Lesions Characterized by Permeation of Cells through Trabecular Bone with or without Bone Destruction

Background

First described in 1913, adamantinoma is a low-grade biphasic malignant bone tumor of probable epithelial origin with a basaloid character and a prominent mesenchymal component, resembling osteofibrous dysplasia. This tumor occurs almost exclusively in the midshaft of the tibia and sometimes the fibula. It is a rare tumor, representing 0.1% to 0.5% of all primary bone tumors. The term adamantinoma was used because of the close resemblance to ameloblastoma (adamantinoma) of the jaws. The derivation of the tumor is uncertain; the most widely accepted conjecture is basal epithelium displacement from skin during embryogenesis. In comparison to other long bones, the anterior tibia is in close proximity to the skin during endochondral bone formation. The epithelial origin is supported by immunohistochemical and ultrastructural studies.

Clinical Features

Adamantinoma occurs most commonly in the second to fifth decades of life, with 75% of affected patients presenting in the second and third decades; the median age is 25 to 35 years. There is a slight male predilection, with a male-to-female ratio of 1.25 : 1.0. This tumor rarely occurs in the pediatric population (3% of cases). Long bones are affected in more than 95% of cases, with the vast majority occurring in the tibia (80% to 85%) and some involving the fibula (10% to 15%). There are rare case reports of adamantinoma arising in the pretibial soft tissue without underlying bone involvement.

The symptoms are indolent and nonspecific, and the tumor progresses slowly. Often, symptoms are present for several years before medical care is sought. The presenting symptom is swelling with or without pain, and there is a history of trauma in about two thirds of affected patients. A tibial bowing deformity may be present due to the anterior placement of the tumor, and one fourth of patients present with a pathologic fracture. Rare cases with hypercalcemia have been reported with adamantinoma with pulmonary metastases.

Radiologic Features

The typical adamantinoma occurs as a mid-diaphyseal osteolytic lesion in the tibia, which is expansile, eccentric, and medullary in location. This tumor involves the anterior metadiaphysis of the tibia in 85% to 90% of cases and may be seen in combination with ipsilateral fibula involvement. Rare cases may involve the ulna, humerus, femur, ribs, spine, and short bones of the feet. The lesion has a “soap bubble” appearance with multifocal ring-shaped radiolucencies surrounded by sclerotic rims. The well-circumscribed lesion usually has a thickened, sclerotic border with the adjacent uninvolved bone, indicative of slow growth, and may be up to 11 cm in length. Due to the anterior tibial location of the lesion, bowing of the bone is a characteristic finding on imaging. There may be a periosteal reaction and extension of the lesion into the pretibial soft tissues (15%). Computed tomography (CT) and magnetic resonance imaging (MRI) findings tend to be nonspecific. MRI is important in planning surgical resection in limb salvage procedures in order to determine the extent of soft tissue and intramedullary involvement and distant cortical foci of tumor (skip lesions). Nuclear bone scans may show increased blood flow and blood pooling in the region of the tumor.

Certain radiologic features mimic osteofibrous dysplasia and fibrous dysplasia. However, adamantinoma may be distinguished from these entities by the midshaft diaphyseal location, anterior cortical bone involvement, lesion extension toward the medullary space, and nodular appearance.

Pathologic Features

Gross examination of the resected specimen demonstrates anterior cortical involvement by tumor and tan intracortical tumor nodules often associated with a periosteal reaction. A sclerotic rim of bone adjacent to uninvolved bone may also be appreciated. The tumor may extend into the marrow space and overlying soft tissues. Usually, such features cannot be appreciated on a bone biopsy specimen.

The tumor is composed of epithelial cells in a fibrotic dense stroma, illustrating the biphasic nature of the adamantinoma ( Fig. 14-1 ). There may be portions of irregular woven bone rimmed by osteoblasts, resembling osteofibrous dysplasia. Adamantinoma has been divided into classic and differentiated (osteofibrous dysplasia–like) types. With classic adamantinoma, the epithelial component is prominent, and the osteofibrous dysplasia–like component is less obvious. There are four epithelial types associated with classic adamantinoma: (1) basaloid, composed of spindle cells surrounded by palisading basal cells at the periphery; (2) squamoid, composed of epithelial cell nests with keratinization; (3) tubular, with glandlike spaces lined by cuboidal to flattened cells; and (4) spindle cells arranged in interlacing fascicles, mimicking fibrosarcoma. The differentiated adamantinoma is composed of predominantly osteofibrous dysplasia–like areas with irregular woven bone spicules lined by osteoblasts in a fibrous background with inconspicuous epithelial nests.

The epithelial cells immunoreact with cytokeratins 5 (75%), 14 (100%), 17 (50%), and 19 (100%), similar to basal cells in the normal epidermis. The epithelial tumor cells also exhibit epithelial membrane antigen (EMA), podoplanin (D2-40), p63, p53, epidermal growth factor receptor, and fibroblastic growth factor 2 reactivity. The presence of p63 reactivity may be helpful in distinguishing metastatic carcinoma with a sclerotic background from adamantinoma. On ultrastructural examination, the epithelial cells demonstrate desmosomes, gap junctions, keratin filaments, tonofilaments, microfilaments, and basal lamina.

The distinction between classic and differentiated adamantinoma was originally defined based on histopathologic evaluation, and this has allowed for characterization of these types of tumors based on age, radiology, histopathology, and behavior characteristics. Classic types occur in patients older than 20 years of age, whereas differentiated types occur in those younger than 20 years of age. Radiologic examination of classic types identifies soft tissue or intramedullary involvement. In contrast, differentiated types are typically intracortical tumors similar to those seen with osteofibrous dysplasia. Classic-type tumors tend to be aggressive in behavior, whereas differentiated-type tumors tend to have an indolent course.

Genetics

Cytogenetic information regarding adamantinoma is sparse due to the rarity of this tumor. Extra copies of chromosomes 7, 8, 12, 19, and 21 have been reported. A single case with nonrecurring translocations has been reported [t(1;13;22); t(15;17)]. Gene array and whole exome or genome analyses have not been published to date.

Differential Diagnosis

The differential diagnosis for adamantinoma includes aneurysmal bone cyst, unicameral (solitary) bone cyst, fibrous dysplasia, nonossifying fibroma, chondromyxoid fibroma, giant cell tumor of bone, eosinophilic granuloma (Langerhans cell histiocytosis), osteomyelitis, chondrosarcoma, hemangioendothelioma, angiosarcoma, and metastatic carcinoma. Recently, adamantinoma-like Ewing sarcoma has been reported but was easily differentiated from adamantinoma using CD99 membranous staining patterns and the presence of the Ewing sarcoma breakpoint region 1–Friend leukemia integration 1 (EWSR1-FLI1) translocation diagnostic of Ewing sarcoma. The primary differential diagnoses are osteofibrous dysplasia, which lacks aggregates of epithelial cells, and metastatic carcinoma.

Clinical Course

Certain clinical features have been associated with aggressive disease and include classic-type morphology, male gender, female gender at a young age, rapid onset of symptoms, pain, lack of squamous differentiation, increased epithelial-to-stroma ratio, and inadequate initial surgical treatment. Local recurrence may occur many years later (up to 7 years), and metastatic disease may occur even decades after the initial diagnosis. Local recurrence is reported to range from 18% to 32%, with metastatic disease ranging from 10% to 30%. This tumor may metastasize to regional lymph nodes and lungs, and less frequently it spreads to bones, liver, and brain. Mortality rates appear to be approximately 15% after limb salvage resection.

Treatment of adamantinoma is en bloc resection with wide surgical margins, limb salvage, and limb reconstruction. These strategies have resulted in a 10-year survival rate of nearly 90%. Limb amputation has not shown any improvement in survival compared to en bloc tumor resection with limb salvage. Radiation therapy and chemotherapy have not proven to be beneficial. Note that tumor recurrence after nonaggressive surgery may be as high as 90%.

Background

Myeloma (multiple myeloma, plasma cell myeloma) is a clonal B-cell neoplasm composed of a proliferation of plasma cells within the bone marrow and extramedullary sites, including cortical bone. This entity is the most frequent tumor that occurs primarily in bone. Myeloma accounts for 10% to 15% of all hematologic malignancies and is responsible for 20% of its deaths. The disease, first recognized in the mid-1800s at autopsy, was characterized by soft bones and bone infiltration by large oval cells with prominent nucleoli (plasma cells). Abnormal proteins were found in the urine of affected patients (Bence Jones proteins), which almost 100 years later were determined to be similar to serum light-chain immunoglobulins. With electrophoresis technique development in the 1930s, it became possible to identify the proteins and provide a clinical test for detection of Bence Jones proteins in urine and light-chain immunoglobulins in serum. By 1961, it was possible to distinguish polyclonal and monoclonal gammopathies and characterize the associated diseases (myeloma, benign monoclonal gammopathy of undetermined significance, Waldenström macroglobulinemia, and AL amyloidosis).

Clinical Features

The majority of patients are in the sixth and seventh decades of life, and the median age is 65 years. Less than 10% of cases occur in patients younger than 40 years of age. There is a slight male predilection for this disease. The incidence in blacks is twice as high as that in whites. In the United States, 20,000 new cases are diagnosed each year, with 10,000 deaths per year attributed to this disease. The classic clinical phenotype is bone abnormalities, hypercalcemia, anemia, leukopenia, thrombocytopenia, renal dysfunction, recurrent infections, and peripheral neuropathy. Bone disease occurs in about 60% of cases and is characterized by lytic lesions. The axial skeleton associated with hematopoiesis is most often involved; the most common sites of involvement are the vertebrae, ribs, skull, pelvis, femur, clavicle, and scapula. Vertebral fractures and compression, osteopenia, and osteoporosis are common and are usually not associated with pain. Hypercalcemia is the most common metabolic abnormality. This is due to osteolysis and bone resorption with calcium being transported into extracellular fluids. Parathyroid hormone–related proteins are not usually elevated in myeloma. Renal dysfunction with renal tubular calcium reabsorption further contributes to hypercalcemia. Renal dysfunction occurs in about 20% to 30% of affected individuals at diagnosis and in more than 50% of patients during the course of the disease. Accumulation of excess light chains in the kidney is primarily responsible for renal impairment. The interaction of light chains with Tamm-Horsfall protein results in tubular casts and obstructive nephropathy (myeloma kidney). Other factors that contribute to renal dysfunction include hypercalcemia, hyperuricemia, dehydration, nephrotoxic medications, radiologic contrast materials, and AL-amyloid/light-chain deposition. Deficiencies in antibody-mediated and cellular immunity lead to recurrent infections, most often involving the upper respiratory tract. Peripheral neuropathy is often present at diagnosis and may be further aggravated by medication toxicity. Extramedullary disease is present in only 1% of cases at diagnosis and in 8% of cases in later stages of the disease.

The vast majority of patients initially have an asymptomatic premalignant form of the disease: monoclonal gammopathy of undetermined significance (MGUS). MGUS is present in 3% of the population by 50 years of age. There is a 1% per year transformation rate from MGUS to myeloma. Most individuals diagnosed with MGUS have had this asymptomatic condition for more than 10 years. There is also an asymptomatic intermediate premalignant form called smoldering (multiple) myeloma. Individuals affected by this form progress to classic myeloma at a rate of 10% per year during the first 5 years following diagnosis, then 3% per year over the next 5 years, and 1.5% per year thereafter.

The diagnosis of myeloma requires (1) > 10% plasma cells in the bone marrow or a biopsy-proven plasmacytoma; (2) serum or urine monoclonal protein level > 3 g/dL; and (3) evidence of end-organ involvement (hypercalcemia, renal insufficiency, anemia, bone lesions). The presence of at least 60% clonal plasma cells in the bone marrow is diagnostic of myeloma regardless of end-organ damage.

Radiologic Features

In contrast to many metastatic malignancies involving bone that induce new bone formation, myeloma is characterized by osteolytic lesions. The lytic lesions tend to be sharply demarcated and not surrounded by a sclerotic rim. Cortical erosion without new periosteal bone formation is common. Multiloculation is present in about 50% of lesions. Initial and most severe changes are detected in the skull, vertebrae, ribs, and pelvis. Generalized osteoporosis with no lytic bone lesions may be present in 10% to 25% of patients. Small subtle lesions may be discovered with CT, MRI, and positron emission tomography (PET) scans. Sclerotic bone lesions may be seen in the clinical condition known as POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes).

Pathologic Features

The bone marrow of the affected bone may show several different patterns, including interstitial, nodular, focal, obliterative and, less frequently, sclerotic. Most often, the tumor is composed of typical-appearing plasma cells: ovoid cells with eccentric nuclei with clock-face condensed chromatin, indistinct nucleoli, and basophilic cytoplasm ( Fig. 14-2 ). A perinuclear amphophilic zone (hof) corresponds to a prominent Golgi complex with well-developed rough endoplasmic reticulum on electron microscopic examination. Less frequently, the tumor cells are composed of cells with scant cytoplasm that resemble small lymphocytes (lymphoplasmacytic or small lymphocyte-like myeloma). This type of myeloma may be mistaken for lymphoma; however, the diagnosis of myeloma can be confirmed by molecular identification of its characteristic translocation [t(11;14)(q13;q32)]. In less differentiated myeloma, the neoplastic cells may have a plasmablastic appearance with prominent nucleoli and a high nuclear-to-cytoplasmic ratio. Poorly differentiated myeloma may resemble large cell lymphoma or leukemia. An anaplastic morphology may occasionally be seen. The plasma cells may contain Russell bodies (cytoplasmic immunoglobulin globules), Dutcher bodies (intranuclear inclusions), or rarely Auer rod–like crystals. In about 10% to 15% of cases, the bone marrow contains deposition of light-chain amyloid. With numerous cytoplasmic fibrils, myeloma cells may take on an appearance similar to Gaucher cells. Amyloid may be deposited in vessel walls, and the supporting tissues as masses between plasma cells. A foreign body–type giant cell reaction to the amyloid deposition may be present.

The immunohistochemical profile of myeloma includes the plasmacytic antibodies CD138, CD38, and MUM1. CD117 (30% to 60%), CD56 (75% to 90%), and CD10 are expressed in neoplastic plasma cells. EMA may be present as well. Myeloma cells express monoclonal cytoplasmic immunoglobulin by kappa and lambda immunostaining, but surface immunoglobulin is absent. Both heavy-chain and light-chain immunoglobulins are expressed in 85% of cases. Light-chain immunoglobulins only are expressed in the remaining 15% of cases. The vast majority of myeloma cells lack CD19 expression. The lymphoplasmacytic type of myeloma expresses CD20 in up to 30% of cases.

Genetics

Reciprocal translocations involving the immunoglobulin heavy-chain locus ( IGH 14q32.33) and several other gene partners occur in about 40% of myelomas. The translocation gene partners are CCND1 at 11q13, CCND3 at 6p21, MAF at 16q23, FGF3R at 4p16.3, WHSC1/MM-SET at 4p16.3, and MAFB at 20q11.1. The translocation breakpoints are near the heavy-chain switch regions.

Reduced life span and high-risk disease are associated with immunoglobulin heavy-chain rearrangement (IgHR) translocations t(4;14) IGH-FGF3R and t(4;16) IGH-MAF , partial loss of chromosome 13 at q14, complete loss of chromosome 13, and partial loss of chromosome 17 at p13. Improved outcome with prolonged survival is associated with hyperdiploidy due to multiple trisomies; polysomy of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21; low frequency of monosomy; and the IgHR translocation t(11;14).

Late secondary genetic changes occur in myeloma and several of these are associated with disease progression. C-MYC (8q24) translocations, activating mutations of NRAS , KRAS , and FGRF3 , as well as inactivating mutations and deletions of TP53, RB1, PTEN, CDKN2A , and CDKN2C are associated with disease progression.

Differential Diagnosis

The radiologic differential diagnosis includes metastatic carcinoma, lymphoma, chronic osteomyelitis, and hyperparathyroidism. Metastatic carcinoma and lymphoma may be detected on nuclear imaging bone scans, and myeloma is usually not detected. Biopsy of a radiologically lytic lesion can usually differentiate among these different entities. Of particular note, plasma cells in chronic osteomyelitis are polyclonal, whereas plasma cells in myeloma are light-chain restricted (monoclonal).

Clinical Course

Myeloma is considered to be an incurable disease, with survival ranging from 6 months to 10 years. The median survival is about 3 years, with only 10% survival at 10 years. With solitary plasmacytoma, two thirds of patients progress to myeloma or develop additional plasmacytoma lesions within a median time of 2 to 3 years. The remaining one third of solitary plasmacytoma patients remain disease free for more than 10 years.

With myeloma, survival time is decreased with higher clinical stage, renal insufficiency, increased percentage of bone marrow infiltration by tumor cells, an increased proliferative index, and certain karyotypic alterations. Poor prognosis is linked to t(4;14), t(14;16), and deletion of TP53 (17p13). Disease progression and poor prognosis are seen with amplification of 1q, loss of 1p, deletion of 13q, and monosomy 13.

MGUS, smoldering multiple myeloma, and asymptomatic early stage multiple myeloma are usually simply followed closely clinically with no treatment. With disease-related symptoms or organ involvement, systemic chemotherapy with melphalan and prednisone is considered to be the standard of care. Addition of bortezomib, a ubiquitin-proteasome pathway inhibitor, has been used with a certain degree of success. The immunomodulators thalidomide and lenalidomide have been used in smoldering multiple myeloma with diminished bone density due to the plasma cell disorder. Intravenous bisphosphonates (zoledronic acid, pamidronate) are used to lessen bone resorption in smoldering and early stage multiple myeloma. This has not been shown to affect disease progression or overall survival.

High-dose chemotherapy followed by autologous bone marrow transplant or reduced intensity conditioning followed by allogeneic stem cell transplant have shown a certain degree of promise. Stem cell transplantation has shown improved progression-free survival, 5-year event-free survival, and overall survival in newly diagnosed myeloma patients. Allogeneic stem cell transplantation has been restricted to younger patients with a human leukocyte antigen (HLA)–identical sibling.

Future novel therapeutic targets involved in the pathogenesis of myeloma have been identified. These include the genes KRAS, RAF1, MAP2K1, PIK3, AKT, JAK, STAT3, PRKC, NFKB , FGFR3, and WNT .

Background

Mast cells were first described in 1878 due to cytoplasmic metachromasia of the cells with toluidine blue dye. Mast cells are derived from pluripotent bone marrow cells that express CD13, CD34, and CD117 (C-KIT). These myeloid lineage cells undergo proliferation and maturation within the body's tissues and organs. Mast cells are found throughout the body, but in particular are located around blood vessels, in well-vascularized tissues, and on surfaces that interface with the external environment. Mast cells function in innate immunity, allergic reactions, and autoimmunity, and they have a high affinity for IgE receptors. Mast cells produce histamine, heparin, proteoglycans (heparin, chondroitin sulfate), leukotrienes (leukotrienes C4 and B4, prostaglandin D2), cytokines (interleukins [ILs] 3, 4, 5, and 8; tumor necrosis factor alpha), and proteases (chymases, tryptase, carboxypeptidase A).

Mast cell diseases are heterogeneous entities that are characterized by mast cell proliferation in various organ systems. Cutaneous mastocytosis involves the skin and primarily occurs in infants and children with spontaneous resolution, usually during puberty. Systemic mastocytosis may involve the bone marrow, liver, spleen, and/or gastrointestinal tract with or without cutaneous involvement. This form of mast cell disease represents 10% of all mast cell diseases and occurs primarily in adults.

The World Health Organization (WHO) classifies mast cell disease as a myeloproliferative disorder with seven types of distinct presentations : (1) cutaneous mastocytosis, (2) indolent systemic mastocytosis, (3) systemic mastocytosis with associated clonal hematologic non–mast cell lineage, (4) aggressive systemic mastocytosis, (5) mast cell leukemia, (6) mast cell sarcoma, and (7) extracutaneous mastocytosis. As with all schemes arrived at by consensus committee, there is a certain degree of controversy regarding this classification system.

Clinical Features

As noted previously, the clinical phenotype of mast cell disease is quite variable, and it ranges from an indolent asymptomatic disorder to progressive tissue destruction and death in extreme cases. Cutaneous mastocytosis presents with red-brown papules and macules that are well demarcated and found primarily on the trunk and proximal extremities (urticaria pigmentosa). Diffuse thickening of the skin, telangiectasia macularis eruptiva perstans, and bullous mastocytosis may also be seen in the diffuse form. With temperature changes and physical irritation, there may be a flare of urticarial lesions (Darier sign). Skin biopsy showing mast cell accumulations usually provides the correct diagnosis.

Systemic mastocytosis tends to involve the bone marrow as well as truncal and proximal extremity sites. Extraosseous sites are involved in about two thirds of patients, with the spleen, lymph nodes, liver, and gastrointestinal tract mucosa being most often affected. Mast cell infiltration of these organs may lead to cytopenia, osteoporosis, pathologic fractures, hepatosplenomegaly, lymphadenopathy, and malabsorption. Symptoms at presentation are associated with the release of mast cell products and may include edema, flushing, diarrhea, pruritus, dyspepsia, nausea, vomiting, abdominal pain, musculoskeletal symptoms, fatigue, hypotension, syncope, tachycardia, and dyspnea. Triggers for a mast cell “attack” include physical exertion, stress, emotional upset, heat, cold, alcohol ingestion, radiologic contrast, nonsteroidal anti-inflammatory medications, opioids, and general anesthesia. Anaphylactic episodes occur in 20% to 50% of patients with systemic mastocytosis. Differentiation from carcinoid syndrome and symptoms associated with pheochromocytoma/paraganglioma is necessary.

Radiologic Features

In systemic mastocytosis, the most common findings with bone involvement are lytic and sclerotic lesions. The lytic lesions are secondary to heparin- and prostaglandin-induced bone resorption, whereas the sclerotic lesions are associated with heparin-induced bone formation. Bone lesions are found in 70% of cases, and most are of a diffuse rather than focal nature. Bone scans show four distinct patterns (normal, focal, multifocal, and diffuse). The lesions may have a mixed sclerotic-lytic appearance. Osteoporosis is seen in 30% to 40% of patients.

Pathologic Features

Mastocytosis involving bone is characterized by oval to somewhat spindled cells with round hyperchromatic nuclei with modest amphophilic to basophilic cytoplasm. The mast cells may be seen in a paratrabecular pattern with paratrabecular fibrosis. At times, there may be intermixed eosinophils. With mast cell disease ( Fig. 14-3 ), mast cells may be identified based on routine histomorphology, metachromasia of cytoplasmic granules with Giemsa or toluidine blue staining, or by immunohistochemical reaction with CD117 (C-KIT), CD25, CD2, or tryptase. Normal mast cells are negative for CD25 but positive for myeloid markers CD117 and CD33. Bone marrow infiltration occurs in three patterns: (1) focal accumulation with normal hematopoiesis in uninvolved areas (type I), (2) focal accumulation with increased granulopoiesis in uninvolved areas (type II), and (3) diffuse infiltration by atypical mast cells (type III).

Genetics

Mast cell disease is characterized by an activating mutation in C-KIT in more than 95% of cases. The most common codon involved is 816 (D816V mutation). The C-KIT proto-oncogene is a member of the tyrosine kinase receptor family and is expressed by mast cells, hematopoietic stem cells, melanocytes, germ cells, and gastrointestinal interstitial (stromal) cells of Cajal. Mast cells have a much greater degree of expression of C-KIT than other cells. Stem cell factor is a cytokine of great importance in development and differentiation of mast cells, and this cytokine interacts with the C-KIT receptor. Gain of function via a C-KIT mutation results in ligand-independent constitutive activation of C-KIT signaling, leading to uncontrolled mast cell proliferation via stem cell factor–independent activation. The C-KIT mutation leads to resistance to tyrosine kinase inhibitors, such as imatinib.

Several other genetic alterations occur in mast cell disease. Platelet-derived growth factor receptor A ( PDGFRA ) and FIP1L1 fusion occurs in about 50% of mastocytosis with eosinophilia cases. This entity has been recently classified by the WHO as a myeloid neoplasm with eosinophilia, with PDGFRA rearrangement (fusion) between platelet-derived growth factor B and PRKG2 also occurring less commonly. These fusion types are responsive to tyrosine kinase inhibitor treatment. Recently identified oncogenic mutations in systemic mastocytosis include the TET-2 oncogene (4q24) and NRAS . Microphthalmia-associated transcription factor (MITF) is a critical transcription factor in mast cell development and has been shown to be upregulated in systemic mastocytosis. Interestingly, MITF expression is regulated by C-KIT.

Differential Diagnosis

The differential diagnosis is primarily related to separation of mast cell disease from a benign mast cell reactive proliferation. As noted earlier, normal and reactive mast cells lack CD25 expression, allowing for differentiation. Differentiation of mast cell disease from a myeloid neoplasm may require molecular analysis for C-KIT mutations and translocation studies to classify the proliferation as a myeloid neoplasm with eosinophilia or a PDGFRA rearrangement. Clinical and radiologic findings are also important in appropriately defining this disease entity.