—  SPECIALTY CONFERENCE  —

Pediatric Pathology

Case 1 - Solid Alveolar Soft Part Sarcoma in Child

Julie C. Fanburg-Smith
Department of Orthopaedic and Soft Tissue Pathology
Armed Forces Institute of Pathology
Washington, D.C.


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Clinical History
A six year old boy was found to have an intramuscular mass. He presented with interference with swallowing and blood tinged saliva. The mass was in the muscle of the tongue, slightly to the left of midline. The mass was surgically removed and the patient received adjuvant chemotherapy with vincristine, adriamycin, and cytoxan for one year. The patient is currently without evidence of disease, 16 years after diagnosis, without a history of recurrence or metastasis.


Case 1 - Slide 1
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Case 1 - Figure 1
At low power, this alveolar soft part sarcoma of the tongue in a child is surrounded by tongue skeletal muscle and separated by thick fibrous septa into large lobules.
Case 1 - Figure 2
Higher magnification reveals the sheet like, non-alveolar pattern of this tumor. The tumor cells are polygonal with vesicular smooth to focally concave dark nuclear membranes and prominent nucleoli. There is a relative paucity of mitotic activity.
Case 1 - Figure 3
Even higher magnification reveals clear to eosinophilic, cytoplasm and apparent thin fibrous septa around each cells or small 2-4 cell clusters. The vessels of the septa are not obvious and there is no loss of cellular cohesion or central necrosis. The cells with clear or webbed eosinophilic cytoplasm mimic lipoblastlike or spiderlike cells.

Case 1 - Figure 4
Some cells appear to have a rhabdoid appearance with eccentric eosinophilic cytoplasm, mimicking rhabdomyosarcoma. Together with the MyoD1 appearance, one may mistake this for rhabdomyosarcoma.
Case 1 - Figure 5
Nuclear contours are round to focally concave, revealing the "cookie bite" nuclear appearance.
Case 1 - Figure 6
Mitotic activity is extremely difficult to find, despite the prominent nucleoli and vascular invasion (see Figure 7).

Case 1 - Figure 7
Vascular invasion outside of tumor capsule is usually found in these tumors.
Case 1 - Figure 8
Periodic acid Schiff with diastase (PAS-D) reveals granular to rhomboid crystalline material in most cases, from involvement of a few to nearly all cells.
Case 1 - Figure 9 - MyoD1
These tumors are notoriously vimentin negative and reveal sometimes strong cytoplasmic MyoD1 staining (as depicted here), not to be confused with a positive interpretation. MyoD1, a skeletal muscle myoregulatory protein, is a nuclear marker and is only read as positive when nuclear.

Pathologic Features
The tumor was completely removed with a small 0.3 cm length of attached overlying mucosa and scant surrounding skeletal muscle of the tongue. The tumor measured 2.5 centimeters in greatest dimension. It was grossly circumscribed, multinodular, hemorrhagic, grey-pink and fleshy to firm in consistency.

Histologically the tumor was without necrosis and was composed of sheets of tumor cells, separated into lobules by thick fibrous septae. At higher magnification, each tumor cell appeared to have its own surrounding fibrous septa. There were no medium to large sized clustering or grouping of tumor cells or obvious alveolar pattern, but 2-4 cells were occasionally grouped. There was no loss of cellular cohesion. The tumor cells were polygonal with eosinophilic cytoplasm and apparent granular to crystalline cytoplasmic inclusions on H&E. The nuclei were eccentric and vesicular with dark nuclear membranes. The nuclear contours were round to oval and often demonstrated focal irregularities, sometimes with concave indentations or a "cookie bite" appearance. The nucleoli were large and single with a basophilic to eosinophilic hue. The tumor was moderately vascular with some gaping vessels; hemorrhage was focally observed. Intravascular invasion was present outside of the tumor's main pseudocapsule. No inflammation was observed. PAS stains with and without diastase demonstrated PAS-positive, diastase resistant granular and crystalline intra-cytoplasmic inclusions.

Immunohistochemical stains were performed with appropriately reactive controls. The tumor cells showed strong diffuse cytoplasmic reactivity for MyoD1 but no nuclear reactivity was observed, equating to a negative immunostain. Vimentin, desmin, S100 protein, glial fibrillary acid protein, smooth muscle actin, skeletal muscle specific myogenin (myf4), keratin, epithelial membrane antigen, and muscle specific actin were negative.

A TFE3 was performed and demonstrated diffusely positive nuclear reactivity.

Discussion
This represents a solid alveolar soft part sarcoma of the tongue in a child. The case was selected to highlight the clinicopathologic features of this rare soft tissue neoplasm, to discuss the morphologic variation (solid type) in children, particularly in the tongue and orbit, and to discuss the broad benign and malignant differential diagnoses of this granular appearing tumor.

Alveolar soft part sarcoma (ASPS) was first described by Chistopherson in 1952. Before this report, cases were designated malignant myoblastoma, angioendothelioma and even liposarcoma. There is no benign counterpart, although the phenotype is largely unknown. Advances have been made to understanding the PAS-positive, diastase-resistant crystals and the molecular events. Overall it is an extremely rare sarcoma, comprising only less than one percent of all soft tissue sarcomas.

Clinically, ASPS typically occurs in older children and young adults, ages 15-35 years old. The most common age, in 41% of cases, is 20-29 years old. Only 12% occur in ages 0-9 and 17% in ages 10-19 years. ASPS are predominantly found in females, particularly in patients younger than 25 years old. In infants and children, ASPS tend to involve the head and neck, especially the orbit and tongue. The current case is within the skeletal muscle of a child's tongue.

The most prevalent anatomic sites for ASPS are the buttocks and thigh (40%), followed by the leg/ popliteal region, chest and trunk, forearm and then arm. The back/neck, retroperitoneum, and other non-soft tissue sites such as orbit, urinary bladder, female genital tract, breast, mediastinum, gastrointestinal tract, and bone, are uncommon. Only three percent occur in the tongue.

ASPS tends to present as a slow growing painless mass with a relative lack of symptoms. A number of cases have metastasized to lung or brain, the latter causing headache, nausea, and visual changes, as the first clinical presentation. The tumors are richly vascular and may cause bruit or hemorrhage, the latter especially during surgical removal. Similarly, our case shows blood tinged saliva and mass causing problems with swallowing, but no pain.

Grossly, ASPS tends to be multilobular, sometimes poorly circumscribed, soft and friable, surrounded by tortuous large caliber vessels. The current case is multinodular, hemorrhagic, and small compared with the usually larger buttocks tumors.

Microscopically, ASPS typically is in a lobular growth pattern, separated by thick fibrous septa. The tumors of the head and neck, particularly orbit and tongue, particularly in infants and young children, may be "solid type" or "compact type" with sheets of polygonal cells, only separated into one or sometimes two to four cell clusters by delicate connective tissue containing sinusoidal thin walled vessels. The tumor cells in the current case did not lose cohesion. In our tongue ASPS study, based on tumors from children of different ages, we believe that as the patient gets older the tumor changes from a more solid sheet-like appearance to groupings of small then larger clusters of cells, which eventually lose cohesion and form an alveolar pattern. This was evident by the very young patients (3 years old) having a very solid primitive appearance of the tumor, compared with the current solid case, and then later adolescent children tumors demonstrating and fully alveolar pattern. The cellular groupings may be centrally necrotic with loss of cell cohesion, forming this "alveolar" pattern.

Cytologically, the cells of both solid and alveolar types are polygonal with smooth to focally concave (cookie bite) large vesicular nuclei with dark, thick nuclear membranes, and prominent nucleoli, sometimes eosinophilic. Nuclear pleomorphism can rarely be observed. The cytoplasm is eosinophilic to sometimes vacuolated; often intracytoplasmic granular to crystalline material can be observed on H&E stain. This often rod-shaped material is PAS positive-diastase resistant. The mitotic activity is surprisingly scant, but there is almost always lymphatic or vascular space invasion present, explaining the propensity for early metastasis. Large caliber vessels may be observed at the edge of the tumor. In the current case, it demonstrated the purely solid variant, with some "spiderlike" cells. No cells were multinucleated, there were only rare mitoses, no pleomorphism, necrosis, or ulceration, and vascular invasion was observed, in tongue vessels outside of the tumor capsule.

In 1959, Masson was the first to describe the ASPS diagnostic cytoplasmic crystalline material. It can be present in rare to up to 100% of tumor cells. In the current case, the material was present in nearly all cells by PAS-D. The granules are probably precursors to the rod shaped crystals. The crystals are found in primary and metastatic ASPS. We now know that the cell surface and cytoplasm in the region of these crystals immunohistochemically stains with MCT1 and CD147 (Ladani et al. 2002). Western blot confirmed the nature of these crystals and ultrastructural immunohistochemistry localized MCT1 and CD147 to the cytoplasmic crystals and their precursor granules. MCT1 is the monocarboylate transporter 1 found in a variety of tissues, including cardiac and skeletal muscle, and tumors, a family which catalyzes the rapid transport of monocarboxylates across plasma membranes from the rough endoplasmic reticulum.. CD147 is its chaperone.

Immunohistochemical stains in ASPS show only consistent negativity for vimentin, unlike any other mesenchymal tumor, and consistent cytoplasmic MyoD1 (which is interpreted as negative). Desmin and S100 protein are occasionally positive, but skeletal muscle specific markers, including MyoD1 and myf4 myogenin, are negative. TFE3 is a molecular marker that can be detected by immunohistochemistry.

Molecular and cytogenetic findings are also recently identified in ASPS, aiding in its current diagnosis. By cytogenetics, ASPS has a specific alteration of der 17 t(X;17) (p11;q25). This non-reciprocal translocation leads to rearrangement and fusion of ASPL (alveolar soft part sarcoma locus), also called ASPSCR1 (alveolar soft part sarcoma chromosome region, candidate 1), and TFE3 (transcription factors for immunoglobulin heavy-chain enhancer 3) genes. Two variants of ASPL-TFE3 gene fusion, involving second and third intron of ASPL, have been reported; however the biological significance of the different fusion types is unknown. Both ASPL-TFE3 gene fusions encode a chimeric protein consisting of the ASPL N-terminal region fused to TFE3 basic helix-loop-helix and leucine zipper DNA-binding domains. Expression of ASPL-TFE3 chimeric protein is believed to cause transcriptional deregulation and has been implicated as a possible tumorogenic mechanism. Detection of t(X;17) translocation or ASPL-TFE3 fusion transcripts, such as nuclear TFE3 by immunohistochemistry are highly specific and sensitive markers for ASPS, however, a similar but reciprocal t(X;17) (p11;q25) translocation and ASPL-TFE3 gene fusion transcripts have been identified in a variant of childhood renal cell carcinoma. Also, TFE3 was found to be involved in several variant translocations associated with renal cell carcinomas with papillary features, in all age groups. This is an example of completely different cell lineage tumors having an identical localized molecular event.

By imaging, ASPS often reveals relatively distinctive characteristics on MR imaging. These lesions have nonspecific intrinsic feature on CT and MR imaging with attenuation similar to muscle, intermediate signal intensity on T1-weighting and high signal intensity on T2-weighting. MR imaging reveals prominent feeding high flow serpentine vascular structures with similar channels within the lesion. Dynamic contrast enhanced CT, arteriography and Doppler sonography may also reveal these vascular structures. Biopsy through the vascular components should be voided to limit bleeding.

The differential diagnosis for solid alveolar soft part sarcoma of the tongue includes rhabdomyoma, granular cell tumor, and less likely clear cell sarcoma, renal cell carcinoma, hibernoma or other fatty tumor, or paraganglioma, which are all more likely in the differential diagnosis when the tumor has an alveolar pattern. Adult rhabdomyoma can be separated by its large eosinophilic cells with small nuclei and the "spider" like cytoplasmic features as the cytoplasm pulls away from the cell membrane, albeit focally depicted in the current case. However, desmin would be diffuse and strong in rhabdomyoma, as would the skeletal muscle nuclear markers: MyoD1 and myf4 (skeletal muscle specific myogenin). ASPS was considered to be a myoid tumor; a consideration which is no longer substantiated. MyoD1 can stain cytoplasm (interpreted as negative) in many non-skeletal muscle tumors. While ASPS also has eosinophilic cytoplasm, granular cell tumor has more granularity than ASPS and contains cytoplasmic circular inclusions with halos, lysosomal material, that are absent in ASPS. Furthermore, the nuclei in benign granular cell tumor are uniform and without diffuse pleomorphism or prominent nucleoli, unlike the prominent nucleoli in ASPS. Lastly, S100 protein is diffusely positive in granular cell tumor, a tumor of nerve sheath phenotype, and is negative in alveolar soft part sarcoma. Clear cell sarcoma is positive for HMB45 protein, stronger than its S100 protein reactivity, which are both absent in ASPS. Renal cell carcinomas are often CD10, EMA, and RCC positive, all negative in ASPS. Finally sometimes ASPS can have clear cytoplasm and mimic lipomatous neoplasms; yet these are often S100 protein positive and specific morphologic differences can separate these from ASPS. Hibernoma, S100 protein positive, has brown fat that may have pale to eosinophilic cytoplasm and sometimes prominent nucleoli; vascular invasion and individual cell or cell grouping by vessels is not identified. True lipoblasts and myxoid change common in early lipoblastoma, are not present in ASPS; the most common type of liposarcoma in children, myxoid liposarcoma, is myxoid and has monovacuolated and bivacuolated lipoblasts, also absent in ASPS. Paraganglioma, often in a clustered Zellballen pattern separated by vessels, is positive for neuroendocrine markers, chromogranin and synaptophysin, and S100 protein for the sustentacular cells, which are all generally negative in ASPS.

Surgery is the mainstay for treatment. The benefit of adjuvant therapy in ASPS is controversial but radiotherapy and/or chemotherapy are generally administered and radiotherapy is particularly used in cases of inadequate surgery. Complete local excision, adjuvant therapy per clinical recommendation, and patient follow-up are advised for all ASPS. ASPS are not assigned a grade (prognosis is on non-histologic features such as location, size, and age of patient); they are staged in adults by the International Union against Cancer (UICC) and the American Joint Committee on Cancer (AJCC) as a TNM system, which incorporates tumor size and depth, regional and distant metastasis. Pappo et al. also used the Intergroup Rhabdomyosarcoma Study clinical grouping system as well as the UICC TNM system for their pediatric ASPS study.

Prognostically, ASPS can metastasize early in the course of disease, sometimes prior to detection of the primary tumor, but can also metastasize decades after the initial diagnosis. ASPS is associated with a deceptively indolent course. Distant metastasis is present in 25% of patients at initial presentation and most commonly involves the lung, bone, and brain. Local recurrence and metastatic involvement can occur over a long period, contrary to other head and neck sarcomas. Local recurrence occurs in 20% of patients. Survival rates for ASPS are 65% at 5 years (20% if there are already metastases at presentation), 38% at 10 years, and 15% at 20 years, but these are much better for pediatric cases, particularly of the head and neck.

In the tongue, solid ASPS has relative good behavior, unlike the metastatic potential for ASPS in other non-head and neck anatomic sites. The better overall survival rate of children, compared with that of adults, particular in head and neck locations, are thought to be due to detection at a smaller size and better resectability. In a study of 19 pediatric patients with ASPS, the 5-year survival was 80% for the whole series, 91% for patients with localized disease, and 100% for patients with tumor < or = 5 cm. The survival was only 31% for those ASPS> 5 cm; 16 of 19 patients were alive (12 of 12 with grossly-resected tumor in the first continuous remission). The current case was only 2.5 centimeters and the patient had 16 years follow-up without recurrence or metastasis.

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