ACCME/Disclosure. Uterine mesenchymal neoplasms: Hereditary aspects. Case 1. Dr. Garg has nothing to disclose

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1 ACCME/Disclosure Uterine mesenchymal neoplasms: Hereditary aspects Karuna Garg, MD University of California San Francisco Dr. Garg has nothing to disclose Case 1 31 year old female Menorrhagia and pelvic pain Multiple fibroids 2 11 cm Underwent myomectomy Gross: 4 masses, cm, no hemorrhage or necrosis 1

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3 Case 1 Possibility of fumarate hydratase (FH) mutation (HLRCC) raised in the comment Patient referred for genetic counselling Case 1 Mother with history of hysterectomy in her 20s for fibroids Maternal grandmother with history of 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) Case 1 Family history highly suggestive (but only in retrospect after genetic counselling which was initiated by pathology report) 3

4 Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome (HLRCC) Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome (HLRCC) Autosomal dominant Germline mutation in fumarate hydratase gene on chromosome 1q42.3 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 4 th decade Typically unilateral single mass High stage and poor prognosis 5 of 9 patients dead of disease (8 44 months) and 3 of 9 alive with disease Early detection of HLRCC could prevent morbidity/mortality from aggressive RCC Uterine leiomyomas HLRCC Cutaneous leiomyomas Renal cell carcinoma Penetrance ~100% ~75% ~15% Median age 2 nd 3 rd decade 2 nd 3 rd decade 4 th decade at diagnosis Uterine leiomyomas: Opportunity for early detection of HLRCC? Chen YB, et al. AJSP

Mehine M et al. N Engl J Med 2013;369:43 53. 1. Germline FH mutation (HLRCC) 2. Somatic FH mutation (NOT HLRCC): Frequency ~1 1.5% of uterine leiomyomas 3. Other mechanisms?

5 HLRCC: Uterine leiomyomas Problem: Uterine leiomyomas are common while HLRCC is not! 20 30% of all women develop uterine leiomyomas by age 30 Up to 80% develop uterine leiomyomas by age 50 years Specific test needed Potential Mechanisms of the Development of Leiomyomas. Mehine M et al. N Engl J Med 2013;369: Germline FH mutation (HLRCC) 2. Somatic FH mutation (NOT HLRCC): Frequency ~1 1.5% of uterine leiomyomas 3. Other mechanisms? HLRCC: Uterine leiomyomas Possible screening criteria: Patient age Personal and family history Fumarate hydratase gene mutation analysis Immunohistochemistry Tumor morphology HLRCC: Early detection Patient age: Multiple highly symptomatic leiomyomas at young age HLRCC associated ULM Sporadic ULM Median age at presentation 28 years 38 years Age at surgery <30 years 45 years Personal and family history: Family history of early surgery for fibroids Personal and/or family history of cutaneous leiomyomas and/or RCC 5

6 FH gene (germline) mutation analysis Highly specific and gold standard (germline testing) Not practical as a screening test Expensive (?) Available in limited laboratories Immunohistochemistry 2SC (2 succinocysteine) FH (fumarate hydratase) 2SC (succinocysteine) IHC Genetic ablation of FH leads to high levels of protein succination 2SC serves as a metabolic biomarker for FH deficiency 2SC IHC Positive staining for 2SC correlates with FH gene mutation 2SC positive in FH deficient renal cysts and renal tumors with known FH mutations Negative in normal tissue (n=200) and non HLRCC tumors (n=1342) Bardella C, et al. J Pathol

AJSP 2016 epub ahead of print 2SC IHC FH IHC Pros: Sensitive and specific Complete loss of FH staining correlates

7 2SC IHC 2SC positive 2SC negative 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: Sensitive and specific Complete loss of FH staining correlates with fumarate hydratase gene mutation Cons: Not commercially available Cannot distinguish between germline and somatic FH mutation 7

FH IHC Loss of FH staining FH mutation present Complete loss of FH

USCAP 2015 Uterine leiomyomas 2/5 (40%) Joseph NM, et al.

AJSP 2015 Cutaneous leiomyomas 6/11 (55%) Buelow B, et al.

result in retained FH IHC Retained FH staining FH IHC Pros: Specific

8 FH IHC Loss of FH staining 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 8

HLRCC: Tumor morphology HLRCC associated renal tumor: Morphology First reported in HLRCC associated renal cell carcinoma Prominent eosinophilic nucleoli surrounded by perinucleolar halos Merino MJ,

9 HLRCC: Tumor morphology HLRCC associated renal 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

10 HLRCC: Tumor morphology Hemangiopericytomatous blood vessels 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 10

11 Cytoplasmic inclusions Nuclear features Cytoplasmic inclusions, multinucleation, symplastic features HLRCC: Morphology Sensitivity and specificity? Reproducibility? 11

12 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) Conclusions: Poor reproducibility Poor sensitivity and specificity Recommend 2SC IHC as screening tool Morphologic features lack sufficient robustness to be a reliable triage feature Morphologic features evaluated: 1. Inclusion like prominent eosinophilic nucleoli with halos 2. Eosinophilic cytoplasmic inclusions 3. Hemangiopericytomatous blood vessels Joseph NM, et al. Am J Surg Pathol 2015 HLRCC: Morphology 5 with FH gene aberrations (2.6%) (germline or somatic) 4 displayed morphologic features suspicious for HLRCC 1 did not (only hemangiopericytomatous blood vessels) 3 additional cases with morphologic features suspicious for HLRCC did not show FH gene mutation HLRCC: Morphology Constellation of findings most useful rather than individual features Pitfalls: Morphologic features not a diffuse finding Small nucleoli show no correlation with FH mutation status Can see pseudo inclusions adjacent to areas of infarct Joseph NM, et al. Am J Surg Pathol 2015 Joseph NM, et al. Am J Surg Pathol

Pseudo inclusions adjacent to areas of infarct HLRCC 5 known HLRCC patients (25

uterine leiomyomas Loss of FH staining by IHC in 12 (1%) (complete sequencing of

in some cases Morphology: summary Constellation of findings helpful (NOT

Cytoplasmic inclusions, ovoid nuclei, bizarre cells High magnification: Nuclear

every case with FH mutation Questionable reproducibility and specificity More

13 Pseudo inclusions adjacent to areas of infarct HLRCC 5 known HLRCC patients (25 41 years) Some morphologic features in 4 cases None in 1 case 1152 sporadic uterine leiomyomas Loss of FH staining by IHC in 12 (1%) (complete sequencing of 10 of these cases revealed somatic FH mutations in 6) Morphologic features seen in some cases Morphology: summary Constellation of findings helpful (NOT DIFFUSE) Low power: HPC like vessels, mild moderate atypia Medium magnification: Cytoplasmic inclusions, ovoid nuclei, bizarre cells High magnification: Nuclear features (prominent eosinophilic macronucleoli surrounded by halos) Not seen in every case with FH mutation Questionable reproducibility and specificity More studies with expanded morphologic criteria and training Harrison WJ, et al. Am J Surg Pathol

14 HLRCC Increased risk for uterine leiomyosarcoma or STUMP? Probably not Cytologic atypia over interpreted? No loss of FH staining in 116 leiomyosarcomas from 88 patients No 2SC positivity in 29 leiomyosarcomas Harrison WJ, et al. Am J Surg Pathol 2015 Reyes C, et al. Mod Pathol 2013 HLRCC Increased association with atypical leiomyomas? 184 uterine smooth muscle tumors, 2SC IHC positive in 50% of Atypical LM The majority of 2SC positive cases (77%, 27/33) had FH associated histologic features Type 1 (n=30): FH morphology (ovoid nuclei with prominent nucleoli) 2SC positive Atypical leiomyomas Poropatich, et al. USCAP 2016 Type 2 (n=23): Spindle cells, smudgy chromatin, inconspicuous nucleoli MED12 and HMGA2 mutations (Proffered papers Monday, March 14, :00 am, Wednesday, March 16, :30 am Poster Session V #145) Summary: HLRCC Uterine leiomyomas can harbor fumarate hydratase gene mutations germline (HLRCC) and somatic Uterine leiomyomas are frequently the first clinical presentation for HLRCC 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 Case 2 14

15 Case Uterus 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

16 Uterus HMB 45 D2 40 Cervical mass Cervical mass 16

17 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) 17

18 Tuberous Sclerosis Tuberous sclerosis Autosomal dominant Mutations in TSC1 (hamartin) or TSC2 (tuberin) CNS manifestations Hamartomas/tumors in multiple organ systems PEComa family of tumors PEComa family of tumors Mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells Spindle or epithelioid Association with blood vessels Myomelanocytic immunophenotype Include CCSCT lung, AML, LAM and PEComa of various sites Renal/hepatic AML and pulmonary LAM strongly associated with TSC Other PEComas less strong association PEComas: Response to mtor inhibitors TSC1/TSC2 mutation Activation of mtor pathway Response to mtor inhibitors 18

Review of extra renal PEComas treated with mtor inhibitors Gynecologic

PEComa (including sclerosing PEComa) 2. PEComatosis 3.

Int J Cancer 2013 Lim and Oliva, Int J Gynecol Pathol 2011 Liang SX, et al.

growth pattern with prominent vascular network Clear to eosinophilic granular

19 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) Dickson M, et al. Int J Cancer 2013 Lim and Oliva, Int J Gynecol Pathol 2011 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

20 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 +/ 20

HMB 45 PEComa of the gynecologic tract Frequency of

study) Case reports of patients with TSC Less than

Germline TSC1/TSC2 mutation TSC1/TS2 abnormalities

PEComas TFE3 translocation PEComas of the female

translocation Morphology Epithelioid and/or

Immunophenotype Smooth muscle markers + Melan A +

Potential for response to mtor inhibitors Yes No

21 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 Germline TSC1/TSC2 mutation TSC1/TS2 abnormalities Sporadic mutation and/or LOH of TSC1/TSC2 Gyn PEComas TFE3 translocation PEComas of the female genital tract TSC1/TSC2 abnormalities TFE3 translocation Morphology Epithelioid and/or spindled Frequently clear cell epithelioid Immunophenotype Smooth muscle markers + Melan A + HMB 45 Focal Strong TFE3 Negative Positive Potential for response to mtor inhibitors Yes No Response to mtor inhibitors No response to mtor inhibitors Schoolmeester JK, et al. Am J Surg Pathol

Am J Surg Pathol 2015 TFE3 HMB 45 PECOMA:

High grade nuclear features 4. Necrosis 5.

Mitotic count 1 per 50 high power fields 1.

Benign 0 0 Uncertain malignant potential

22 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 SMA Criteria 1. Size 5 cm 2. Infiltrative borders 3. High grade nuclear features 4. Necrosis 5. Vascular invasion 6. Mitotic count 1 per 50 high power fields 1. Size 5 cm 2. High grade nuclear features 3. Necrosis 4. Vascular invasion 5. Mitotic count 1 per 50 high power fields Benign 0 0 Uncertain malignant potential Tumors with 1 of the following 1. Nuclear pleomorphism or multinucleated giant cells 2. Size 5 cm Malignant

PEComatosis Lymphangioleiomyomatosis (LAM) Frequently associated with TSC (6 cases reported of which 4 associated with TSC) Scattered small nodules in multiple sites

including uterus, cervix and adnexa TSC associated or sporadic Fadare O, et al. World J Surg Oncol 2004 Lymphangioleiomyomatosis (LAM) PEComatosis versus LAM?

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;

Pathology. 35(12):1776 1785, December 2011. DOI: 10.1097/PAS.0b013e318235edbd FIGURE 1.

The white circle indicates the site of a LAM lesion, and the asterisk indicates an LCC within the lymphatics.

23 PEComatosis Lymphangioleiomyomatosis (LAM) Frequently associated with TSC (6 cases reported of which 4 associated with TSC) Scattered small nodules in multiple sites (uterus, cervix, ovary, peritoneum, omentum, small bowel) Abnormal proliferation of smooth muscle like cells Most commonly in lung but can involve many other organs including uterus, cervix and adnexa TSC associated or sporadic 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): , December DOI: /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 23

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

Am J Surg Pathol 2015 Summary Tuberous sclerosis Tuberous sclerosis can have gynecologic manifestations Most patients already diagnosed with tuberous sclerosis Possibility of TSC could be raised

24 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 Tuberous sclerosis can have gynecologic manifestations Most patients already diagnosed with tuberous sclerosis Possibility of TSC could be raised if multiple PEComa family of tumors or PEComatosis/LAM of gynecologic organs Lymph node LAM typically sporadic Acknowledgements Dr Charles Zaloudek (UCSF) Dr Rob Soslow (MSKCC) Dr Victor Reuter (MSKCC) UCSF Gyn team UCSF Genetic counsellors Thank you! 24

25 References 1. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet. Apr 2002;30(4): Chen YB, Brannon AR, Toubaji A, et al. Hereditary leiomyomatosis and renal cell carcinoma syndrome associated renal cancer: recognition of the syndrome by pathologic features and the utility of detecting aberrant succination by immunohistochemistry. The American journal of surgical pathology. May 2014;38(5): Merino MJ, Torres Cabala C, Pinto P, Linehan WM. The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. The American journal of surgical pathology. Oct 2007;31(10): Harrison WJ, Andrici J, Maclean F, et al. Fumarate Hydratase deficient Uterine Leiomyomas Occur in Both the Syndromic and Sporadic Settings. The American journal of surgical pathology. Nov Lehtonen R, Kiuru M, Vanharanta S, et al. Biallelic inactivation of fumarate hydratase (FH) occurs in nonsyndromic uterine leiomyomas but is rare in other tumors. The American journal of pathology. Jan 2004;164(1): Sanz Ortega J, Vocke C, Stratton P, Linehan WM, Merino MJ. Morphologic and molecular characteristics of uterine leiomyomas in hereditary leiomyomatosis and renal cancer (HLRCC) syndrome. The American journal of surgical pathology. Jan 2013;37(1): Reyes C, Karamurzin Y, Frizzell N, et al. Uterine smooth muscle tumors with features suggesting fumarate hydratase aberration: detailed morphologic analysis and correlation with S (2 succino) cysteine immunohistochemistry. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. Jul 2014;27(7): Joseph NM, Solomon DA, Frizzell N, Rabban JT, Zaloudek C, Garg K. Morphology and Immunohistochemistry for 2SC and FH Aid in Detection of Fumarate Hydratase Gene Aberrations in Uterine Leiomyomas From Young Patients. The American journal of surgical pathology. Nov 2015;39(11): Garg K, Tickoo SK, Soslow RA, Reuter VE. Morphologic features of uterine leiomyomas associated with hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report. The American journal of surgical pathology. Aug 2011;35(8): Alsolami S, El Bahrawy M, Kalloger SE, et al. Current Morphologic Criteria Perform Poorly in Identifying Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome associated Uterine Leiomyomas. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists. Nov 2014;33(6): Bardella C, El Bahrawy M, Frizzell N, et al. Aberrant succination of proteins in fumarate hydratase deficient mice and HLRCC patients is a robust biomarker of mutation status. The Journal of pathology. Sep 2011;225(1): Merino M, Stratton, P., Linehan, MW., Lara Otero, K. Fumarate Hydratase assist to recognize smooth muscle tumors associated with Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome (HLRCC). Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2014;27(Suppl 2). 15. Dickson MA, Schwartz GK, Antonescu CR, Kwiatkowski DJ, Malinowska IA. Extrarenal perivascular epithelioid cell tumors (PEComas) respond to mtor inhibition: clinical and molecular correlates. International journal of cancer. Journal international du cancer. Apr ;132(7): Vang R, Kempson RL. Perivascular epithelioid cell tumor ('PEComa') of the uterus: a subset of HMB 45 positive epithelioid mesenchymal neoplasms with an uncertain relationship to pure smooth muscle tumors. The American journal of surgical pathology. Jan 2002;26(1): Folpe AL, Mentzel T, Lehr HA, Fisher C, Balzer BL, Weiss SW. Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. The American journal of surgical pathology. Dec 2005;29(12): Schoolmeester JK, Howitt BE, Hirsch MS, Dal Cin P, Quade BJ, Nucci MR. Perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: clinicopathologic and immunohistochemical characterization of 16 cases. The American journal of surgical pathology. Feb 2014;38(2): Schoolmeester JK, Dao LN, Sukov WR, et al. TFE3 translocation associated perivascular epithelioid cell neoplasm (PEComa) of the gynecologic tract: morphology, immunophenotype, differential diagnosis. The American journal of surgical pathology. Mar 2015;39(3): Agaram NP, Sung YS, Zhang L, et al. Dichotomy of Genetic Abnormalities in PEComas With Therapeutic Implications. The American journal of surgical pathology. Jun 2015;39(6): Rao Q, Cheng L, Xia QY, et al. Cathepsin K expression in a wide spectrum of perivascular epithelioid cell neoplasms (PEComas): a clinicopathological study emphasizing extrarenal PEComas. Histopathology. Mar 2013;62(4): Fadare O, Parkash V, Yilmaz Y, et al. Perivascular epithelioid cell tumor (PEComa) of the uterine cervix associated with intraabdominal "PEComatosis": A clinicopathological study with comparative genomic hybridization analysis. World journal of surgical oncology. 2004;2: Liang SX, Pearl M, Liu J, Hwang S, Tornos C. "Malignant" uterine perivascular epithelioid cell tumor, pelvic lymph node lymphangioleiomyomatosis, and gynecological pecomatosis in a patient with tuberous sclerosis: a case report and review of the literature. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists. Jan 2008;27(1): Lim GS, Oliva E. The morphologic spectrum of uterine PEC cell associated tumors in a patient with tuberous sclerosis. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists. Mar 2011;30(2): Hayashi T, Kumasaka T, Mitani K, et al. Prevalence of uterine and adnexal involvement in pulmonary lymphangioleiomyomatosis: a clinicopathologic study of 10 patients. The American journal of surgical pathology. Dec 2011;35(12): Schoolmeester JK, Park KJ. Incidental Nodal Lymphangioleiomyomatosis Is Not a Harbinger of Pulmonary Lymphangioleiomyomatosis: A Study of 19 Cases With Evaluation of Diagnostic Immunohistochemistry. The American journal of surgical pathology. Oct 2015;39(10): Rabban JT, Firetag B, Sangoi AR, Post MD, Zaloudek CJ. Incidental Pelvic and Para aortic Lymph Node Lymphangioleiomyomatosis Detected During Surgical Staging of Pelvic Cancer in Women Without Symptomatic Pulmonary Lymphangioleiomyomatosis or Tuberous Sclerosis Complex. The American journal of surgical pathology. Aug 2015;39(8):

Uterine mesenchymal tumors: Hereditary perspectives

Uterine mesenchymal tumors: Hereditary perspectives Two hereditary syndromes are known to be related to uterine mesenchymal tumors: Hereditary Leiomyomatosis and Renal Cell Carcinoma syndrome (HLRCC) and