Journal of Cytology
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Year : 2008  |  Volume : 25  |  Issue : 3  |  Page : 89-92
Cytology of soft tissue tumors: Malignant small round cell tumors


Department of Cytology and Gynaecologic Pathology, P.G.I.M.E.R, Chandigarh, India

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How to cite this article:
Rajwanshi A. Cytology of soft tissue tumors: Malignant small round cell tumors. J Cytol 2008;25:89-92

How to cite this URL:
Rajwanshi A. Cytology of soft tissue tumors: Malignant small round cell tumors. J Cytol [serial online] 2008 [cited 2019 Dec 13];25:89-92. Available from: http://www.jcytol.org/text.asp?2008/25/3/89/44038


Malignant small round cell tumor (MSRCT) is a group of morphologically similar neoplasms with variable histogenesis and biological behavior. [1] This group of tumors with different origin includes: Neuroblastoma (NB), Ewing's sarcoma (EWS)/Primitive neuroectodermal tumor (PNET), malignant lymphoma (ML), rhabdomyosarcoma (RMS), Wilm's tumor (WT), Desmoplastic small round cell tumor (DSRCT). Other differential diagnoses of MSRCTs include small cell osteogenic carcinoma and synovial sarcoma.

Differential diagnoses are difficult due to their undifferentiated or primitive character. Malignant small round cell tumors are characterized by small relatively undifferentiated cells. Accurate diagnosis is required for many of these tumors and imprecise diagnoses, such as small cell tumor, should be strongly discouraged. This would enable the institution to implement appropriate therapeutic protocols, including new adjuvant chemotherapy in advanced malignancy. [2]

A vast majority of MSRCTs are difficult to differentiate using light microscopy alone. In the last few years, a variety of ancillary diagnostic techniques such as immunohistochemistry, electron microscopy, cytogenetics, and molecular genetics have provided precious tools for addressing this diagnostic dilemma. The immunocytochemical panel that is useful in the diagnosis of round cell tumors is shown in [Table 1]. The use of ancillary studies has proven to be a decisive step in fine needle aspiration (FNA) diagnosis. [3] It is well recognised that immunophenotyping of antigens to identify the tissue of origin is critical in the diagnosis of MSRC tumors. The recent molecular genetic characterization of the chromosome abnormalities characteristic of small round cell tumors has resulted in greatly improved detection strategies, based mainly on the techniques of fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR).

Ewing's sarcoma: Ewing's sarcoma (EWS) is a malignancy of the bone and soft tissue that is usually seen in the paediatric population but may also be found in adults. It is an undifferentiated neoplasm composed of small round cells lacking any specific differentiation. In the majority of the cases, abundant cytoplasmic glycogen can be demonstrated by PAS. [4] FNAC reveals tumor cells that are uniform in size and shape and that are present singly or in small clusters. Nuclei are round to slightly irregular with inconspicuous nucleoli. The cytoplasm has vacuoles and the cells are arranged in variable numbers of pseudorosettes. Electron microscopic examination confirms the presence of glycogen in areas corresponding to cytoplasmic vacuoles. There may be scattered cell junctions, but usually no cytoplasmic filaments or neurosecretory granules are seen. [1]

MIC2 is a specific marker for ES and PNET. MIC2 is a ubiquitous pseodoautosomal gene located on the short arms of both X and Y chromosomes. The gene product, a cell membrane protein, is recognized by monoclonal antibody (MoAb) HBA-71 and MoAb 12E7 and RFB-1. [5] Although a sensitive marker, MIC2 is not specific and can be seen in some cases of other small round cell tumors such as RMS, WT, small cell carcinoma of the lung, and T-cell non-Hodgkin's lymphomas, [6],[7] whereas neuroblastomas have been found to be universally negative for MIC2. [8] The utility of FLI-1 expression in EWS/PNET is specific and useful in differential diagnoses. FLI-1 has been recently proposed as an additional immunohistochemical marker of ES/PNET alongside the traditional MIC2. [9]

Approximately 90% of ES/PNET have a specific t(11.22) (24, q 12) translocation that results in the fusion of EWS and FLI-1 genes. Various other translocations have been described that involve other members of the ETS gene family. The t(21.22) (q12:q12) translocation involves the ERG gene whereas t(7:22) t(q22:q12) involves the ETV1 gene. These transcripts can be detected using molecular techniques such as RT-PCR and FISH. [10]

Neuroblastoma: Neuroblastoma (NB) is the most common malignant tumor of infancy and childhood. The majority (90%) of the tumors, occur in patients less than ten years of age and there is a slight male preponderance. The tumor arises from the undifferentiated precursor cells of the sympathetic nervous system but the adrenal gland is found to be the seat of primary growth in about a quarter of the cases. In FNAC smears, the tumor cells may be disposed singly or arranged in small clusters. The cells are small and undifferentiated with a high nuclear cytoplasmic ratio. Small clusters of cells may be separated by pale blue to light purple fibrillar matrix, and structures corresponding to pseuodorosettes are seen in histological sections. [1] A panel of monoclonal antibodies directed against neuroblastoma has been found to be a valuable aid to diagnosis. The most widely used antibodies are neuron specific-enolase (NSE), protooncogene product 9.5 (PGP 9.5), and NB84 which are detected in about 75-80% of all cases. But NB84 positivity can be seen in other tumors also such as Ewing's Sarcoma, squamous cell carcinoma, and leiomyosarcoma, and NSE positivity can also be seen in RMS. [11],[12]

Neuroblastomas are characterized by the deletion of the short arm of chromosome 1 (1p 36; 2-3) and amplification of the protooncogene MyCN abnormality of the chromosome number. Deletion of 1p is the common cytogenetic abnormalities. Most (90%) of the cases show the secretion of catecholamines and therefore, almost all neuroblastomas produce enzymes such as tyrosine hydroxylase (TH) and DOPA carboxylase which are the some of the first enzymes in the catecholamine biosynthetic pathway. RT-PCR can be used to detect mRNA of TH and DOPA carboxylase and is very helpful in differentiating NB from other MSRCTs. [13]

Rhabdomyosarcoma: Pediatric soft tissue sarcomas account for approximately 5% of all childhood cancers and over one-half of them are rhabdomyosarcomas. They are classified into two main morphological categories: embryonal (ERMS) and alveolar (ARMS). [14]

ERMS and ARMS are fairly easy to distinguish based on histology results but have overlapping cytological features. Clinically, the age and site of presentation are useful in their distinction. ERMS is common in the 1 st decade of life and occurs in the head, neck, and urogenital regions. ARMS occur predominantly in the soft tissues of the limbs and are seen in the 2 nd and 3 rd decades of life. [14]

The tumor cells vary from small, undifferentiated, round cells to large pleomorphic cells with abundant eosinophilic cytoplasm. The nuclei are large with marked pleomorphism. Aspiration smears from this tumor reveal cells that vary considerably in size and shape, but usually contain moderate to abundant amounts of cytoplasm which stain deep blue and contain occasional, small, cytoplasmic vacuoles. [15] A variable proportion of cells is much larger with abundant pale blue to grey, opaque cytoplasm. Within the cytoplasm of some of these cells is an ill-defined, relatively dense, inclusion-like area indicating myogenic differentiation. Tumors with this morphology are predominantly composed of undifferentiated cells with only occasional cells showing features of myogenic differentiation. However, precise distinction between these subtypes of RMS may not be possible in all cases and many require the application of special techniques. [16]

In the vast majority of cases, the immunocytochemistry panel includes myogenic markers such as desmin, myoglobin, muscle-specific actin, and sometimes, a more specific marker (MyoD1). [17],[18]

ARMS is characterized by translocation involving the FKHR gene on chr-13 and Pax3/7 gene on chromosome 2 or 1 respectively. Among these tumors, 90% show t(2:13) q (35:Q14) and 10% show variant t(1:13) (p36q14). Both PAX3 and PAX7 regions encode related DNA binding domains which may alter the expression of a common group of target genes. [19]

Wilm's tumor: Wilm's tumor (WT) is a common pediatric, malignant tumor. It is seen primarily in infants and 50% of the cases occur before the age of three years. It is a malignant neoplasm of the kidney which morphologically resembles embryonal renal tissue. FNAC of WT reveals blastemal tissue characterized by loosely arranged, small, undifferentiated cells in which there are scattered large, pale-staining cells disposed in a random fashion. Tubular differentiation is represented by a circular arrangement of larger, pale-staining, epithelial cells with smaller, more undifferentiated cells at the periphery. [20] Mesenchymal elements are usually composed of spindle-shaped cells, although occasional, large pleomorphic cells with abundant cytoplasm may be seen. Although the diagnosis can be readily made when all three components (blastemal, epithelial, and mesenchymal) of WT are present, some tumors only show the blastemal component in which case, ancillary studies such as electron microscopy and ICC play an important role in making a correct diagnosis. Positivity for CK, EMA, and VIM is seen in the majority of cases whereas NSE positivity can be a pitfall in the diagnosis of WT. [21]

Synovial sarcoma: Synovial sarcomas which account for 5-10% of soft tissue sarcomas, typically arise in the paraarticular region in adolescents and young adults. Two major histological subtypes are the classic biphasic and the monophasic types. The biphasic type contains both epithelial and spindle cells, [22] whereas the monophasic type is entirely composed of spindle cells. Accurate categorization usually requires ICC and other ancillary studies. EMA positivity is seen in 95% of the cases whereas CK positivity is seen in 40% of the cases. [23] Cytogenetic studies have revealed a characteristic chromosomal translocation L(x18,) in more than 90% of the tumors. Cloning of the translocation breakpoints showed that L(x:18) results in the fusion of two novel genes, designated syt at (18q11) and ssx(xpn) . The xp11 breakpoint involves two closely related genes, ssx 1 and ssx2 located in the vicinity of the ornithine aminotransferase-like (OATL) pseudogenes 1 and 2 respectively. The L(x:18) results in the formation of a chimeric protein which can be detected by RT-PCR. [24]

Desmoplastic small round cell tumor: This tumor typically occurs in adolescent males and may be located in the abdomen, pelvis, retroperitoneum, scrotum, or pleura. It shows a nesting growth pattern with an intense desmoplastic stroma and focal epithelial differentiation in some areas. [1]

Aspiration smears are characterized by undifferentiated round cells arranged in sheets and sometimes surrounded by dense, collagenous stroma. When the desmoplastic stroma is not represented, a morphological diagnosis may be difficult. [25] Characteristically, IHC reveals staining for CK and desmin. [26] Molecular studies have shown a specific reciprocal translocation, t(11:22) (p13q12). The molecular characterization of the breakpoint rejoin has revealed the creation of a fusion gene between the EWS gene and Wilm's tumor gene ( WT ). There is a fusion of the EW S gene on chromosome 22 with WTI gene on chromosome 11, which can be detected by RT-PCR. [27]

Malignant lymphoma: Small, noncleaved cell lymphomas and lymphoblastic lymphomas constitute the great majority of childhood lymphomas. Although rare, large cell lymphomas may be seen in children. Although the ICC of FNA material is usually adequate for establishing the diagnosis of malignant lymphomas, the precise phenotype may best be determined by FCM which usually provides adequate quantization of antigen expression. Immunoreactivity of the neoplastic cells for LCA (CD45) defines the tumor as a lymphoma. [1]

In cases of Burkitt's and nonBurkitt's lymphomas, demonstration of the characteristic chromosomal translocation t(8:14) involving the c-myc protooncogene on chromosome 8 and the gene for the heavy chain of immunoglobulin on chromosome 14 may help confirm the diagnosis. In some cases, there may be a t(2:8) chromosomal translocation involving c-myc and kappa light chain genes and t(8:22) involving c-myc and the lambda light chain genes. These translocations can be readily recognized by routine cytogenetics or by using F1SH or RT-PCR.

 
   References Top

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24.De Leeuw B, Balemans M, OIde Weghuis D, Geurts van Kessel A. Identification of two alternative fusion genes, SYT-SSX1 and SYT-SSX2, in t(X; 18)(p11.2; q11.2)-positive synovial sarcomas. Hum Mol Genet 1995;4:1097-9.  Back to cited text no. 24    
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27.Sawyer JR, Tryka AF, Lewis JM. A novel reciprocal chromosome translocation t(11;22)(p13;q12) in an intraabdominal desmoplastic small round-cell tumor. Am J Surg Pathol 1992;16:411-6.  Back to cited text no. 27  [PUBMED]  

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Correspondence Address:
Arvind Rajwanshi
Department of Cytology and Gynaecologic Pathology, PGIMER, Chandigarh - 160 012, Union Territory
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9371.44038

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