Moderators: Dr. V.VIJAYA SREEDHAR ( Professor & HOD) Dr. PADMAVATHI ( Associate Professor) Dr.SRILAKSHMI (Assistant Professor) Dr. Suresh PG Dr.B.S.chathanya PG
Topics
Introduction
Definition
Introduction
The term small round cells are used to describe the lesions in which dominant population consists of relatively small cells with basophilic nuclei and little or no cytoplasm.
These round cells tumors have several histological pattern, immunohistochemical & electronmicroscopic features that can help in differential diagnosis.
Cell sizes
Conventional cell size compared to 1) lymphocyte or 2) intermediate squamous cell 3) histiocyte nucleus Small cell =2-2 and half times . Intermediate cell = 3-6 times. Large cell = 6-10 times .
Definition
Small round blue cell tumor is the name given to a group of highly malignant neoplasms that occur mostly in the pediatric age group. Although this term could also apply to some adult neoplasms, notably small cell carcinoma of the lung, the term has become widely associated with childhood cancer.
The name is derived from the primitive, highly cellular nature of these lesions, which typically present a vast sea of dark-blue nuclei on hematoxylin-based stains.
Pancreatoblastoma
Pleuropulmonary blastoma Medulloblastoma
Retinoblastoma
Cortical saucerization
DIFFERENTIAL DIAGNOSIS
In young age patients the main DD for Ewings sarcoma
Wilms tumor
Location WT1 postivity .
NEUROBLASTOMA
Definition
A neuroblastoma is a neuroblastic tumor arising from primitive sympathetic ganglia and containing variably differentiated neural elements and variable amounts of Schwann cells.
Epidemiology Neuroblastomas are relatively common lesions in children and constitute the single most common intraabdominal malignancy and nonhematopoietic, non- CNS pediatric cancer.
NEUROBLASTOMA
NEUROBLASTOMA
Terminology and Synonyms Neuroblastomas comprise the most primitive end of the spectrum and contain no Schwann cell elements or fully differentiated ganglion cells. Ganglioneuroblastomas contain variable amounts of fully mature ganglionic neurons in addition to Schwann cell elements. Neuroblastoma and the Ewing sarcoma family of tumors share several pathologic features, such as rosettes and primitive histology, and are sometimes referred together as the primitive neuroectodermal tumor family.
NEUROBLASTOMA
Clinical features
Neuroblastoma is the most common solid tumor of children <1 year of age.
It typically presents as an abdominal mass, although it can also arise in sympathetic ganglia of the neck, thorax, and pelvis . The adrenal gland is the most common site of origin, and neuroblastoma - can be considered a tumor of the sympathetic nervous system, with production of catecholamines.
NEUROBLASTOMA
The ratio of the precursor molecule, HVA, to its product, VMA, correlates with the degree of tumor differentiation and survival. Other hormonal substances produced by neuroblastoma, such as vasoactive intestinal polypeptide, can cause a paraneoplastic syndrome with watery diarrhea and hypokalemia.
Other paraneoplastic syndromes can result from immune phenomena. In the opsoclonus myoclonus syndrome, antibodies produced against the tumor cause cerebellar ataxia and rapid eye movements. Horner syndrome, Ondines curse, and a host of other unusual clinical symptoms can also occur.
NEUROBLASTOMA
Neuroblastoma only rarely metastasizes to the lung. Conversely, aggressive PNETs typically exhibit pulmonary metastases. Both tumors can show bone marrow metastases, but this phenomenon is more typical of neuroblastoma. Radiologic Features
Stippled calcification by X-ray or CT, in patient
NEUROBLASTOMA
Gross
Neuroblastoma may present as a large (>10 cm) mass and is lobulated, encapsulated, soft, tangray, hemorrhagic, sometimes cystic, and often calcified. Intra-adrenal lesions may show a thin rim of residual adrenal gland flattened against the capsule of the neuroblastoma. Ganglioneuroblastoma and ganglioneuroma tumors are more firm and tanwhite. Ganglioneuroblastomas often contain nodules of grossly different appearance and consistency.
NEUROBLASTOMA
Microscopic features
Neuroblasts are small, dark cells with high nuclear-to-cytoplasmic ratio and stippled chromatin. Neuroblastoma usually has high mitotic activity and karyorrhexis, and is often hemorrhagic.
Ganglion cells maturing from neuroblasts are defined as having an enlarged, eccentrically located nucleus with a prominent nucleolus and synchronously abundant amphophilic cytoplasm that is twice or more the diameter of the nucleus.
Microscopic features
stroma refers to Schwann cell elements and not neurofibrillary material. The mitosiskaryorrhexis index (MKI) is a semiquantitative value derived from counting the number of mitoses and fragmented karyorrhectic nuclei in a 40X objective, high-power field. MKI (mitosis/karyorrhexis index):
Microscopic features
Homer Wright rosettes are composed of lightly eosinophilic, neurofibrillary cores surrounded by wreaths of round, hyperchromatic nuclei with coarsely granular chromatin and inconspicuous nucleoli.
NEUROBLASTOMA
Immunohistochemical Findings
Synaptophysin, chromogranin, neurofilament, NSE, and protein gene product 9.5 may be positive in neuroblastoma. CD99 is generally negative.
Genetics
Differential diagnosis
Other small blue cell tumors, primitive neuroectodermal tumor, rhabdomyosarcoma, lymphoma, desmoplastic small round cell tumor
RHABDOMYOSARCOMA
Rhabdomyosarcomas are an important category because they represent the largest subgroup of sarcomas in children. Types of Rhabdomyosarcoma
Embryonal
Alveolar Pleomorphic
EMBRYONAL RHABDOMYOSARCOMA
Definition
A primitive soft tissue sarcoma, showing a variable degree of embryonic skeletal muscle differentiation.
Incidence and Location The most frequent sarcoma of childhood and the most frequent type of rhabdomyosarcoma, occurring in 3 per 1 million children younger than 15 years The head and neck region and genitourinary system are most frequently involved.
EMBRYONAL RHABDOMYOSARCOMA
Clinical Features
Variable and aspecific, depending on site of involvement, and ranging from painful/less mass, obstruction, or bleeding.
Gross Findings Poorly circumscribed masses
MICROSCOPY
1) CONVENTIONAL 2) BOTRYOID VARIANT 3) SPINDLE CELL VARIANT 4) ANAPLASTIC VARIANT
EMBRYONAL RHABDOMYOSARCOMA
GENETICS Structural and numeric changes are quite frequent, including extra copies of chromosomes 2, 8, and 13. Allelic loss in chromosomal region 11p15. Immunohistochemical Features Staining for desmin, or myogenin/MyoD1 should be present.
EMBRYONAL RHABDOMYOSARCOMA
Prognosis The botryoid and paratesticular spindle cell variants have a good prognosis (> 90% overall survival rate), the conventional and nonparatesticular spindle cell variants an intermediate prognosis anaplastic variant a poor prognosis ( 45%)
Definition
ALVEOLAR RHABDOMYOSARCOMA
A high-grade round cell sarcoma with an alveolar or solid growth pattern with variable rhabdomyoblastic differentiation. Incidence and Location Rare (20% to 25% of all childhood rhabdomyosarcomas) Deep soft tissues of the extremities most frequently involved. Sex, Race, and Age Distribution Children and young adults between 2 and 25 years of age are mainly affected No sex or race predominance
ALVEOLAR RHABDOMYOSARCOMA
Clinical Features
ALVEOLAR RHABDOMYOSARCOMA
All alveolar rhabdomyosarcomas show round cell features, reminiscent of lymphoma, but with variable rhabdomyoblastic differentiation.
The conventional type of alveolar rhabdomyosarcoma is characterized by fibrovascular septa that separate the tumor into nests.
ALVEOLAR RHABDOMYOSARCOMA
The tumor cells are relatively large, the largest ones (15 to 30 m) often showing rhabdomyoblastic differentiation with eccentric eosinophilic cytoplasm, with or without cross striations.
Multinucleated giant (wreath) cells are often present as well and are of help in the (differential) diagnosis.
ALVEOLAR RHABDOMYOSARCOMA
ALVEOLAR RHABDOMYOSARCOMA
Genetics t(2;13)(q35;q14) or t(1;13)(p36;q14) as variant translocation Juxtaposition of the PAX3 (chromosome 2) or PAX7 (chromosome 1) with the FKHR on chromosome 13 Immunohistochemical Features Staining for desmin should be present or myogenin/MyoD1 should be present Myogenin expression more diffuse than in embryonal type of rhabdomyosarcoma.
ALVEOLAR RHABDOMYOSARCOMA
Prognosis and Treatment
LYMHOMA OF BONE
Approximately one-third of lymphomas originate in tissues other than lymph nodes. These tissues have native population of lymphoid cells, such as lung, gastrointestinal tract, and bone.
LYMHOMA OF BONE
Approximately 5% of extranodal lymphomas are primary in bone. It accounts for 7% of all malignant bone tumors.
LYMHOMA OF BONE
Clinical Features Primary lymphoma of bone occurs at any age. However, 50% of patients are older than 40 years. Rarely, children may experience development of primary lymphoma of bone. In a child, a variant of this neoplasm may be the precursor B-cell (lymphoblastic) lymphoma. The femur and pelvis are the most common bones to be involved.
LYMHOMA OF BONE
Radiologic Features Lymphoma of bone is usually a poorly defined, permeative lytic lesion Occasionally, a lesion may have extensive osteosclerosis, a feature that often leads lymphoma of bone to be misdiagnosed as Paget disease Occasionally, the permeative pattern of bone destruction is subtle and difficult to appreciate on plain radiographs. MRI may show a strikingly strong signal on T2weighted images.
MICROSCOPY
IHC
Ewing sarcomas will be positive with CD99 and negative with CD45.
However, precursor B-cell lymphoblastic lymphomas can also be positive with CD99, and negative with CD45and CD20. Therefore, it may be easy to misdiagnose a lymphoblastic lymphoma as a Ewing sarcoma.
Additional markers such as Tdt, CD43, and CD79a that are expressed by lymphoblastic lymphoma but not Ewing Sarcoma In adults, primary lymphoma of bone may be confused with multiple myeloma.
LYMHOMA OF BONE
Immunostains can also be helpful because myeloma cells show strong cytoplasmic immunoglobulin light-chain stain restriction, whereas they are weakly positive or negative for CD45 and CD20. In contrast, most B-cell lymphomas show the converse staining pattern, with strong positivity for CD45 and CD20, and little reactivity for CD138 and immunoglobulin light chains. Metastatic carcinoma must also be included in the differential diagnosis in adults. Some lymphomas are anaplastic and may be confused with metastatic epithelial neoplasms. Therefore, cytokeratin stains should be performed to rule out metastatic carcinoma.
PROGNOSIS
This disease is best treated with radiation and chemotherapy. Lymphomas of bone without visceral or nodal disease have a good prognosis with this therapy. In patients with lymphoma confined to the bone, reported 5-year survival rates range from 60% to 90%.
A small round cell desmoplastic tumor is a primitive polyphenotypic neoplasm usually arising in the abdomen and characterized by small cell nests enmeshed in a dense fibrous stroma.
Incidence and Location
Rare 15 to 35 years of age Almost always occurs in mesothelial lined spaces, particularly the abdomen and pelvis, but may rarely occur in other locations
DSRT
Clinical Features DSRCT is far more common in men than in women (male/female ratio, 4:1). Most patients have a large intra-abdominal mass, with symptoms attributable to mass effect.
Cytogenetics
Similar to Ewing sarcoma and alveolar Rhabdomyosarcoma, desmoplastic small round cell tumor is cytogenetically defined by a reciprocal translocation: the t(11;22)(p13;q12).
This translocation creates a fusion gene that transcribes a chimeric protein containing portions of the WT1 protein and the EWS protein
DSRT
The fusion protein produced by the WT1/EWS gene is capable of inducing the expression of endogenous platelet-derived growth factor- A, which is a powerful mitogen and chemoattractant. Thus, by fusion with EWS, WT1 is converted from a tumor suppressor gene into an oncogene.
DSRT
Gross Findings Large, fibrous mass, often with necrosis and hemorrhage Microscopic Findings Nests of malignant round blue cells in a highly vascular, desmoplastic stroma. Occasional cases with pleomorphism and rhabdoid cells. Glandular and papillary structures may rarely be seen
DSRT
Immunohistochemical Findings Coexpression of desmin, cytokeratins, and vimentin, often in a dot-like pattern. Positivity with antibody to carboxyl-terminal WT1, reflecting Presence of EWS-WT1 fusion protein. Positive for CD99 in up to one-third of cases. Positive for epithelial markers such as EMA and Ber-Ep4; negative for mesothelial markers such as calretinin and CK5/6 Neuron-specific enolase positive; negative for chromogranin A and synaptophysin
PROGNOSIS
> 75% of patients dead of disease in < 5 years. progression-free survival may be increased with aggressive debulking, in patients whose tumors have responded to multiagent chemotherapy
MESENCHYMAL CHONDROSARCOMA
Definition High-grade biphasic sarcoma composed of undifferentiated small blue cells and islands of well-formed hyaline cartilage. Incidence and Location These tumors are rare, comprising less than 1% of soft tissue sarcomas. The most common location is within the soft tissues of the Craniospinal axis, including the paraspinal musculature; The meninges represent the most common extraskeletal site for this tumor
MESENCHYMAL CHONDROSARCOMA
Sex and Age Distribution Male and female individuals are affected equally Tumors occur at all ages; however, the majority occur in the second through the fourth decades of life
MESENCHYMAL CHONDROSARCOMA
Clinical Features Patients present with a soft tissue mass similar to other soft Tissue sarcomas. Because of their association with the craniospinal axis, focal Neurologic signs or symptoms, or both, may occur Radiologic Features Cartilaginous-type calcification is often present on plain Radiographs that otherwise show a nonspecific appearance.
MESENCHYMAL CHONDROSARCOMA
Gross Findings
MCs have a wide range in size from less than 5.0 to greater than 20.0 cm.
The tumors appear grossly well defined and have a tangray cut surface. Focal hemorrhage or necrosis is commonly present. Gritty areas representing the calcified cartilage are often present.
MICROSCOPY
MESENCHYMAL CHONDROSARCOMA
Immunohistochemistry
Vimentin labels the small blue cells and the chondrocytes.
CD99 is positive within the blue cell component, whereas S-100 labels the chondrocytes.
Differential Diagnosis
Islands of cartilage, which allow distinction of MC from Ewing sarcoma/PNET. This differential may be extremely difficult on small biopsy samples. Molecular genetic examination for the translocation associated with Ewing sarcoma/PNET (t[11;22]) is extremely helpful in resolving this differential. Solitary fibrous tumor and synovial sarcoma are two tumors that may exhibit sheets of small, rather undifferentiated appearing cells often associated with a hemangiopericytoma- like vascular pattern. These tumors do not show islands of hyaline cartilage
MESENCHYMAL CHONDROSARCOMA
Prognosis and Treatment
MCs are high-grade, clinically aggressive tumors that are treated by a combination of surgery and systemic chemotherapy. Up to 50% of patients have died of disease at 5-year follow up.
MICROSCOPY
Microscopically, the rhabdoid cells have eccentric nuclei with prominent nucleoli and abundant cytoplasm with round, hyaline inclusions. Some lesions have less abundant cytoplasm, potentially simulating a hematopoietic neoplasm.
Divide the tissue properly so that fresh and frozen material is available for additional studies
Electron microscopy may be useful in difficult cases and requires only minimal amounts of properly fixed tissue. Standard cytogenetics requires sterile, fresh tissue. If limited tissue is available, histology comes first, followed by frozen tissue for biology studies.
Lymphoma
Leukemic infiltrate
Patterns
Septate or lobulated round cell pattern
Small round cells are divided by fibrous/fibrovascular septate Ewing`s sarcoma Alveolar Rhabdomysarcoma
Pattern
Round cell pattern with Rosettes
A `rosette is like a flower, with the cells being arranged radially around a central area. Flexners( also called Flexner- Winterstein, true rosettes)-contain clearly delineated empty central lumen. e.g. Retinoblastoma. Homer Wright rosette-center has no lumen,but abundant fibrillary material e.g. Neuroblastoma Primitive neuroectodermal tumor( PNET)
Carefully review the clinical data after first reviewing histologic sections
Look into Age of presentation Site of presentation Radiological features Paraneoplastic syndromes Cathecholamine tests
Refernces
Small round cell tumours chapter 31 text book of modern soft tissue pathology Weidner , Cote, Suster, Weise. Internet
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