Head & Neck/Endocrine Pathology Evening Session USCAP Boston, MA March 23, 2015 Bruce M. Wenig, MD Department of Pathology Mount Sinai Health System New York, NY
Nothing to Disclose
Case 1 Clinical History 9 year old healthy female presented with one month history of a tongue mass. Her mother noted the mass after her daughter bit her tongue and there was a lot of bleeding. Over the course of a month the mass continued to grow and rapidly enlarge. No significant contributing history. Case contributed by Ray Franklin, MD, PhD Orlando Regional Medical Center Orlando, FL
Case 1 Clinical History • Otolaryngology referral: – large, ulcerated mass located on mid- glossal area
Case 1 Clinical History • Imaging: – CT: • contrast enhanced: intensely enhancing mass measuring 3.3cm in greatest axial dimension and 4cm in craniocaudal span
Diagnosis? Case 1
Case 1 Differential Diagnosis • Lingual thyroid • Granular cell tumor • Rhabdomyoma • Rhabdomyosarcoma • Paraganglioma • Something else?
S100
CD68
Inhibin
NSE
SYN
Desmin
Myogenin
MyoD1
VIM
CD31
Ki67
Case 1 Differential Diagnosis • Lingual thyroid • Granular cell tumor • Rhabdomyoma • Rhabdomyosarcoma • Paraganglioma • Something else?
TFE3
TFE3
DPAS
DPAS
Case 1 Findings • Light microscopic findings • Intracytoplasmic DPAS-positive granules • TFE3 positive • Also positive for INI-1, ± NSE, ± MyoD1 • Negative for: – S100 protein, SOX10, inhibin, calretinin – desmin, myogenin, myoglobin, actins – synaptophysin, chromogranin – cytokeratins, EMA, thyroglobulin, HMB45
Case 1 Diagnosis • Consistent with alveolar soft part sarcoma • Recommendation: – Evaluate for ASPL-TFE3 gene fusion translocation • Complete excision and metastatic work-up • Rearrangement involving TFE3 gene region in 77% of nuclei
Alveolar Soft Part Sarcoma Diagnosis Case 1
Alveolar Soft Part Sarcoma (ASPS) Definition • Rare clinically and morphologically distinct, slow-growing but highly malignant soft tissue sarcoma of uncertain histogenesis
ASPS Clinical • Represents < 1% of all sarcomas • F > M prior to age 30; M>F after age 30 • Occurs at any age but most frequent in the 2nd-4th decades of life: – rarely occurs prior to 5 years of age • Sites of occurrence is age dependent: – in adults, most often occurs in the lower extremities, especially the anterior upper thigh, as well as the buttock – in children, most often occurs in the head and neck, in particular the tongue and orbit
ASPS Clinical • Presentation: slow-growing, painless mass: – due to slow growth and lack of pain, these lesions may be clinically overlooked and initial presentation may be that of metastatic disease – early metastasis is a characteristic clinical feature – common metastatic sites include: brain & lungs • As a result of its rich vascularity, some lesions may be associated with: – bleeding (clinically and/or following biopsy) – pulsation with an audible bruit – massive hemorrhage during surgery
ASPS Histology • Characterized by an alveolar, organoid or nestlike growth separated by thin-walled fibrovascular septae lined by a single layer of flattened endothelial cells: – loss of cohesion due to necrosis and/or central degeneration within the cell nests results in pseudoalveolar pattern of growth
Vascular Invasion
ASPS Histology • Characterized by an alveolar, organoid or nestlike growth separated by thin-walled fibrovascular septae lined by a single layer of flattened endothelial cells: – loss of cohesion due to necrosis and/or central degeneration within the cell nests results in pseudoalveolar pattern of growt h • In younger ages (i.e., infants and children) there is a greater tendency to more solid/diffuse pattern of growth in which the nestlike pattern is inconspicuous or absent
Crystals DPAS
ASPS Crystals • Intracytoplasmic diastase-resistant, PAS-positive rhomboid or rod-shaped crystalline material considered to be a diagnostic feature for this tumor: – seen in approximately 80% of tumors – can be identified in both primary and metastatic lesions – variably identified from case to case: • in some tumors crystals are abundantly present and readily identified while in other tumors may be rare to absent – intracytoplasmic diastase-resistant, PAS-positive granules are present believed to represent precursors of the crystals
ASPS Crystals • Nature of crystals not been entirely determined but expression of a monoclonal antibody to monocarboxylate transporter 1 (MCT1) identified in cytoplasm of cells: – MCT1 belongs to family of transporter proteins that catalyzes rapid transport of monocarboxylates across plasma membranes – protein normally associated with rough endoplasmic reticulum and is transported to plasma membrane in association with its chaperone CD147 – MCT1 and CD147 identified in surface of cells of ASPS as well as in cytoplasm in region of crystals
ASPS IHC Neoplastic cells: • – variable reactivity for vimentin and myogenic markers, including desmin, muscle specific actin and MyoD1: • initially expression of MyoD1, a regulatory gene in the control of myogenic differentiation, strongly supported skeletal muscle differentiation for ASPS, but the inability to consistently duplicate this finding, as well as the absence of convincing evidence of skeletal muscle differentiation raises doubts relative to skeletal muscle differentiation
ASPS IHC Neoplastic cells: • – TFE3 immunoreactivity (nuclear staining) present in most but not all cases: • can be identified in other neoplasms including paraganglioma, granular cell tumor, adrenal cortical carcinoma, renal Xp11 translocation carcinoma – S100 protein and neuron specific enolase may be identified in approximately 25% of cases but considered nonspecific reactivity – negative for cytokeratins, epithelial membrane antigen, neurofilament protein, GFAP, chromogranin, synaptophysin, HMB45, CD68 and SOX10
ASPS Cytogenetics & Molecular Genetics Specific translocation der(17)t(x;17)(p11;q25) • Unbalanced translocation results in fusion of the TFE3 transcription • factor gene on Xp11.2 (a member of the basic-helix-loop-helix family of transcription factors) to ASPSCR1 gene (referred to as ASPL) at 17q25; ASPL/TFE3 fusion gene: • – encodes for a fusion gene that localizes to nucleus – functions as aberrant transcription factor – among soft tissue sarcomas considered highly specific and sensitive for ASPS – also found in association with subset of pediatric renal cell carcinoma characterized by: • pseudopapillary architecture, epithelioid cells with abundant clear cytoplasm and well defined borders, and psammomatous calcifications • these tumors have been termed Xp11 Translocation Carcinoma
ASPS Differential Diagnosis • Lingual thyroid • Granular cell tumor
S100 protein
GCT v ASPS GCT (n=11) ASPS (n=13) • No crystals • Crystals • S100 protein positive (100%) • S100 protein negative (100%) • SOX10 positive (100%) • SOX10 negative (100%) • Inhibin positive (100%) • Inhibin negative (100%) • Calretinin positive (100%) • Calretinin positive (46%) • Nestin positive (100%) • Nestin negative (100%) • TFE3 positive (91%) • TFE3 positive (100%) Chamberlain et al. Hum Pathol 2014;45:1039-44
ASPS Differential Diagnosis • Lingual thyroid • Granular cell tumor • Rhabdomyoma • Rhabdomyosarcoma • Paraganglioma • Metastatic renal cell carcinoma • Crystal storing histiocytosis • Metastatic ASPS from soft tissue site (e.g., thigh) to the oral cavity: – rare but reported occurrence
ASPS Treatment and Prognosis • Complete surgical resection is the treatment of choice: – surgery includes radical excision of both the primary and any metastatic foci • Adjunctive radiation and/or chemotherapy have been advocated predicated on several factors: – resectability of the tumor – presence of metastatic disease • Local recurrence is uncommon • Metastatic disease is a frequent occurrence: – can be seen early in the disease course – may be the initial presentation – frequently occurs to brain, lungs and bone – nodal metastasis is uncommon
ASPS Treatment and Prognosis • Prognosis is poor: – 60% 5-year survival – 38% 10-year survival – 15% 20-year survival • Prognosis may correlate to: – age at diagnosis: • improved prognosis associated with younger age: – less tendency to metastasize – tend to be smaller tumors – more amenable to complete resection – localization to the tongue and orbit may allow for earlier diagnosis and smaller tumor size
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