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Alveolar soft part sarcoma (ASPS) is a rare neoplasm of uncertain cell of origin. Known to occur in adolescents and young adults, this tumor usually involves the muscles and deep soft tissues of the extremities and trunk. Orbital localization is rare and not yet subjected to cytological assessment, as per our literature search. We present here two cases of ASPS diagnosed by aspiration cytology, one in the orbit and the other in the lower extremity. The cells displayed abundant clear to finely vacuolated cytoplasm, often with disrupted margins and flowing of the cytoplasmic material; prominent nucleoli and scattered bare nuclei were also seen in the background. Two close cytological differential diagnoses include metastatic renal cell carcinoma and paraganglioma. Intracytoplasmic periodic acid schiff (PAS) positive, diastase-resistant, needle-shaped crystals and corresponding rhomboid crystals with regular lattice pattern on ultrastructure are the hallmarks of this neoplasm. Due to its slowly progressive clinical course and poor outcome, preoperative diagnosis of ASPS through fine-needle aspiration cytology may be essential for deciding therapy, especially in rare and difficult locations like orbit, where adjuvant radiation may not be possible.
Alveolar soft part sarcoma (ASPS) is a relatively rare neoplasm, comprising approximately 1% of all soft tissue sarcomas. A distinct feature of this tumor is its occurrence in adolescents and young adults.[2,3] In adults, it commonly involves the muscles and deep soft tissue of the extremities, trunk, head and neck, while in children and adolescents, head and neck region is a more frequent site.
ASPS usually presents as a soft, painless, slow-growing mass lesion, with poor prognosis. Thus, the tumor can grow up to a large size without causing specific symptoms. Prognosis worsens with recurrence and metastasis, which commonly involves lung, bone, central nervous system and liver.[2,3]
The normal cellular counterpart of this soft tissue tumor is not yet well understood. Besides the characteristic pattern on histology, the cytomorphology has been described in few case series and isolated reports.[4–8] Cytological evaluation and confirmation of lesions in rare anatomical locations like orbit may be at times challenging, but necessary for its potentially aggressive nature and early implementation of available treatment options.
A 25-year-old male presented with mild pain in the right eye on and off since 1 year, along with progressive proptosis and periorbital swelling for last 4 months. He complained of diminution of vision and diplopia since 3 months, which initially progressed but became static at the time of presentation. There was no history of any trauma, loss of consciousness or fever. Examination of extraocular muscles showed restricted upward gaze. Computed tomography (CT) scan showed a mildly enhancing right orbital mass abutting superior rectus muscle with displacement of eyeball anteriorly, inferiorly and laterally. Magnetic resonance imaging (MRI) revealed a lobulated right supraorbital extradural mass lesion, predominantly occupying superomedial extraconal compartment and infiltrating intraconally. The mass was isointense to grey matter and showed heterogeneous contrast enhancement. No intracranial extension was noted. Aspiration cytology smears revealed scattered and groups of monotonous population of cells with round to oval nuclei, prominent large nucleoli, few with intranuclear inclusions and abundant pale finely vacuolated to granular cytoplasm. Few cells also showed disrupted cytoplasm, with fraying of the cytoplasmic margins [Figure 1a]. Few larger fragments had cohesive cells in clusters, while other areas showed central round nuclei in a sea of cytoplasm. Bare nuclear forms were also noted. Periodic acid Schiff (PAS) with diastase stain revealed magenta pink intracytoplasmic granules and occasional slender crystalline structures [Figure 1b]. The tumor, located between orbital roof and globe, was excised through right supraorbital keyhole craniotomy. The excised mass was soft to firm, highly vascular, non-suckable, with ill-defined plane of cleavage. Histopathology showed characteristic alveolar pattern and cellular morphology of ASPS [Figure 1c]; however, the immunohistochemical panel applied was not contributory. Electron microscopy showed increased number and abnormal clustering of mitochondria, prominent endoplasmic reticulum, glycogen vacuoles, along with few electron-dense bodies [Figure 2]. However, the characteristic rhomboid crystalline lattice was not seen. On extensive workup and thorough imaging, no mass lesion was detected at any other site. Radiation was difficult in this patient with orbital lesion due to the fear of visual compromise; hence, he was offered chemotherapy, with no further growth of the lesion or metastatic disease on 6 months of follow-up.
A 43-year-old male presented with a slowly growing mass in the right thigh for 7 years, which rapidly increased in size during the last few months. There was no history of fever or trauma. A well-defined firm, nontender swelling measuring 10 × 8 cm was appreciated, situated deep to quadriceps, with smooth surface and prominent vessels on the overlying skin. No inguinal lymph nodes were palpable. On MRI, a well-demarcated heterointense lesion was seen in the anterior compartment of the thigh with no bony involvement. Angiography showed hypervascular tumor with feeder vessels from the femoral artery. Fine-needle aspiration cytology (FNAC) from the swelling yielded hemorrhagic cellular smears displaying numerous dissociated cells, stripped naked nuclei, binucleated cells and few cohesive clusters consisting of polyhedral cells entrapped in thin fibrous septae forming small abortive alveolar clusters. These cells had abundant clear cytoplasm, central to eccentrically placed nuclei and prominent central nucleoli. A diagnosis of ASPS was considered, with differential diagnoses of metastatic renal (clear) cell carcinoma (RCC), clear cell sarcoma of tendon sheath and granular cell tumor (GCT). Wide excision and ligation of feeder vessels were carried out. On histopathology, the tumor cells were separated by fibrous tissue into well-defined nests and some of the central cells were detached to form the typical alveolar pattern of ASPS. PAS stain showed diastase-resistant intracytoplasmic needle-like structures [Figure 1d]. The patient died of lung metastasis after 9 months of surgical excision.
ASPS has not been very commonly subjected to cytological evaluation, and cytomorphology of the tumor has been documented through small series and isolated reports. Hence, lesions in rare sites like orbit can still pose a diagnostic challenge. Cytological differential diagnoses for clear, vacuolated to granular cells include metastatic renal (clear) cell carcinoma (RCC), epithelioid sarcoma, clear cell sarcoma, melanoma, paraganglioma, and GCT.[2,4,7,9,10] RCC usually presents at an older age group than ASPS, with hematuria, flank pain and abdominal mass; clear or finely vacuolated cytoplasm is observed more commonly in RCC. Paraganglioma tends to have more striking anisonucleosis without prominent large nucleoli, as seen in ASPS. Epithelioid sarcoma has more nuclear pleomorphism, and clear cell sarcoma has smaller nuclei without marked nucleolomegaly, as compared to ASPS. Melanoma has better preserved cytoplasm, usually with pigmentation and absence of granular background.[2,4,7,9] A vague acinar pattern, abundant finely granular to vacuolated cytoplasm with fuzzy border and metachromatic background, predominantly central nuclei, and some dispersed bare nuclei with prominent acidophilic macronucleoli favor a cytological diagnosis of ASPS.
ASPS lacks a normal cellular counterpart; hence, attempts at determining the cell of origin did not yield conclusive results, and no immunohistochemical panel is consistently reliable in this direction. Non-specific markers like neuron-specific enolase and vimentin were found to be expressed in 30-50% of ASPS. Similarly, smooth and skeletal muscle actin and desmin have also been reported to be positive in nearly 50% of cases. More specific muscle markers like MyoD1 or myogenin also did not show consistent positivity in subsequent studies. Antibodies commonly used to exclude other differentials are pan-cytokeratin and epithelial membrane antigen (RCC), S-100 protein (GCT), S-100/HMB-45/melan-A (melanoma and clear cell sarcoma) and neuroendocrine markers (paraganglioma). In the two patients described here, routine immunohistochemistry was not contributory in favoring the diagnosis of ASPS or any of its differentials.
Recently, a specific unbalanced translocation, der (17)t (X: 17)(p11;p25), resulting in the formation of ASPL–TFE3 fusion gene has been demonstrated in ASPS. The resultant ASPL–TFE3-oncoprotein causes activation of aberrant transcription. Hence, expression of this fusion gene through molecular genetics or nuclear staining of TFE3 through immunohistochemistry can specifically diagnose ASPS. However, in our cases, genetic studies or immunohistochemistry for TFE3 was not done as these are not available in our laboratory.
At least 80% of ASPS illustrate the presence of characteristic intracytoplasmic PAS-positive, diastase-resistant needle shaped crystals, while PAS-positive granules are present in almost all cases. Hence, absence of crystals does not rule out ASPS, but their presence on cytology smears is of great diagnostic importance. It has been shown that the precrystalline cytoplasmic granules of ASPS contain monocarboxylate transporter 1 and CD147. On ultrastructure, the tumor cells have numerous mitochondria, prominent smooth endoplasmic reticulum, glycogen, and well-developed Golgi apparatus. The crystals highlighted on PAS stain have a characteristic rhomboid shape with regular lattice pattern.[1,2,4] Both of our cases showed PAS-positive, diastase-resistant intracytoplasmic granules and crystals. Electron microscopy (EM) was possible in the orbital lesion, which did not show the characteristic crystalline lattice. However, clusters of mitochondria, prominent endoplasmic reticulum and electron-dense deposits within vacuolar spaces were noted.
Due to less number of cases, treatment protocol has not been uniformly standardized; it generally involves wide surgical excision with adjuvant radiation. Palliative chemotherapy may be recommended for metastatic disease. The prognosis is usually poor; the more adverse prognostic factors are older age at diagnosis, large size of the tumor and presence of metastasis at presentation.[2,3]
To conclude, orbital ASPS, in spite of a rare site and limited cytology literature, should be considered in the differential diagnosis of preoperative aspirates showing large clear to vacuolated cells with round nuclei and prominent nucleoli. Diagnosis can be confirmed by PAS-positive, diastase-resistant cytoplasmic crystals or demonstration of the corresponding rhomboid crystals by electron microscopy of the aspirated material. Orbital lesions are difficult to treat, as postoperative radiation should be avoided in these patients to prevent loss of vision.
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Conflict of Interest: None declared.