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Alveolar Soft Part Sarcoma.

Alveolar soft part sarcoma (ASPS) is a rare neoplasm. It represents 0.2% to 0.9% of all soft tissue sarcomas (1) and tends to occur between ages 15 to 35 years and is rare in patients younger than 5 years and older than 50 years. (2) It is more common in females than it is in males with a 2:1 ratio. This ratio is seen more in the first 3 decades of life but shows a slightly male predominance thereafter. (3,4) In adults, ASPS tends to involve the deep soft tissues in the thigh or buttock. In children and infants, ASPS has a predilection for the head and neck region, with the tongue and orbit being the most common sites. (2) Other organs reported include the urinary bladder, (5) breast, (6) larynx, (7) and the uterine cervix. (8) Bone involvement, although rare, can occur. The most commonly involved sites are the fibula, tibia, and ileum. A recent case report also mentioned the involvement of less-common sites, such as the clavicle and meninges. The meningeal involvement was thought to be either primary or metastasis disease. (9) Typically, patients note a painless, slowly growing mass. An unusual clinical presentation with rapidly growing ASPS of the cheek has been recently reported. (10) Some patients present primarily with metastatic disease, especially of the brain or lungs. Metastasis can also occur long after resection of the primary tumor, even if there is no local recurrence. (11) On imaging, because of the very vascular nature of this tumor, it is contrast enhancing. (12) In addition, ASPS tends to have high signal intensity on T1- to T2-weighted images on magnetic resonance imaging. (13)

PATHOLOGY

Gross Morphology

Alveolar soft part sarcoma is usually a poorly circumscribed mass with a soft and rubbery consistency that has a tan-pale to yellow cut surface, which may be accompanied by areas of hemorrhage or necrosis, especially in large tumors.

Microscopic Features

Alveolar soft part sarcoma has a distinctive and characteristic, nested or organoid growth pattern. The nests tend to be uniform in size and shape, although some variation may be present. The nests are separated by delicate sinusoidal vascular channels lined by a flattened, single layer of endothelial cells. The cells may appear discohesive with focal necrosis in the center of the nests giving rise to the so-called, commonly seen, pseudoalveolar pattern. In infants and children, the tumor may show a solid, diffuse growth pattern with no nested architecture or intervening vascular channels. (14) This should be remembered when ASPS is suspected in this age population. Nevertheless, the histologic features of ASPS have no prognostic significance, (2) and the better prognosis reported for tumors with this solid growth is due to their occurrence in the pediatric patient population and their propensity to involve the head and neck region. (15,16)

The neoplastic cells are uniform in size, polygonal to round, with well-defined cellular borders. The cytoplasm is abundant, eosinophilic, and glycogen-rich and can have a clear to vacuolated appearance. The nuclei are uniform, round, centrally located, and contain 1 or 2 prominent nucleoli (Figure 1). Pleomorphic features have been reported, (15) and mitotic figures are rare. (14) Vascular invasion is frequently seen.

A characteristic feature of ASPS is the presence of intracytoplasmic, periodic acid-Schiff, diastase-resistant rhomboid- or rod-shaped crystals (Figure 2). They are present in both primary and metastatic disease, are found in approximately 80% of cases, and vary in number from absent to very few in some cases to numerous in others. (14) In addition, the periodic acid-Schiff, diastase-resistant gran ules digestion are also present in almost all cases and are thought to contain monocarboxylate transporter 1 and CD147. (17)

Immunohistochemistry

Alveolar soft part sarcoma is consistently positive for an antibody that detects the carboxyl terminal portion of the transcription factor E3 (TFE3) gene retained in the fusion protein. (2) The pattern of expression is strong nuclear staining (Figure 3). (18) Cathepsin K is a protease whose expression is driven by microphthalmia transcription factor (MITF) in osteoclasts. (19) Cathepsin K is consistently and diffusely positive in ASPS (Figure 4). (19) Although these 2 immunohistochemical stains are highly sensitive, they are not entirely specific because other tumors also show positivity (described below). Often, ASPS is positive for desmin and muscle-specific actin. (16) S100 is rarely positive. Myogenin and Myo D1 were initially thought to be promising markers; however, subsequent studies have not identified convincing expression of either. (20,21) The positive Myo D1 cytoplasmic staining pattern that can be seen in ASPS is mostly related to cross-reactivity with undetermined cytoplasmic antigen. (21) Alveolar soft part sarcoma is consistently negative for keratin, epithelial membrane antigen (EMA), paired box 8 (PAX8), human melanoma black (HMB-45), synaptophysin, chromogranin, and hepatocyte paraffin 1 (HepPar1).

Cytogenetics

Alveolar soft part sarcoma is characterized by a specific chromosomal alteration, der(17)t(X:17)(p11:q25), resulting in the fusion of the TFE3 transcription factor gene (from Xp11) with alveolar soft part sarcoma critical region 1 (ASPSCR1), also known as alveolar soft part sarcoma locus (ASPL) at 17q25. The detection of the fusion transcript (ASPSCR1-TFE3) by real-time polymerase chain reaction and fluorescence in situ hybridization for TFE3 rearrangement are considered high-yield methods for diagnosis. The same gene fusion is also seen in a subset of translocation-associated renal cell carcinomas (RCCs). However, in ASPS, the translocation is unbalanced, whereas it is balanced in translocation associated RCC. The ASPSCR1-TFE3 fusion protein acts as an aberrant transcription factor resulting in activation of the MET signaling pathway believed to promote angiogenesis and cell proliferation. (2) In a study performed by Tsuji et al, (22) they showed the sensitivity and specificity of TFE3 immunohistochemistry for ASPS to be 92% and 92%, respectively. The same group showed the sensitivity and specificity of ASPSCR1-TFE3 fusion transcript detected by real-time polymerase chain reaction obtained from formalin-fixed, paraffin-embedded tissue for ASPS to be 100% for both. They concluded that detection of ASPSCR1-TFE3 fusion transcript has superior sensitivity as compared with TFE3 immunohistochemical stain. This is especially helpful in cases where ASPS presents with an unusual histology or location.

Differential Diagnosis

The differential diagnosis includes other primary soft tissue neoplasms, such as rhabdomyoma, hibernoma, clear cell sarcoma of soft tissue, perivascular epithelioid cell neoplasm (PEComa), paraganglioma, and granular cell tumor. Metastatic tumors with similar cytologic features can mimic ASPS, such as clear cell RCC, hepatocellular carcinoma, adrenocortical carcinoma, and melanoma.

Rhabdomyoma is a benign, skeletal muscle tumor that has large polygonal cells with vacuolated cytoplasm and no nuclear atypia. Although cytoplasmic granules and rodlike inclusions can be seen, which may mimic the granules and crystals seen in ASPS, the tumor cells are positive for muscle markers desmin and myogenin. Hibernomas have large cells with eosinophilic cytoplasm and central nuclei with no prominent nucleoli. No nested growth pattern is seen, and S100 can be positive.

Clear cell sarcoma is composed of epithelioid cells with clear to eosinophilic cytoplasm usually grouped into nests separated by collagenous strands. Alveolar architecture can also be seen. Melanoma markers, such as S100, HMB-45, and melanoma-associated antigen recognized by T cells (Mart-1), are consistently positive. Unlike melanoma, clear cell sarcoma has a reciprocal translocation t(12:22) resulting in the fusion of EWS RNA-binding protein 1 (EWSR1) with activating transcription factor 1 (ATFT) in more than 90% of cases. In a study performed by Zheng et al, (23) cathepsin K showed positivity in 3 of 12 cases (25%) of clear cell sarcoma (one showed focal positivity). They suggested that a diffuse staining pattern favors ASPS.

A PEComa can look similar to ASPS because it may contain cytoplasmic eosinophilic granules positive for periodic acid-Schiff and show TFE3 positivity. However, a PEComa is positive for MART-1 and HMB-45, whereas ASPS is negative. (16) A recently reported (24) PEComa of the urinary bladder showed positive TFE3 by immunohistochemical stain, showed TFE3 rearrangement by fluorescence in situ hybridization, had a malignant behavior, and caused the death of the patient. Paraganglioma and granular cell tumor also enter the differential diagnosis. The first is positive for neuroendocrine markers synaptophysin and chromogranin and shows positivity for S100 in the sustentacular cells. In addition, primary paragangliomas are almost never seen in the limbs. (16) Granular cell tumors, unlike ASPS, lack the fine intercellular vascularity and are positive for S100, SOX10, inhibin, and nestin. This panel showed 100% sensitivity and specificity to distinguish granular cell tumor from ASPS in a study performed by Chamberlain et al. (25) One pitfall to consider is that a subset of granular cell tumors is positive for TFE3. (18) Interestingly, 10 out of 11 (91%) of the granular cell tumors showed TFE3 positivity in the same study. (25) Unlike ASPS, both paraganglioma and granular cell tumor lack cytoplasmic glycogen. (14)

Although EMA, PAX8, and RCC are positive in clear cell RCC, they are negative in ASPS. Hepatocellular carcinoma is positive for Hep-Par1, glypican-3, and polyclonal carcinoembryonic antigen (P-CEA). Renal cell carcinoma and adrenocortical carcinoma are usually readily diagnosed clinically and radiographically. Also, adrenocortical carcinoma is positive for Mart-1, inhibin, and synaptophysin, whereas ASPS is negative.

As mentioned, immunolabeling for cathepsin K can be helpful in the differential diagnosis of ASPS because it is negative in conventional RCC, ASPSCR1-TFE3 translocation RCC, adrenocortical carcinoma, and paraganglioma. (19) However, its role in differentiating ASPS from other potential mimickers is relatively limited because it is positive in melanoma, granular cell tumor, and other tumors (19) (Table). Therefore, the best practical application for cathepsin K in this setting is when the clinical, radiologic, histomorphologic, and immunohistochemical data are competing between ASPS and ASPCR1-TFE3 translocation RCC, where both will be positive for TFE3 immunohistochemical stain, whereas cathepsin K will show positivity in the former but not in the latter.

However, whether the differential expression of either marker (ie, TFE3 and cathepsin K) in ASPS is diagnostically significant is not known, and to our knowledge, has not been reported.

Treatment and Prognosis

Alveolar soft part sarcoma has a high incidence of metastatic disease, which may precede the detection of the primary tumor. (11,26) Local recurrence occurs in 20% to 30% of cases. (16) Prognosis is largely dependent on the initial presentation (localized versus metastatic disease), tumor size, and age. (4,11,15,27) Patients with localized disease at presentation have a 71% 5-year survival rate, compared with 20% for patients with metastatic disease at time of diagnosis. (4) Patients who present with large tumors are most likely to have metastasis at the time of diagnosis. (11,15) Of note, children have an excellent 5-year survival rate of up to 100%, especially if the tumor arises in the head and neck. (15) More recent data (28) report a 5-year survival rate for children to be 83%. The better prognosis among children is not well understood. Differences in biologic characteristics of pediatric and adult ASPS have been proposed as a possible explanation. (15) In a case-series study reported by Ogura et al, (29) pediatric tumors tended to be smaller than those in adult patients, with the larger tumor size resulting in increased risk of distant metastasis. Radical resection is the treatment of choice for localized disease. Metastatic ASPS is usually resistant to conventional chemotherapy and radio-therapy. The recent identification of the role of ASPSCR1-TFE3 in the MET signaling pathway promoting tumor cell proliferation and angiogenesis is considered the cornerstone for targeted molecular therapy in ASPS, namely antiangiogenic drugs and MET kinase inhibitors, with ongoing clinical trials showing promising initial results. (30,31) More specifically, the ASPSCR1-TFE3 fusion protein induces strong overexpression of MET receptor tyrosine kinase, leading to strong autophosphorylation and activation of the downstream kinase cascade. Therefore, inhibiting expression of MET will lead to decreased cell growth. Because the detection of TFE3 by immunohistochemical stain is not entirely specific, the detection of the fusion transcript gene (for example, by real-time polymerase chain reaction) may represent an additional tool to support the diagnosis and confirm the presence of the translocation. Monoclonal antibodies against cathepsin K have been studied in women with metastatic breast cancer to the bones, and because cathepsin K is expressed in ASPS, it may represent a potential therapeutic target. (32,33)

We thank Andrew M. Bellizzi, MD, and Jason L. Hornick, MD, for graciously providing the TFE3 and cathepsin K immunohistochemical stained slides.

Please Note: Illustration(s) are not available due to copyright restrictions.

References

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(8.) Kang WD, Heo SH, Choi YD, Choi HS, Kim SM. Alveolar soft part sarcoma of the uterine cervix in a woman presenting with postmenopausal bleeding: a case report and literature review. Eur J Gynaecol Oncol. 2011; 32(3):359-361.

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(12.) Lorigan JG, O'Keffe FN, Evanz HL, Wallace S. The radiologic manifestations of alveolar soft-part sarcoma. AJR Am J Roentgenol. 1989; 153(2):335-339.

(13.) Suh JS, Cho J, Lee SH, et al. Alveolar soft part sarcoma: MR and angiographic findings. Skeletal Radiol. 2000; 29(12):680-689.

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(15.) Casanova M, Ferrari A, Bisogno G, et al. Alveolar soft part sarcoma in children and adolescents: a report from the Soft-Tissue Sarcoma Italian Cooperative Group. Ann Oncol. 2000; 11(11):1445-1449.

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(17.) Landanyi M, Antonescu CR, Drobnajak M, et al. The precrystalline cytoplasmic granules of alveolar soft part sarcoma contain monocarboxylate transporter 1 and CD147. Am J Pathol. 2002; 160(4):1215-1221.

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(22.) Tsuji K, Ishikawa Y, Imamura T. Technique for differentiating alveolar soft part sarcoma from other tumors in paraffin-embedded tissue: comparison of immunohistochemistry for TFE3 and CD147 and of reverse transcription polymerase chain reaction for ASPSCR1-TFE3 fusion transcript. Hum Pathol. 2012; 43(3):356-363.

(23.) Zheng G, Martignoni G, Antonescu C, et al. A broad survey of cathepsin K immunoreactivity in human neoplasms. Am J Clin Pathol. 2013; 139(2):151-159.

(24.) Williamson SR, Bunde PJ, Montironi R, et al. Malignant perivascular epithelioid cell neoplasm (PEComa) of the urinary bladder with TFE3 gene rearrangement: clinicopathologic, immunohistochemical, and molecular features. Am I Surg Pathol. 2013; 37(10):1619-1626.

(25.) Chamberlain BK, McClain CM, Gonzalez RS, Coffin CM, Cates JM. Alveolar soft part sarcoma and granular cell tumor: an immunohistochemical comparison study. Hum Pathol. 2014; 45(5):1039-1044.

(26.) Fanburg-Smith JC, Miettinen M, Folpe AL, Weiss SW, Childers EL. Lingual alveolar soft part sarcoma; 14 cases: novel clinical and morphological observations. Histopathology. 2004; 45(5):526-537.

(27.) Ogose A, Yazawa Y, Ueda T, et al; Japenese Musculoskeletal Oncology Group. Alveolar soft part sarcoma in Japan: multi-institutional study of 57 patients from the Japanese Musculoskeletal Oncology Group. Oncology. 2003; 65(1):7-13.

(28.) Kayton ML, Meyers P, Wexler LH, Gerald WL, LaQuaglia MP. Clinical presentation, treatment, and outcome of alveolar soft part sarcoma in children, adolescents, and young adults. J Pediatr Surg. 2006; 41(1):187-193.

(29.) Ogura K, Beppu Y, Chuman H, et al. Alveolar soft part sarcoma: a single-center 26-patient case series and review of the literature. Sarcoma. 2012; 2012: 907179. doi:10.1155/2012/907179.

(30.) Tsuda M, Davis IJ, Argani P, et al. TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Res. 2007; 67(3):919-929.

(31.) Lazar AJ, Lahat G, Myers SE, et al. Validation of potential therapeutic targets in alveolar soft part sarcoma: an immunohistochemical study utilizing tissue microarray. Histopathology. 2009; 55(6):750-755.

(32.) Jensen AB, Wynne C, Ramirez G, et al. The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial. Clin Breast Cancer. 2010; 10(6):452-458.

(33.) Mitton B, Federman N. Alveolar soft part sarcomas: molecular pathogenesis and implications for novel targeted therapies. Sarcoma. 2012; 2012:428789. doi:10.1155/2012/428789.

Omar I. Jaber, MD; Patricia A. Kirby, MD

Accepted for publication September 5, 2014.

From the Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Omar I. Jaber, MD, Department of Pathology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242 (e-mail: Omar-jaber@uiowa.edu).

Caption: Figure 1. Alveolar soft part sarcoma. Nests of tumor cells with abundant eosinophilic cytoplasm and central nuclei with prominent nucleoli (hematoxylin-eosin, original magnification X200).

Caption: Figure 2. Alveolar soft part sarcoma. Periodic acid-Schiff, diastase-resistant intracytoplasmic crystals (original magnification X600).

Caption: Figure 3. Transcription factor E3 (TFE3) staining in alveolar soft part sarcoma. Note the strong nuclear staining pattern (original magnification X200).

Caption: Figure 4. Cathepsin K staining in alveolar soft part sarcoma. Note the cytoplasmic staining (original magnification X200).
Differential Expression of Transcription Factor E3
(TFE3) and Cathepsin K Among Alveolar Soft Part
Sarcoma (ASPS) and Potential Mimickers

Differential Diagnosis         TFE3             Cathepsin K

ASPS                     Positive            Positive
ASPSCR1-TFE3
translocation RCC        Positive            Negative
PEComa                   Positive            Positive
Granular cell tumor      Positive/negative   Positive
Clear cell sarcoma       Negative            Positive/negative
Melanoma                 Negative            Positive

Abbreviations: ASPSCR1-TFE3, alveolar soft part sarcoma critical
region 1-transcription factor E3; PEComa, perivascular epithelioid
cell neoplasm; RCC, renal cell carcinoma.
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Title Annotation:Resident Short Review
Author:Jaber, Omar I.; Kirby, Patricia A.
Publication:Archives of Pathology & Laboratory Medicine
Date:Nov 1, 2015
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