Head & Neck/Endocrine Pathology Evening Session USCAP Boston, - - PowerPoint PPT Presentation

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

Case 1

Diagnosis?

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

Case 1 Diagnosis

Alveolar Soft Part Sarcoma

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 growth

• 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

DPAS Crystals

ASPS Crystals

• Intracytoplasmic diastase-resistant, PAS-positive rhomboid
• r 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)

• No crystals
• S100 protein positive (100%)
• SOX10 positive (100%)
• Inhibin positive (100%)
• Calretinin positive (100%)
• Nestin positive (100%)
• TFE3 positive (91%)

ASPS (n=13)

• Crystals
• S100 protein negative (100%)
• SOX10 negative (100%)
• Inhibin negative (100%)
• Calretinin positive (46%)
• Nestin negative (100%)
• 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

ASPS Treatment and Prognosis

• Prognosis:

– Tumor size:

• larger tumors often associated with distant

metastasis – Presence of metastasis:

• portends poor prognosis but resection of

solitary metastasis may be of prognostic benefit – Location of tumor:

• lingual ASAP reported to have a substantially

better prognosis than ASPS of other sites

Case 1 Summary

• Pediatric lingual tumor
• Lingual thyroid, granular cell tumor,

myogenic tumors

• Alveolar soft part sarcoma:

– Tendency to be solid/diffuse without characteristic alveolar growth pattern – Suspicion by H&E requires histochemical, IHC and molecular analysis

Case 1 Summary

• Tendency to be invasive with vascular

invasion  frequently metastatic

• Complete surgical resection
• Prognosis considered poor:

– Younger age – Tongue and orbit – Smaller tumor – Absence of metastatic disease

CD31

VIM