Enlarging Toe Mass in a 13-Year-Old Girl

List of Abbreviations Used: RNA = ribonucleic acid A 13-year-old girl who was morbidly obese presented with a 3.5-month history of an enlarging mass of her left second toe. She denied any specific trauma to this toe. It had become ulcerated and failed to heal with conservative treatment. Physical examination revealed a discrete distal bulge of the left second toe projecting laterally. There was a 1.5 × 1.5 cm deeply excavated, stellate ulcer on the dorsum of the toe superior to the bulge. Laboratory evaluation included a normal serum uric acid level and unremarkable coagulation and hematology studies except for an elevated erythrocyte sedimentation rate of 32 mm/hour (normal, 0–20 mm/hour). A bone scan showed increased tracer uptake in the distal left second toe. Radiographs and magnetic resonance imaging (MRI) were obtained and are shown in Figures 1 to 4.Fig 1.: Anteroposterior radiograph of the left second toe at initial presentation.Fig 2.: Sagittal proton density-weighted MR image.Fig 3.: Coronal T1-weighted spin-echo MR image.Fig 4.: Coronal short Tau inversion recovery MR image.Based on the history, physical findings, laboratory studies, and radiologic imaging, what is the differential diagnosis? RADIOGRAPHIC AND IMAGING INTERPRETATION Radiographs (Fig 1) show eccentric soft tissue swelling extending distally from the left second toe’s web space. There is no calcification, fat density, or other apparent internal matrix. The adjacent phalanges and joint spaces are normal without bone destruction, erosions or periosteal reaction. The sagittal proton density-weighted image (Fig 2) shows an eccentric, well-defined mass in the soft tissue with subtle inhomogeneity of its internal contents. Although the superior cortex of the middle phalynx is not well seen on this sagittal image, the coronal images (Figs 3, 4) did not show a definite cortical break and do show relative lack of marrow edema. T1-weighted spin-echo (SE) (Fig 3) and T2-weighted short Tau inversion recovery (STIR) (Fig 4) coronal image show the mass to have a low to intermediate T1 and a high T2 signal, possibly related to tumor necrosis. The STIR image is fat suppressed and shows possible thin septa within the lesion. DIFFERENTIAL DIAGNOSIS Chronic infection or abscess (including granulomata) Benign soft tissue neoplasm (neurofibroma, hemangioma), hamartoma, or fibromatosis Giant cell tumor of the tendon sheath Soft tissue sarcoma (osteosarcoma, synovial sarcoma, Ewing’s sarcoma, peripheral primitive neuroectodermal tumor, rhabdomyosarcoma) or lymphoma. An open biopsy of the left second toe was obtained (Fig 5). Based on the history, physical findings, radiographic studies, and histologic picture, what is the diagnosis and how should this lesion be treated?Fig 5.: Low power photomicrograph of the soft tissues of the toe (Stain, hematoxylin and eosin; original magnification, ×10).PATHOLOGY Light Microscopic and Gross Features The original biopsy material was composed of multiple, irregularly shaped, tan-pink fragments that were focally hemorrhagic. They measured in aggregate 2.6 × 2.1 × 0.6 cm. Tissue submitted for intraoperative consultation had extensive zones of necrosis admixed with granulation tissue. A small population of small blue round cells was appreciated along one edge of the tissue submitted for frozen sectioning (Fig 5) but was not present on deeper levels of the permanent sections. Only karyorrhectic debris was observed in association with the necrotic tissue. Once the preliminary diagnosis of malignant small blue round cell tumor was made based on the frozen section from the open biopsy, definitive excision was delayed awaiting results of the permanent section. After confirmation of this diagnosis, the patient returned to the operating room for a ray resection of the second toe. The definitive specimen from the second toe ray resection was that of a misshaped 7.5 × 2.9 × 2.4 cm left second digit with a discrete distal bulge projecting laterally. The sagittal cut surface reveals a solid gray-white lobulated tumor that partially surrounded the interphalangeal articulation. There was no gross osseous involvement. Histologic sections showed tumor lobules that filled the space between the periosteum of the phalanges and the upper to middermis of the overlying skin. These lobules were composed of nests of neoplastic intermediate-sized round to oval blue cells with a high mitotic to karyorrhectic index. This index recognizes mitoses often are difficult to recognize when cells are undergoing apoptosis or necrosis resulting in karyorrhectic debris and when cells are counted, no attempt is made to separate these two phenomena. These blue cells clustered and had a focal perivascular distribution. The cell’s nuclei were small, with a chromatin pattern that could be described as diffuse or minimally speckled and without nucleoli but with small chromatin centers. The surrounding cytoplasm was indistinct. The mitotic cell count among this cell population was low with only a rare cell seen to be engaged in mitosis. Sections of the skin and soft tissues from the second left toe ray resection showed nests of neoplastic intermediate-sized round to oval blue cells with a high mitotic to karyorrhectic index. The tumor lobules filled the space between the periosteum of the phalanges and the upper to middermis of the overlying skin. An ulcer on the dorsum of the toe was covered by a fibrinopurulent exudate. The ulcer bed contained granulation tissue, suture and a few entrapped nests of small blue round tumor cells. The phalanges and metatarsals showed a fatty marrow and are free of neoplastic disease. Ultrastructural Features By transmission electron microscopy, a mixture of light and dark cells were observed, characteristic of Ewing’s sarcoma. The tumor cells contained pools of glycogen, a modest number of organelles, cell junctions, occasional cilia and rare rudimentary cell processes (Fig 6). No neurosecretory granules were appreciated, which made the diagnosis of neuroendocrine tumor untenable. Z band material, large numbers of intermediate filaments, or basement membrane material were not observed thereby excluding rhabdomyosarcoma and several soft tissue and metastatic tumors in the differential diagnosis. The intercellular space contained minimal collagen deposition.Fig 6.: Transmission electron photomicrograph showing a population of light and dark cells with prominent cytoplasmic glycogen granule in the center of the field surrounded by sparse organelles (Original negative magnification, ×11,000).Immunohistochemical Features The neoplastic cells in the original biopsy specimen were intensely positive with the O13 monoclonal antibody that recognizes an epitope on the p30/32MIC2 protein (Fig 7). Immunostaining the tumor cells with antineuron specific enolase and antisynaptophysin showed a high background but no specific reactivity within the cells, mitigating against peripheral primitive neuroectodermal tumors. Occasional CD3 positive cells were present, consistent with reactive lymphocytes interdigitating with the tumor cells. The tumor was nonreactive to antibodies directed against actin, desmin, keratin, and leukocyte common antigen (CD 45) excluding muscle, epithelial, and most lymphoid cells, respectively.Fig 7.: Immunohistochemical staining of neoplastic cells showing near uniform strong membranous immunoreactivity with nonstaining of vasculature and pseudocapsule on right (O13 monoclonal antibody, Hematoxylin counterstain; original magnification, ×25).Immunohistochemical staining of tumor cells from the definitive specimen again shows the cells to be diffusely and intensely positive for O13 monoclonal antibody, in a somewhat membranous pattern of immunoreactivity typical for Ewing’s sarcoma. Antineuron specific enolase reaction is equivocal whereas antichromogranin and anticytokeratin are negative. Molecular Diagnostics Fresh tumor tissue was sent to Jesse Jenkins, MD, PhD at St Jude’s Children’s Research Hospital, Memphis, TN. He was able to ascertain that the tissue was positive for the EWS/FLI-1 fusion transcript by reverse transcriptase-polymerase chain reaction, consistent with the Ewing’s sarcoma/primitive neuroectodermal tumor group of tumors. DIAGNOSIS Extraosseous Ewing’s sarcoma. DISCUSSION Ewing’s sarcoma is the second most common malignant bone tumor of childhood. Its peak incidence is in the early second decade of life but can occur in infants and toddlers. 27 Males predominate and it is rare in African-Americans. 21 The most common site is the medullary portion of the metadiaphyseal region of long bones but essentially all bones are at risk, and, as shown by the current case, can occur as primary tumors of soft tissue. 6,37 Depending on the site and duration, symptoms and signs can include pain, swelling, tenderness, fever, and/or hematologic abnormalities. 24,48 Nonhealing ulcers in children should be viewed with suspicion as presentation of malignancy rather than infection, requiring a more thorough evaluation. When Ewing’s sarcoma is osseous in origin, radiographs may show aggressive destruction, ranging in pattern from permeative to confluent with poorly demarcated lysis. 35 Sclerosis in Ewing’s sarcoma (aside from periosteal reactions) is frequent and usually only found within the original confines of bone, helping to separate it from osteosarcoma with soft tissue extension. 41 Active periosteal reactions (lamellated, sunburst, or both) also are frequent except when Ewing’s sarcoma is located in the bones of the hands or feet. 35 Large soft tissue masses may be associated with the lesion. Focal external erosion of the periosteal surface of the involved bone (saucerization) is seen infrequently. 35 When Ewing’s sarcoma is extraskeletal in origin, its imaging presentation can be similar to the imaging presentation in the current case. It commonly arises within the extremities. The soft tissue mass is not associated with calcifications or apparent bone involvement. 33 On cross-sectional imaging, the lesion usually is well-marginated and can have central areas of low attenuation on computed tomography scans or increased T2 signal on MRI scans. 3,33,36 Grossly an off-white lesion with increasing amounts of red and yellow coloration, dependent on hemorrhage and necrosis, respectively, often is identified and the lesion may be liquid in consistency. Microscopically, the cells are packed tightly, round and regular with lightly speckled, ground-glass or clear nuclei. Necrosis and glycogen intracellularly often are present. 7,10 A two-cell dimorphism composed of large viable and small apoptotic cells is characteristic, which corresponds to the light and dark cells appreciated on transmission electric microscopy. 25,26 Mitotic rates usually are low. Matrix production, other than fibrous tissue, is absent. The filigree growth pattern that is characterized by infiltrating strands of tumor separated by thin, vascularized fibrous septa portends a worse prognosis as does a high (> 10 per high power field) mitotic index as was seen in the current case. 21 The rudimentary cell processes, seen on ultrastructural examination, place this tumor in a category slightly deviant from classic Ewing’s sarcoma. A group from the Mayo Clinic described their experience with soft tissue Ewing’s sarcoma. 42 When compared with soft tissue primitive neuroectodermal tumors, they found no difference between the two groups in relation to age, gender, tumor location, or stage. Additionally, the 5-year survival and disease-free interval essentially were identical. 42 Regarding Ewing’s sarcoma of bone, a large cell atypical variant has been described, as have attempts to divide tumors into typical and atypical subtypes. 31 Therapy may alter the histomorphology. 17 Ewing’s sarcoma metastasizes early to the lungs and other bones. The primary site of disease is the most accurate predictor of clinical behavior: patients with tumors of the pelvis have a worse prognosis whereas patients with tumors of the hands, feet, and craniofacial bones have a better prognosis. 17,20,40,43 Many other prognostic factors have been championed with variable degrees of reproducibility including age at diagnosis, tumor size or volume, degree of extraosseous extension, serum lactic dehydrogenase levels, and response to chemotherapy. 2,11,16 Histogenesis has been controversial until the molecular era. Ewing’s sarcoma cells now are thought to be (ultra) primitive neuroectodermal cell. 44 It shares a characteristic translocated karyotype [t(11,22)(q24,q12)] with primitive neuroectodermal tumor (including Askin tumor), small cell osteosarcoma, and is closely related to desmoplastic small round cell tumor [t(11,22)(p13,q12)]. 39,45 Subsets of Ewing’s sarcoma show a chromosome 22 deletion. 39,44 It now is known that this 11q24 translocation results in a unique rearrangement at a breakpoint, resulting in a fusion of the Ewing’s sarcoma gene (involved in RNA binding) with one of two ETS oncogenes (FLI-1 or ERG). 14,32,39,45,49 These later genes encode transcriptional activators, repressors, or both. The Type 1 EWS-FLI-1 fusion is associated with a less aggressive clinical course which, in turn, is attributable to a less active chimeric transcription factor. 23 Multiple splicing variant has been reported, some of which may select for localized disease or site. 45 As in the current case, Ewing’s sarcoma cells are nonreactive immunohistochemically to most intermediate filaments (except vimentin), S100 protein, vascular, lymphoid, and macrophage markers but are variably immunoreactive to cytokeratin, basement membrane proteins, Type I collagen, neuron specific enolase, Leu 7, and synaptophysin. 9,19,29,30,34,46 They are, however, intensely immunoreactive with antibodies against the pseudoautosomal MIC2 gene product also known as p30/32MIC2 (HBA-71, O13). 5,13,47 Current treatment has focused on chemotherapy, radiation, and surgery where indicated. This therapy aims to eliminate the primary tumor and metastatic disease. Aggressive multiagent chemotherapy is used to control micrometastasis and help to achieve permanent local control. Some controversy still exists concerning the role of surgery or radiation alone in the treatment of the primary site of Ewing’s sarcoma. 12,22,38 Although successful in the treatment of local disease, radiation is not without its own morbidity. In patients who are skeletally immature, radiation of the entire bone may cause epiphyseal injury that may lead to significant limb discrepancy and angular deformities. 4 Additional morbidity of radiation therapy is local recurrence in irradiated primary sites. Furthermore, even after successful initial therapy, secondary malignancies arising from primary irradiated sites have been reported. 2,8 However, in selected patients, low dose radiation after surgery when combined with limited surgery offers the possibility of local control of disease. 28 Current indications for surgery in patients with Ewing’s sarcoma include relatively small tumors, tumors that are easily accessible surgically, and tumors in expendable anatomic sites. 18 Ewing’s sarcoma of the foot meets all of these criteria. A distal extremity or foot tumor lends itself to amputation because of the tumor size, surgical accessibility, and because of the excellent functional results in young patients with below-the-knee amputation. Several large series have reported that patients who underwent surgical excision of their nonmetastatic primary tumor had a better survival rate than those who did not undergo resection. 1,15,40 When the benefits of amputation and its morbidity are considered, in addition to the hazards of radiation to these young patients, amputation is an excellent alternative to the treatment of patients with Ewing’s sarcoma of the foot. As noted above, 9 days after presentation, this patient underwent a ray resection of the left second toe to include the entire metatarsal. She received chemotherapy but no radiation therapy. At 20 months followup, the patient does not have evidence of recurrence.