen deposited in onion skin lamellar pattern.

    Atypical: As compared to conventional ES, the cells are larger in size (20-24µm) and heterogeneous in morphology with better delimited cell contours. The cells consist of eosinophilic cytoplasm with irregular, grooved nuclei. 14,15

    PNET or ES with neuroectodermal differentiation:14 Morphological features are similar to conventional ES with at least one third of the tumor showing Homer-Wright rosettes or pseudorosettes (includes a group of six to ten cells oriented towards a central core filled with fibrillar material). The nuclei of cells is round or elongated with condensed chromatin. In another pattern, a fibrillary background which may adopt a lobulated configuration intermingled with less densely packed cell population may be seen. Nests of tumoral cells remain within the collagen bundles.

    Immunohistochemistry: Both ES and PNET express the membrane antigen p30/32MIC2/HBA71/CD99 or 12E7/O13; a MIC2 gene product. P30/32 and 12E7 are different epitopes on MIC2 gene product. Although, CD99 is not specific for ES/PNET (expressed even by lymphoblastic leukemias, weakly by alveolar rhabdomyosarcoma etc), combination with other markers like Friend Leukemia Integration 1 Transcription Factor (FLI1) - a gene product belonging to E-twenty six (ETS) trascription factor, Human Natural Killer 1 (HNK1)- a neuronally expressed adhesion molecule and caveolin-1 a product of a gene CAV 1 that encodes slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells, gives more accurate diagnosis and helps to avoid erroneous diagnosis. Neuronal markers like neuron-specific-enolase, S-100, etc are positive in PNET but the cells are negative for chromogranin and synaptophysin.14,16,17

    Cytogenetics: Translocation, t(11;22) (q24;q12) i.e., fusion between the 5’end of the EWS gene from chromosome band 22q12 with the 3’ portion of the 11q24 FLI1 gene is seen. This EWS/ETS fusion protein blocks the differentiation of pluripotent marrow stromal cells. Rest 10-15% of the cases have t(21;22) (q22;q12) fusing EWS to a closely related ETS gene.16


    Rhabdomyosarcoma (RMS) is composed of neoplastic mesenchymal cells showing varying degrees of striated muscle cell differentiation. It accounts for about 5% to 10% of all childhood malignancies.18 Head and neck RMS when compared to other parts of the body have a distinct prognostic and biologic behaviour. They are anatomically divided into two categories: Parameningeal -- consisting of RMS of nose, nasopharynx, paranasal sinuses, middle ear, mastoid, infratemporal fossa and pterygopalatine fossa. Non-parameningeal -- consisting of RMS of the scalp, orbit, parotid gland, oral cavity, oropharynx and larynx.18 Horn and Enterline (1958) described four histologic subtypes of RMS: Pleomorphic, Embryonal, Alveolar and Botryoid types. Only embryonal RMS (generally seen in children) and alveolar RMS (common in adults) belong to the family of small round cell tumors.10

    The intergroup rhabdomyosarcoma studies have shown that in head and neck region 71% of tumors were of embryonal type and

    13% of alveolar type.19 According to a study by J. Hicksa and C. Flaitz, primary head and neck rhabdomyosarcomas occur in 35% of children.20

    Embryonal Rhabdomyosarcoma: (E-RMS)

    According to the World Health Organization, E-RMS is “a variant of rhabdomyosarcoma featuring sheets of primitive round and differentiating rhabdomyoblasts admixed in various proportions”.10 (Fig 2) This lesion is named for its remarkable resemblance to developing muscle in embryos and foetus. Just as embryonal skeletal musculature appears to condense out of a primordial soup of gelatinous matrix and primitive mesenchyme, so is embryonal rhabdomyosarcoma and is typified by alternating areas of cellular condensation and laxity.21 The tumor cells vary from being small undifferentiated round or spindle shaped cells to number of differentiated cells with eosinophilic cytoplasm characteristic of rhabomyoblasts floating in a sea of primitive mucous ground substance. Cross-striations are discernible in 50–60% of cases.1,21

    The tumor cells vary from being small undifferentiated round or spindle shaped cells to number of differentiated cells with eosinophilic cytoplasm characteristic of rhabomyoblasts floating in a sea of primitive mucous ground substance. Cross-striations are discernible in 50–60% of cases.1,21

    Alveolar rhabdomyosarcoma: (A-RMS)

    Most of these tumors are composed of round cells with scanty cytoplasm and nuclei that is uniform in size and shape with coarse chromatin. Sometimes it consists of one or two prominent nuclear folds. Nuclear necrosis and pyknosis with high mitotic activity is usually observed.10 A-RMS usually consists of two patterns:

  • 1. Classic: Are highly cellular, poorly differentiated, and aggressive-appearing lesions that typically form nests separated by a prominent framework of fibrovascular septa. From this fibrous buttress hang rows of tumor cells, with loss of tumor cell cohesion in the periphery of the alveolar nests and increased cohesion in their central portions. 10,21
  • 2. Solid: These variants show crowded, highly cellular, undifferentiated round cell without fibrovascular septa. Solid alveolar rhabdomyosarcomas have biological features and clinical behaviour
  • identical to those of typical alveolar rhabdomyosarcomas.21
  • Immunohistochemistry: Cells are positive for desmin and muscle-specific actin. A more sensitive maker for this tumor is MAB 5.8A, which recognizes the MyoD1 gene product. MYoD1 is a DNA-binding phosphoprotein that binds to the enhancer sequence of muscle-specific genes, regulating their transcription. Another specific marker is myogenin which is detected at the early stage of myogenic differentiation.22

    Cytogenetics: Alveolar RMS shows t(2;13)(q35;q14) translocation. The genes involved are PAX3 (paired box gene) on chromosome 2 and FKHR (Forkhead domain) on chromosome13. Embryonal RMS are usually hyper-diploid and do not show t(2;13). There is loss of heterozygosity for 11p15 region. The neoplasms have extra copies of chromosome 2,8,9,11,12 and 13.8

    Olfactory Neuroblastoma

    Primary pediatric head and neck Neuroblastoma is rare, with metastatic disease being the more common mode of involvement in this anatomic region.25 Esthesino neuroblastoma (ENB) or Olfactory neuroblastoma is an uncommon malignant neoplasm of the nasal vault which was first described in 1924, in French literature. ENB represents about 5% of all nasal malignant tumors.24

    Skolnik et al. were able to find only about 100 reported cases in the world literature up to the year 1966. More recently, Broich and colleagues have found about 1000 new cases of ENB being reported.25 According to a study, the mean age at presentation was 53 years, (range: 40-70years) with a moderate male predominance (male:female ratio being 55:45).47

    Histopathology: ENB is thought to originate from basal cells of olfactory epithelium which express neural cell adhesion molecule and the mammalian homologue of Drosophila-achaete-scute (MASH) gene.25 Cantrell et al described characteristics of ENB as a lesion which is compartmentalized into lobules by slender vascular fibrous septa. The lobules contain cells with almost nonexistent cytoplasm, round nuclei with sharply defined chromatin and plexiform intercellular fibrils. True rosettes/ Flexner-Wintersteiner rosettes (consists of spaces lined by columnar cells

    with nuclei oriented radially around the space) and pseudorosettes / Homer Wright rosettes are seen (Fig 3). Cytoplasm shows secretory granules similar to catecholamine granules.24,25 Robert et al classified this tumor into three different types considering its clinical and histopathological appearance:

  • 1. Pattern I: A tumor with sheets of small, round cell separated by connective tissues septa; pseudorosettes or Homer Wright rosettes are seen.
  • 2. Pattern II: Consists of cells with round to oval nuclei with clear nuclear membranes, scanty cytoplasm and indistinct cell borders. True rosettes or Flexner-Wintersteiner are seen.
  • 3. Pattern III: Pattern similar to neuroblastoma with production of neuropil, a wispy, light pink, fibrillar material produced by undifferentiated neuroblasts. Rosettes are seen with abundant haemorrhage, fibrosis and hemosiderin deposition. Clusters of lymphocytes and islands of dystrophic calcification are seen.24
  • Immunohistochemistry: The cells are positive for neuron specific enolase and neural filament protein. S-100 and vimentin are positive in sustentacular cells.22

    Cytogenetics: In nineteenth century, ENB tumours were found to express HASH, the human homologue of the MASH gene. The demonstration by RT-PCR of HASH gene expression, although still investigational, could become the diagnostic procedure of choice to detect ENBs.25

    Malignant Lymphomas

    Lymphomas are the heterogeneous group of clonal malignant disease that share the single characteristic of arising as the result of somatic mutation in a lymphocyte progenitor. A lymphoma may arise in lymph nodes or any organ, either by spread from lymphatic sites or as a manifestation of primary extranodal disease.26 According to studies done by Pecorari et al and Eisenbud et al, Lymphomas are the third most frequent malignant tumor of the maxillofacial region following squamous cell carcinoma and salivary gland neoplasms. According to Epstein et al it is the second most common malignant disease in the oral region.27 Most of the head and neck lymphomas are of B-cell origin.28 Traditionally, the lymphomas are divided into Hodgkin’s (HL) - shows presence of Reed-Sternberg cells and Non-Hodgkin’s lymphomas (NHL) - no Reed Sternberg cells are seen because of their difference in histology and pattern of behaviour.27,29

    Non-Hodgkin’s lymphoma

    NHLs are much less predictable than Hodgkin’s disease and have a far greater predilection to disseminate to extra nodal tissues.27 Lymphomas account for 50% to 59% of the head and neck malignant neoplasms in children. A decided majority of non-Hodgkin’s lymphomas arise in lymph nodes, 24% of these malignancies arise in extra nodal sites. Lymphomas arising within the oral cavity accounts for less than 5% of all oral malignancies and approximately 85% of the lesions involve the tonsils and palate.29 To date, only 12 cases of the non-Hodgkin’s lymphoma of the tongue has been mentioned in the literature.30 Diffuse large lymphomas is most frequently encountered type27 and comprised of 50% of oral lymphomas in one series of study.26

    The frequent lymphomas occurring in nasopharynx and Waldeyer’s ring are small B-cell lymphomas such as small lymphocytic lymphoma, mantle cell lymphoma, natural killer (NK)/T cell lymphomas and follicular lymphoma. In salivary glands, mucosa associated lymphoid tissue (MALT) lymphomas are common. The other types include plasmablastic lymphoma and Burkett’s lymphoma.31 In a study, diffuse large cell lymphoma (Fig 4) was diagnosed in 38% and small cell lymphoma in 27.4% of cases. The rest of the cases include plasmacytoma, Immunoblastic lymphomas and Burkett’s lymphoma.29 Increasing number of HIV cases present with oral lymphomas especially plasmablastic lymphomas.31,32 Some of the features of commonly found NHL in head and neck region along with IHC and cytogenetic features are elicited in Table 1.

    Hodgkin’s Lymphoma (HL):

    Characterized histologically by infiltration of the involved organ with Reed-Sternberg or Hodgkin’s cells in an appropriate cellular background.34

    Hodgkin’s cells:37 Neoplastic large ovoid cells with indistinct cell borders, indented vesicular nucleus with thick nuclear membrane and huge hyperchromatic intensely acidophilic nucleolus.

    Reed-Sternberg cell: (RS cells): Large cell with two or more often mirror-image nuclei, each containing a single prominent nucleolus. The nucleoli are typically large and round and often resemble inclusion bodies. Chromatin is usually condensed at the nuclear membrane, giving rise to a thickened nuclear border and a clear halo-like space around the nucleolus. The cytoplasm is abundant and slightly eosinophilic.42

    Sl no



    Immunohisto chemistry



    Diffuse large B cell lymphoma

    Large irregular or lobated nuclei, size equal to or exceeding the nuclei of normal macrophage with scant cytoplasm. Two types:

  • A. Germinal centre like DLBCL.
  • B. Activated peripheral blood B-cell type33
  • Positive for CD20, CD45 and monotypic Ig.

    Positive for CD20, CD 10, BCL 6


    Trisomy gains of 3q, 18q21-q22 and loss of 6q21-22. Increased expression of NF


    Small lymphocytic lymphoma (SLL)

    Proliferation of non-activated, mature looking small lymphocytes selectively involving the interfollicular regions or B-zones of the node. The para-immunoblasts and pro-lymphocytes are hallmark of SLL. 34

    CD 20 +ve, weak monotypic surface Ig. Ki 67 index is low

    Deletions of 13q14.


    Follicular lymphoma

    Nodular growth of monotonous cells. Three types: 1. Contains small cells (size of normal lymphocyte) 2. Has large cells (2 to 3 times the size of normal lymphocyte, resembles mitotically active germinal centre cell) 3. Intermediate (contains both small and large lymphocytic cells). Internodular and intercellular reticulin is more abundant. 35-37

    CD19, CD20, CD10, BCL-2 positive.



    Mantle cell lymphoma

    Medium to large sized monomorphic round neoplastic cells, arranged in diffuse or nodular pattern, hyalinised small blood vessels, and scattered epithelioid cells. 31

    Positive for CD5, CD20, CD43, BCL 1, negative for CD10, BCL 6

    t(11;14)(q13;q32). Increased cyclin D1 expression.


    Plasma cell neoplasias

    Three types: Multiple myeloma (multiple bones involved), solitary bone plasmacytoma, and extramedullary plasmacytoma. Shows proliferation of mature and immature plasma cell (eccentrically placed nuclei with cartwheel appearance), bone marrow plasmacytosis, osteolytic lesions, M-protein in serum, and Bence-Jones protein in urine. 38,39

    To identify monoclonal immune-globulins i.e., Ig G, lambda, Ig kappa.

    t(8;14), t(2;8) or t(8;22), translocation between myc and IgH.


    Burkitt’s lymphoma

    Three variants:

    1. Endemic: refers to Burkitt’s occurring in African children. Epsten Barr Virus (EBV) + in all most all cases.

    2. Sporadic: Occurs in all geographic areas. EBV + in 15%-30% of cases.

    3. Immunodifficiency associated: Common in HIV+ patients. May show plasmacytoid differentiation. Uniform or slightly pleomorphic medium sized cells, moderate amount of cytoplasm, squaring off edges between the neighbouring cells, starry sky pattern due to admixed tingible body macrophages, high mitotic rate and necrosis. 37,40

    Positive for CD 20, CD10, Monotypic Ig

    80% with t(8;14) translocation, 20% t(2;8) or t(8;22)


    MALT lymphoma

    Observed in salivary glands, thyroid, stomach etc, originate from marginal zone B cells, shows cellular heterogeneity with monocytoid B cells, small lymphocytes, plasma cells, and occasionally large lymphocytes.

    Two variants:

    1. Few cases show prominent follicular growth pattern resulting from follicular colonization, absence of lymphoepithelial lesions, centrocyte-like (CCL) cells representing minimal plasma cell differentiation (follicular growth type).

    2. Few cases show marginal zone distribution pattern of CCL cells, presence of colonized follicles lymphoepithelial lesions and plasma cells.41

    Positive for CD20, and surface Ig D. Negative for CD10, CD5

    Trisomy 3, t(11;18) (q21;q21),27-32 t(1;14) (p22;q32),33

    and t(14;18) (q32;q21). 34.49


    NK/T cell lymphoma

    Tissue densely populated by abnormal lymphocytes (small, intermediate and large), areas of necrosis and angiocentric and angiodestructive growth pattern.34

    CD56 +ve and CD2 +ve.

    Absence of surface CD3 but presence of cytoplasmic CD3.

    Lack of TCR genes rearrangements.


    Plasmablastic lymphoma

    Found in HIV infected patients, diffuse infiltration of large neoplastic cells in the oral submucosa with eccentrically placed nuclei and paranuclear hof,

    CD 4-ve, and CD2-ve. VS38c + ve and CD79a

    interspersed with tingible body macrophages. High proliferative and mitotic activity, apoptotic figures, and single cell necrosis seen.32


    Table 1: Features of NHL (DLBCL: Diffuse large B-Cell lymphoma, CD: Cluster of Differentiation, NF: Neurofilament, BCL: B-Cell lymphoma, EBV: Epstein-Barr Virus, MALT: Mucosa associated lymphoid tissue, TCR: T-cell receptor, HIV: Human Immunodeficiency virus, LMP: Latent membrane protein, SLL: Small lymphocytic lymphoma, CCL: Centrocyte-like)

    Sl No

    Small round cell tumor




    Ewing’s sarcoma Family of Tumors

    P30/32 and 12E7 along with FLI1, HNK, and CAV1

    1. t(11;22)(q24;q12) 2. t(21;22) (q22;q12): 10-15% of cases



    MAB 5.8, myogenin


    2.Loss of heterozygosity for 11p15 region

    3.extra copies of 2,8,9,11,12 and 13


    Olfactory Neuroblastoma

    NSE, NF, S-100

    Express HASH gene


    Non-Hodgkin’s Lymphoma

    Summarized in table 1

    Summarized in table1


    Hodgkin’s lymphoma

    H-RS positive for CD30, CD15, CD40

    Gains of 2p, 9p, 16p, 17q, 19q, 20q, and losses of 6q, 11q, and 13q.

    Table 2: Summary of immunohistochemical and Cytogenetic feature of SRCTs

    Sl No

    Name of the tumor


    Histopathological feature




    Small cell ostosarcoma:2,43

    Peak in 4th decade of life

    The cells grow in solid nests or in lobules with densely cellular central areas and decreasing cellularity with deposition of more extracellular material (osteoid) at the periphery

    Osteocalcin Osteonectin

    CBFA 1 gene positive.


    Round cell liposarcoma: 2,43

    adults, rarely children

    Round to angulated small cells containing one or more lipid droplets, arborizing vasculature, scant myxoid matrix

    Vimentin and S-100 positive.

    t(12:16) (q13:p11)


    Poorly differentiated synovial sarcoma:



    The tumor arises from pluripotential mesenchymal cells near joints surfaces, tendons -rarely involves head and neck region. Solid small cell areas with round to oval nuclei and scant cytoplasm.

    Cytokeratin, EMA positive.

    t(X:18) (p11:q11).


    Small cell melanoma: 2,43


    Primitive small cells with scant cytoplasm.

    Ultrastructure shows melanosomes.

    Positive for S-100, Human Melanoma Black -45 (HMB-45).

    Chromosomes 1, 6, 7, 9, and 10 are preferentially affected.


    Mesenchymal chondrosarcoma: 43

    peak in second decade

    Primitive small oval and round cells, hemangiopericytoma vascular pattern, islands of cartilage or hyalinization.

    CD 99, S-100 positive and collagen II positive.

    Has unique del (13; 21) (q10; q10) translocation.


    Small cell carcinoma:44

    Median age 60 years.

    Oval to angulated cells with hyperchromatic nuclei and scant cytoplasm, destructive growth pattern, necrosis.

    Positive for epithelial membrane antigen, cytokeratin, and chromogranin.44


    Merkel cell carcinoma: 45


    Tumor originates either from neural crest or stem cell and consists of small blue round cells.

    Positive for CK 20 (paranuclear dot), NSE, NF, EMA, chromogranin, and synaptophysin.

    Table 3: The differential diagnosis summarized in the table form

    The Hodgkin’s or RS cells (H-RS cells) are positive for CD30, CD15 (forms paranuclear globule with or without cell membrane staining), HLA-DR, CD25, CD40, CD138 and negative for BCL-6, J-chain and EMA (Epithelial Membrane Antigen). Background cells are usually CD4+ve. Latent membrane protein (LMP) 1 is positive if the patient is EBV infected.34 Variants of RS cells37 (Fig 5)

  • 1. RS cells of lymphocytic and histiocytic (L and H) type: These RS cells with folded, overlapping nuclear lobes (popcorn) are commonly observed in the lymphocyte predominance type.
  • 2. RS cells of Lacunar type: Characteristic for the nodular sclerosis type of
  • Hodgkin’s lymphoma, these cells have abundant, lightly acidophilic or water-clear cytoplasm, lobulated nuclei and small nucleoli.
  • 3. RS cells of anaplastic type: Commonly seen in the lymphocyte depletion type, these cells are large and markedly pleomorphic, with hyperchromatic bizarre nuclei with prominent nucleoli.
  • 4. RS cells of mummified variant: A degenerated or apoptotic cell that may be seen singly or in clusters. Cells have darkly staining eosinophilic cytoplasm and a dense pyknotic nucleus.
  • Figure 1: The photomicrograph of hematoxylin and eosin stained section showing Ewing’s sarcoma (a) [Courtesy: Sara Hafezi et al. Ewing’s Family of tumors of the Sinonasal Tract and Maxillary Bone. Head Neck Pathol 2011;5:8-16], poorly differentiated embryonal rhabdomyosarcoma (b) [Courtesy: Enzinger and Weiss. Goldblum JR. Soft Tissue Tumors; 5th edition. China, Mosby, Inc., an affiliate of Elsevier. 2008. 599-618p], True rosettes (c; Arrows) [courtesy:http://www.pathpedia.com/education/eatlas/histopathology/eye_and_ocular_adnexa/retinoblastoma/retinoblastoma], with pseudorosettes [courtesy:http://neuropathology-web.org/chapter7/images7/7-17bl.jpg], diffuse large cell lymphoma (d) [Courtesy: Francisco Vega et al. Extranodal lymphomas of the head and neck. Annals of Diagnostic Pathology: 2005;9:340-

    350] and Variants of RS Cells (e): Classical bilobed cell, (f): Popcorn cell, (g): Lacunar variant. [Courtesy: Harry L Ioachim. Lymph node Biopsy. 1st edition, JB Lippincott. 1982.]

    Histopathology: WHO classifies Hodgkin’s lymphomas as:

  •  Nodular Lymphocyte Predominant Hodgkin lymphoma (NLPHL): Multiple crowded or well-separated nodules consisting of bland-looking small lymphocytes interspersed with pink-staining histiocytes. L and H cells are found within or in between the nodules. IHC shows L and H cells to be positive for CD 20, BCL-6, J-chain, EMA and CD 40, polytypic B lymphocytes ( Ig M and Ig D +) and CD 3+ T lymphocytes form rosettes around L and H cells.
  •  Classical Hodgkin lymphoma
  •  Nodular sclerosis: Lymph node capsule is thickened with multiple broad birefringent vascularised collagen bands extending into the parenchyma resulting in the formation of multiple nodules. The nodules shows presence of lacunar cells arranged singly, in aggregates or in sheets. The background shows small lymphocytes, plasma cells, eosinophils, neutrophils and histiocytes.
  •  Mixed cellularity: The lymphnode is partially or fully effaced and consists of RS cells in the background of eosinophils, neutrophils, lymphocytes, plasma cells and histiocytes.
  •  Lymphocyte rich classical HL: Characterized by diffuse or nodular growth consisting of mononuclear and rare diagnostic RS cells scattered in a background of small lymphocytes. Do not show presence of L & H cells.
  •  Lymphocyte depletion: Two types:
  • o Diffuse fibrosis type: Diagnostic RS cells are rare with background showing disorderly distributed reticular, fibrous and amorphous, proteinaceous material. There is depletion of all cellular elements.
  • o Reticular Type: Hypercellular with abundance of RS cells but other mature inflammatory cells are sparse. Disordered non-birefringent fibrosis and necrosis are present.34
  • Immunohistochemistry: The Hodgkin’s or RS cells (H-RS cells) are positive for CD30, CD15 (forms paranuclear globule with or without cell membrane staining), HLA-DR, CD25, CD40, CD138 and negative for BCL-6, J-chain and EMA. Background cells are usually CD4+ve. Latent membrane protein 1 is positive if the patient is EBV infected. IHC in NLPHL shows L and H cells to be positive for CD 20, BCL-6, J-chain, EMA and CD 40, polytypic B lymphocytes (IgM and IgD+) and CD 3+ T lymphocytes form rosettes around L and H cells.35

    Cytogenetics: HL is difficult to karyotype, one of the main reason being scarcity of neoplastic RS cells. According to a recent study by Christian Steid et al, copy number alterations found in more than 20% of cases included gains of 2p, 9p, 16p, 17q, 19q, 20q and losses of 6q, 11q and 13q.44


    A precise histological diagnosis of SRCTs was of less relevance when treatment simply involved resection and radiotherapy, but the continued development of disease-specific therapeutic strategies, and the concomitant improvement in prognosis, has rendered accurate tumour diagnosis and classification of paramount importance. Thus, a correct diagnosis is essential for patients with a small round cell tumour.49 Since these tumors are morphologically similar, a combination of histopathology, immunohistochemistry and cytogenetics helps in accurate distinction.


    We would like to acknowledge Dr. Radhika MB, Prof & Head and Staff members, Department of Oral Pathology, for helping us in preparation of the manuscript.

    Author Affiliations

    1.Dr.Reshma V, Senior Lecturer, Krishnadevaraya College of Dental Sciences and Hospital, 2.Dr.Kavita Rao, Professor and Head, 3.Dr.Priya NS, Reader, 4.Dr.Umadevi HS, Reader, VS Dental College and Hospital, 5.Dr.Mohsin G, Senior Lecturer, Krishnadevaraya College of Dental Sciences and Hospital, 6.Dr.Sreelatha Hosthor, Senior Lecturer, Department of Oral Pathology, Rajiv Gandhi University of Health Sciences, Krishnadevaraya College of Dental Sciences and Hospital, Bangalore.


  • 1. Weiss SW, Goldblum JR. Enzinger and Weiss’s Soft Tissue Tumors. 5th Ed. China; Mosby Inc., an affiliate of Elsevier: 2008. P. 60-177.
  • 2. Leon ME, Hou JS, Galindo LM and Garcia FU. Fine-Needle Aspiration of Adult Small-Round-Cell Tumors Studied
  • with Flowcytometry. Diag Cytopathol 2004;31:147–54.
  • 3. Rossi S, Nascimento AG, Canal F, Dei Tos AP. Small round-cell neoplasms of soft tissues: An integrated diagnostic approach. Curr Diag Pathol 2007;13:150–63.
  • 4. de Alava E. Diagnosis of small round cell tumours of bone. Curr Diag Pathol 2001;7:251-61.
  • 5. Mierau GW, Weeks DA, Hicks MJ. Role of electron microscopy and other special techniques in the diagnosis of childhood round cell tumors. Human Pathol 1998;29(12):1347-55.
  • 6. Kast R, Rabah R, Wills H, Poulik J, Auner GW, Klein MD. Differentiation of small round blue cell tumors using Raman spectroscopy. J Pediat Surg 2010;45:1110-4.
  • 7. Cohn SL. Diagnosis and classification of the small round-cell tumors of childhood. Am J Pathol 1999:155(1);11-5.
  • 8. Noguera R. Cytogenetics and Tissue Culture of Small Round Cell Tumors of Bone and Soft Tissue. Semin Diag Pathol 1996;13(3):171-83.
  • 9. Alrawi SJ, Tan D, Sullivan M, Winston J, Loree T, Hicks W, et al. Peripheral Primitive Neuroectodermal Tumor of the Mandible with Cytogenetic and Molecular Biology Aberrations. J Oral Maxillofac Surg 2005:63;1216-21.
  • 10. d'Amore ES, Ninfo V. Soft Tissue Small Round Cell Tumors: Morphological Parameters. Semin Diag Pathol 1996;13(3):184-203.
  • 11. Siegal GP, Oliver WR, Reinus WR, Gilula LA, Foulkes MA, Kissane JM, et al. Primary Ewing’s Sarcoma Involving the Bones of the Head and Neck. Cancer 1987:60;2829-40.
  • 12. da Fonseca MA, Abrams RB. Ewing’s sarcoma of the mandible in a young patient: case report. Pediatr Dent 1992;14:402-4.
  • 13. Hafezi S, Seethala RR, Stelow EB, Mills SE, Leong IT, MacDuff E, et al. Ewing’s Family of Tumors of the Sinonasal Tract and Maxillary Bone. Head Neck Pathol 2011:5:8-16.
  • 14. Llombart-Bosch A, Contesso G, Peydro-Olaya A. Histology, immunohistochemistry and electron microscopy of small round cell tumors of bone. Semin Diag Pathol 1996;13(3):153-70.
  • 15. Hameed M. Small Round Cell Tumors of Bone. Arch Pathol Lab Med 2007;131:192-204.
  • 16. Yeshvanth SK, Ninan K, Bhandary SK, Lakshinarayana KP, Shetty JK, Makannavar JH. A Rare case of extraskeletal Ewing’s sarcoma of the sinonasal tract. J Cancer Res Therap 2012;8(1):142-4.
  • 17. Prasad DDK, Veena NR, Reddy SP. Structure and Expression of Human Fli-l Gene. Cancer Res 1992;15(52):5833-7.
  • 18. Al-Khateeb T, Bataineh AB. Rhabdomyosarcoma of the oral and maxillofacial region in Jordaninans: A retrospective analysis: Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93:580-5.
  • 19. Doval DC, Kannan V, Acharya RS, Mukherjee G, Shenoy AM, Bapsy PP. Rhabdomyosarcoma of the tongue. Br J Oral Maxillofac Surg 1994;32:183-6.
  • 20. Hicks J, Flaitz C. Rhabdomyosarcoma of the head and neck in children. Oral Oncol 2002;38:450-59.
  • 21. Elizabeth Montgomery, Alan D. Aron. Clinical Pathology of soft tissue tumors. 1st Ed. New York; Marcel Dekker: 2001. P. 580.
  • 22. Meis-Kindblom JM, Stenman G, Kindblom LG. Round cell tumors: differential diagnosis. Semin Diag Pathol 1996;13(3):231-41.
  • 23. Frank DK, Ramaswamy G, Tavin E, Moscatello AL. Poorly differentiated paediatric head and neck neuroblastoma. A diagnostic dilemma. Int J Pedi Otorhinolaryngol 1995;33(2):103-11.
  • 24. Bhoweer AK, Chitre AP. Esthesino neuroblastoma. J Indian Acad Oral Med Radiol 2008;20(4):157-61.
  • 25. Dulguerov P, Allal AS, Calcaterra TC. Esthesioneuroblastoma: a meta-analysis and review. Lanc Oncol 2001;2:683–90.
  • 26. van der Waal RI, Huijgens PC, van der Valk P, van der Waal I. Characteristics of 40 primary extranodal non-Hodgkin lymphomas of the oral cavity in perspective of the new WHO classification and International prognostic Index. Int J Oral Maxillofacial Surg 2005;34:39195.
  • 27. Kolokotronis A, Konstantinou N, Christakis I, Papadimitriou P, Matiakis A, Zaraboukas T, et al. Localized B-cell non-Hodgkin’s lymphoma of oral cavity and maxillofacial region: A clinical Study: Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:303-10.
  • 28. Pazoki A, Jansisyanont P, Ord RA. Primary Non-Hodgkin’s Lymphoma of the Jaws: Report of 4 cases and Review
  • of the literature. J Oral Maxillofac Surg 2003;61:112-17.
  • 29. Epstein JB, Epstein JD, Le ND, Gorsky M. Characteristics of oral and paraoral malignant lymphoma: A population-based review of 361 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;92:519-25.
  • 30. Maheshwari GK, et al. Primary non-Hodgkin’s lymphoma of oral tongue. Turk J Cancer 2001;31(3):121-4.
  • 31. Chang CC, Rowe JJ, Hawkins P, Sadeghi EM. Mantle-cell lymphoma of the hard palate – a case report and review of the differential diagnosis based on the histomorphology and immunophenotyping pattern. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;96:316-20.
  • 32. Delecluse HJ, Anagnostopoulos I, Dallenbach F, Hummel M, Marafioti T, Schneider U, et al. Plasmablastic Lymphomas of the Oral Cavity: A New Entity Associated With the Human Immunodeficiency Virus Infection. Blood 1997;89(4):1413-20.
  • 33. Jham BC, Duarte BBC, Fernandes AM, Batista AC, Johann R, Aguiar MCF, Gomez RS, et al. Primary diffuse large B-cell lymphoma of the oral cavity. J Br Pathol Med Lab 2007;43(5):369-72.
  • 34. Fletcher CD. Diagnostic histopathology of tumors. 2nd Ed. Vol 2, China. Churchill Livingstone, Elsevier. 2000. P. 1113-74.
  • 35. Mann RB, Jaffe ES, Berard CW. Malignant Lymphomas - A Conceptual Understanding of Morphologic Diversity - A Review. Am J Pathol 1979;94(1):105-61.
  • 36. Kumar, Abbas, Fausto, Mitchell. Robbins Basic Pathology. 8th Ed. Philadelphia; Saunders an imprint by Elseiver: 2007.
  • 37. Loachim HL, Medeiros LJ. Loachims’s Lymph Node Pathology. 4th Ed. Lippincott Williams and Wilkins; Wolters Kluwer business: 2009. P. 313-391.
  • 38. Seoane J, Aguirre-Urizar JM, Esparza-Gómez G, Suárez-Cunqueiro M, Campos-Trapero J, Pomareda M. The
  • spectrum of plasma cell neoplasia in oral pathology. Med Oral 2003;8:269-80.
  • 39. Shafer, Hine and Levy. Shafer’s Text book of Oral Pathology, 6th Ed. New Delhi, India; Reed Elsevier India Private Limited: 2009. P. 183.
  • 40. Ferry JA. Burkitt’s lymphoma: Clinicopathologic features and differential diagnosis. Oncologist 2006;11:375–83.
  • 41. Tsang RW, Gospodarowicz MK, Pintilie M, Wells W, Hodgson DC, Sun A, et al. Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. J Clin Oncol 2003;21:4157-64.
  • 42. Miller DR, Bachner RL. Blood diseases of infancy and childhood. 6th Ed. Elsevier; P 662.
  • 43. Pellitteri PK, Ferlito A, Fagan JJ, Suárez C, Devaney KO, Rinaldo A. Mesenchymal chondrosarcoma of the head and neck. Oral Oncol 2007;43:970– 75.
  • 44. Kim SG, Jang HS. Small cell carcinoma of the oral cavity. J Oral Maxillofac Surg 2001;69:680-84.
  • 45. Yom SS, Rosenthal DI, El-Naggar AK, Kies MS, Hessel AC. Merkel cell carcinoma of the tongue and head and neck oral mucosal sites. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;101:761–68.
  • 46. Tarkkanen M, Knuutila S. The diagnostic use of cytogenetic and molecular genetic techniques in the assessment of small round cell tumours. Curr Diag Pathol 2002;8:338-48.
  • 47. Jethanamest D, Morris LG, Sikora AG, Kutler DI. Esthesioneuroblastoma: a population-based analysis of survival and prognostic factors. Arch Otolaryngol Head Neck Surg 2007;133(3):276-80.
  • Corresponding Author

    Dr. Reshma V

    No 29, MIG, KHB Colony 2nd stage,

    Basaveshwarnagar, Bangalore- 560079,

    Karnataka State, India.

    Ph: +91-9916707538

    Email: reshmav132@gmail.com

    Source of Support: Nil, Conflict of Interest: None Declared.


    • There are currently no refbacks.

    Creative Commons License
    This work is licensed under a Creative Commons Attribution 3.0 License.

    Indexed In Ebscohost Index Copernicus UlrichsWebOpenJGateGoogle Scholar DOAJ Gale Cengage Learning Research Gate
    System Developed By Stanford University Arizona State University Simon Fraser University Canadian Centre For Studies In Publishing University of British Columbia - Faculty of Education
    W3C XHTML v1.0 Verified W3C verified Valid CSS v2.1 PHP5 Enabled Made On Mac Apache Enabled MySQL Powered
    Published by Celesta Software Pvt Ltd