Uterine Mesenchymal Neoplasms: Hereditary Aspects Karuna Garg, MD University of California San Francisco
4/8/2016
ACCME/Disclosure
• Dr. Garg has nothing to disclose Uterine mesenchymal neoplasms: Hereditary aspects Karuna Garg, MD University of California San Francisco
Case 1
• 31 year old female • Menorrhagia and pelvic pain • Multiple fibroids • 2‐11 cm • Underwent myomectomy • Gross: 4 masses, 1.4‐10.5 cm, no hemorrhage or necrosis
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Case 1
• Possibility of fumarate hydratase (FH) mutation (HLRCC) raised in the comment • Patient referred for genetic counselling
Case 1 Case 1
• Mother with history of hysterectomy in her 20s • Family history highly suggestive (but only in for fibroids retrospect after genetic counselling which • Maternal grandmother with history of was initiated by pathology report) hysterectomy in her 30s for fibroids • Exam revealed macules on her legs ?cutaneous leiomyomas (mother also has them) • Fumarate hydratase germline mutation detected • Patient referred for urologic surveillance (renal tumor)
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Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome (HLRCC) • Autosomal dominant Hereditary Leiomyomatosis and • Germline mutation in fumarate hydratase Renal Cell Carcinoma Syndrome gene on chromosome 1q42.3 (HLRCC) • FH acts as a tumor suppressor gene • Second hit in tumor (often LOH) • Predisposes to cutaneous and uterine leiomyomas (Reed syndrome) and renal cell carcinoma (variable pentrance)
HLRCC: Renal cell carcinoma HLRCC
th • 4 decade Uterine Cutaneous Renal cell leiomyomas leiomyomas carcinoma • Typically unilateral single mass Penetrance ~100% ~75% ~15% • High‐stage and poor prognosis Median age 2nd‐3rd decade 2nd‐3rd decade 4th decade at diagnosis • 5 of 9 patients dead of disease (8‐44 months) and 3 of 9 alive with disease
Early detection of HLRCC could prevent Uterine leiomyomas: Opportunity morbidity/mortality from aggressive RCC for early detection of HLRCC?
Chen YB, et al. AJSP 2014
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Potential Mechanisms of the Development of HLRCC: Uterine leiomyomas Leiomyomas.
Problem: Uterine leiomyomas are common while HLRCC is not!
‐ 20‐30% of all women develop uterine Mehine M et al. N Engl J Med 2013;369:43‐53. leiomyomas by age 30 ‐ Up to 80% develop uterine leiomyomas by age 1. Germline FH mutation (HLRCC) 50 years 2. Somatic FH mutation (NOT HLRCC): Frequency ~1‐1.5% of uterine leiomyomas Specific test needed 3. Other mechanisms?
HLRCC: Uterine leiomyomas HLRCC: Early detection
Possible screening criteria: Patient age: • Patient age Multiple highly symptomatic leiomyomas at young age HLRCC associated ULM Sporadic ULM • Personal and family history Median age at presentation 28 years 38 years • Fumarate hydratase gene mutation analysis Age at surgery <30 years 45 years • Immunohistochemistry Personal and family history: • Tumor morphology ‐ Family history of early surgery for fibroids ‐ Personal and/or family history of cutaneous leiomyomas and/or RCC
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FH gene (germline) mutation analysis Immunohistochemistry
• Highly specific and gold standard (germline • 2SC (2 succinocysteine) testing) • FH (fumarate hydratase) • Not practical as a screening test • Expensive (?) • Available in limited laboratories
2SC (succinocysteine) IHC 2SC IHC
‐ Positive staining for 2SC correlates with FH ‐ Genetic ablation of FH leads to high levels of gene mutation protein succination ‐ 2SC positive in FH deficient renal cysts and ‐ 2SC serves as a renal tumors with known FH mutations metabolic biomarker for FH deficiency ‐ Negative in normal tissue (n=200) and non‐ HLRCC tumors (n=1342)
Bardella C, et al. J Pathol 2011
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2SC positive 2SC negative 2SC IHC
FH mutation present 2SC positive Renal cell carcinoma 9/9 Chen YB, et al. AJSP 2014
Uterine leiomyomas 5/5 Joseph NM, et al. AJSP 2015 Cutaneous leiomyomas 11/11 Buelow B, et al. AJSP 2016 epub ahead of print
2SC IHC FH IHC
Pros: • Complete loss of FH staining correlates with ‐ Sensitive and specific fumarate hydratase gene mutation
Cons: ‐ Not commercially available ‐ Cannot distinguish between germline and somatic FH mutation
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Loss of FH staining FH IHC
FH mutation present Complete loss of FH staining Renal cell carcinoma 12/14 (86%) Chen YB, et al. USCAP 2015
Uterine leiomyomas 2/5 (40%) Joseph NM, et al. AJSP 2015
Uterine leiomyomas 10/11 (90%) Harrison WJ, et al. AJSP 2015
Cutaneous leiomyomas 6/11 (55%) Buelow B, et al. AJSP 2016 epub ahead of print
Missense mutations in the FH gene can result in retained FH IHC
Retained FH staining FH IHC
Pros: ‐ Specific ‐ Commercially available
Cons: ‐ Low sensitivity ‐ Cannot distinguish between germline and somatic FH mutation
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HLRCC‐associated renal tumor: Morphology HLRCC: Tumor morphology
• First reported in HLRCC associated renal cell carcinoma • Prominent eosinophilic nucleoli surrounded by perinucleolar halos
Merino MJ, et al. AJSP 2007
HLRCC: Tumor morphology
• Uterine leiomyomas in HLRCC display cytologic features similar to renal tumors (prominent eosinophilic nucleoli surrounded by perinucleolar halos)
Sanz‐Ortega J, et al. Am J Surg Pathol 2013
9 4/8/2016
Hemangiopericytomatous blood vessels HLRCC: Tumor morphology
‐ Eosinophilic inclusions in the cytoplasm ‐ Hemangiopericytomatous blood vessels ‐ Ovoid nuclei ‐ “Alveolar edema” ‐ Cellular ‐ Multinucleation ‐ Symplastic features
Reyes C, et al. Mod Pathol 2013
Alveolar edema Ovoid nuclei
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Cytoplasmic inclusions Nuclear features
Cytoplasmic inclusions, multinucleation, symplastic features HLRCC: Morphology
• Sensitivity and specificity? • Reproducibility?
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HLRCC: Morphology
• 194 unselected patients <40 years age • Myomectomy or hysterectomy • IHC for FH and 2SC • FH gene mutation analysis on selected cases (performed on tumor tissue)
• Morphologic features evaluated: 1. Inclusion like prominent eosinophilic nucleoli with Conclusions: ‐ Poor reproducibility halos ‐ Poor sensitivity and specificity 2. Eosinophilic cytoplasmic inclusions ‐ Recommend 2SC IHC as screening tool Morphologic features lack sufficient robustness to be a reliable triage 3. Hemangiopericytomatous blood vessels feature
Joseph NM, et al. Am J Surg Pathol 2015
HLRCC: Morphology HLRCC: Morphology
• 5 with FH gene aberrations (2.6%) (germline • Constellation of findings most useful rather than or somatic) individual features • 4 displayed morphologic features suspicious for HLRCC • Pitfalls: • 1 did not (only hemangiopericytomatous ‐ Morphologic features not a diffuse finding blood vessels) ‐ Small nucleoli show no correlation with FH • 3 additional cases with morphologic features mutation status suspicious for HLRCC did not show FH gene ‐ Can see “pseudo‐inclusions” adjacent to areas of mutation infarct
Joseph NM, et al. Am J Surg Pathol 2015 Joseph NM, et al. Am J Surg Pathol 2015
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“Pseudo‐inclusions” adjacent to areas of infarct
HLRCC Morphology: summary
‐ 5 known HLRCC patients (25‐41 years) • Constellation of findings helpful (NOT DIFFUSE) ‐ Some morphologic features in 4 cases ‐ Low power: HPC‐like vessels, mild‐moderate atypia ‐ None in 1 case ‐ Medium magnification: Cytoplasmic inclusions, ovoid nuclei, bizarre cells
‐1152 sporadic uterine leiomyomas ‐ High‐magnification: Nuclear features (prominent eosinophilic macronucleoli surrounded by halos) ‐Loss of FH staining by IHC in 12 (1%) (complete sequencing of 10 of these cases revealed somatic FH • Not seen in every case with FH mutation mutations in 6) • Questionable reproducibility and specificity ‐Morphologic features seen in some cases • More studies with expanded morphologic criteria and training
Harrison WJ, et al. Am J Surg Pathol 2015
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HLRCC HLRCC
• Increased risk for uterine leiomyosarcoma or • Increased association with atypical leiomyomas? • 184 uterine smooth muscle tumors, 2SC IHC positive in STUMP? 50% of Atypical LM ‐ Probably not ‐ The majority of 2SC positive cases (77%, 27/33) had FH‐associated histologic features ‐ Cytologic atypia over‐interpreted? Atypical leiomyomas ‐ No loss of FH staining in 116 leiomyosarcomas from 88 patients Type 1 (n=30): Type 2 (n=23): ‐ No 2SC positivity in 29 leiomyosarcomas ‐ FH morphology (ovoid nuclei with ‐ Spindle cells, smudgy chromatin, prominent nucleoli) inconspicuous nucleoli ‐ 2SC positive ‐ MED12 and HMGA2 mutations
Poropatich, et al. USCAP 2016 Harrison WJ, et al. Am J Surg Pathol 2015 (Proffered papers ‐ Monday, March 14, 2016 ‐ 8:00 am, Wednesday, March 16, 2016 ‐ 9:30 am Poster Session V #145) Reyes C, et al. Mod Pathol 2013
Summary: HLRCC
• Uterine leiomyomas can harbor fumarate hydratase gene mutations – germline (HLRCC) and somatic • Uterine leiomyomas are frequently the first clinical presentation for HLRCC Case 2 • Beneficial to recognize HLRCC early • Patient age, presentation, personal and family history could be clues (educate your clinical colleagues) • Morphologic features • Consider IHC for FH/2SC • If abnormal, correlate with clinical history and proceed to genetic counseling and mutation analysis
14 4/8/2016
Uterus Case
• 44 year old female with history of tuberous sclerosis and postmenopausal bleeding • Endometrial biopsy showed endometrioid adenocarcinoma, FIGO grade 1 • Underwent TAH‐BSO and pelvic lymph node dissection
Uterus Uterus
15 4/8/2016
Uterus HMB‐45 D2‐40
Cervical mass Cervical mass
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HMB‐45 Desmin Pelvic lymph nodes
HMB‐45 D2‐40 Case
• Endometrioid adenocarcinoma, FIGO grade 1, invasive into outer myometrium
Consistent with history of tuberous sclerosis: • Myometrium: Lymphangioleiomyomatosis (LAM) • Cervical mass: PEComa • Pelvic lymph nodes: Lymphangioleiomyomatosis (LAM)
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Tuberous Sclerosis
• Autosomal dominant • Mutations in TSC1 (hamartin) or TSC2 Tuberous sclerosis (tuberin) • CNS manifestations • Hamartomas/tumors in multiple organ systems • PEComa family of tumors
PEComas: Response to mTOR inhibitors PEComa family of tumors TSC1/TSC2 “Mesenchymal tumors composed of histologically and mutation immunohistochemically distinctive perivascular epithelioid cells” • Spindle or epithelioid • Association with blood vessels Activation of • Myomelanocytic immunophenotype mTOR pathway • Include CCSCT lung, AML, LAM and PEComa of various sites
• Renal/hepatic AML and pulmonary LAM strongly associated with TSC Response to • Other PEComas less strong association mTOR inhibitors
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Review of extra‐renal PEComas treated with mTOR inhibitors Gynecologic manifestations of TSC
Spectrum of manifestations: 1. PEComa (including sclerosing PEComa) 2. PEComatosis 3. Lymphangioleiomyomatosis (LAM)
Lim and Oliva, Int J Gynecol Pathol 2011 Dickson M, et al. Int J Cancer 2013 Liang SX, et al. Int J Gynecol Pathol 2008
PEComa: Morphology
• Epithelioid and/or spindled • Nested growth pattern with prominent vascular network • Clear to eosinophilic granular cytoplasm • Pushing/infiltrative/permeative pattern of myometrial invasion • Extensive hyalinization (sclerosing PECOma) • Pigment
Schoolmeester JK, et al. Am J Surg Pathol 2015
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PEComa: Immunohistochemistry
Positivity for smooth muscle and melanocytic markers • HMB‐45 • MITF • Melan‐A • Cathepsin K
• Desmin • SMA • Caldesmon
• Pankeratin rarely positive • PAX‐8 +/‐ (more frequent in epithelioid tumors) • TFE3 +/‐
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HMB‐45 PEComa of the gynecologic tract
• Frequency of TSC ‐ 1/16 (Nucci study) ‐ 1/8 (Vang study) ‐ 0/6 (Folpe study) ‐ Case reports of patients with TSC
Less than 10% of all GYN tract PEComas are TSC‐associated
PEComas of the female genital tract Gyn PEComas
TSC1/TSC2 abnormalities TFE3 translocation Morphology Epithelioid and/or spindled Frequently clear cell epithelioid TSC1/TS2 TFE3 Immunophenotype abnormalities translocation Smooth muscle markers + ‐ Melan‐A+ ‐ HMB‐45 Focal Strong Germline Sporadic mutation TFE3 Negative Positive TSC1/TSC2 and/or LOH of mutation TSC1/TSC2 Potential for response to Yes No mTOR inhibitors
Response to mTOR inhibitors No response to mTOR inhibitors
Schoolmeester JK, et al. Am J Surg Pathol 2015
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TFE3‐translocation associated PEComas
Schoolmeester JK, et al. Am J Surg Pathol 2015
TFE3 HMB‐45 PECOMA: Prognostic classification
Folpe AL, et al. AJSP 2005 Schoolmeester JK, et al. AJSP 2014
Criteria 1. Size≥ 5 cm 1. Size≥ 5 cm 2. Infiltrative borders 2. High‐grade nuclear features 3. High‐grade nuclear features 3. Necrosis 4. Necrosis 4. Vascular invasion 5. Vascular invasion 5. Mitotic count ≥ 1 per 50 high SMA 6. Mitotic count ≥ 1 per 50 high power fields power fields
Benign 00 Uncertain Tumors with 1 of the following 1‐3 malignant 1. Nuclear pleomorphism or potential multinucleated giant cells 2. Size≥ 5 cm Malignant ≥2 ≥4
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PEComatosis Lymphangioleiomyomatosis (LAM)
• Abnormal proliferation of smooth muscle like cells • Most commonly in lung but can involve many other organs including uterus, cervix and adnexa ‐ Frequently associated with TSC (6 cases reported of which 4 associated with TSC) ‐ Scattered small nodules in multiple sites (uterus, cervix, ovary, peritoneum, • TSC associated or sporadic omentum, small bowel)
Fadare O, et al. World J Surg Oncol 2004
Lymphangioleiomyomatosis (LAM) PEComatosis versus LAM?
Prevalence of Uterine and Adnexal Involvement in Pulmonary Lymphangioleiomyomatosis: A Clinicopathologic Study of 10 Patients. Hayashi, Takuo; MD, PhD; Kumasaka, Toshio; MD, PhD; Mitani, Keiko; MT, CT; Terao, Yasuhisa; MD, PhD; Watanabe, Masao; MD, PhD; Oide, Takashi; MD, PhD; Nakatani, Yukio; MD, PhD; Hebisawa, Akira; MD, PhD; Konno, Ryo; MD, PhD; Takahashi, Kazuhisa; MD, PhD; Yao, Takashi; MD, PhD; Seyama, Kuniaki; MD, PhD
American Journal of Surgical Pathology. 35(12):1776‐ 1785, December 2011. DOI: 10.1097/PAS.0b013e318235edbd
FIGURE 1 . Schematic illustrating the distribution of LAM lesions in the female genital tract. The white circle indicates the site of a LAM lesion, and the asterisk indicates an LCC within the lymphatics. Note that the majority of LAM lesions in sporadic LAM (patients 1 to 7) are located along the outer area of the uterine myometrium, but those in TSC‐LAM (patients 8 to 10) appear diffusely in the myometrium.
TSC‐associated LAM: Diffuse involvement of myometrium with ill‐defined margins Sporadic LAM: Outer myometrium with well demarcated margins
© 2011 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
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Nodal lymphangioleiomyomatosis
• Often incidental finding in staging for gynecologic tumors • Single or multiple lymph nodes • Variable size • Only rarely associated with TSC (patient typically already diagnosed with TSC) • Not a harbinger of development of pulmonary LAM
Schoolmeester JK, Park KJ. Am J Surg Pathol 2015 Rabban JT, et al. Am J Surg Pathol 2015
Summary‐Tuberous sclerosis Acknowledgements
• Tuberous sclerosis can have gynecologic • Dr Charles Zaloudek (UCSF) manifestations • Dr Rob Soslow (MSKCC) • Most patients already diagnosed with • Dr Victor Reuter (MSKCC) tuberous sclerosis • Possibility of TSC could be raised if multiple • UCSF Gyn team PEComa family of tumors or • PEComatosis/LAM of gynecologic organs UCSF Genetic counsellors • Lymph node LAM typically sporadic Thank you!
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