PEComa (January 2016): Molecular Oncology Tumor Boards

ASCO University
Jan 13, 2016 9:19 AM

User Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert pathologist and medical oncologist. This month’s topic is led by Drs. Jason Hornick (Brigham and Women’s Hospital) and Victor Villalobos (University of Colorado Denver).

Please Note: There will be two related patient cases posted this month! The second case will be posted January 18th at the time of faculty responses to Case #1.

Users are encouraged to leave comments and post questions about the case in order to generate a wide discussion among the cancer care community. You can also receive email notifications when new comments are posted by clicking the “Follow this Conversation” option located at the bottom of this page.

Supplemental resources related to the case are attached for reference.

Comments

12011

ASCO University
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 13, 2016 9:24 AM

Patient Case #1

Age/Sex: 35-year-old female

Medical History: Patient initially presented with 10 cm mass in her uterus.  This was felt initially to be a leiomyoma and she subsequently underwent a uterus sparing resection.  Pathology was found to be malignant and at the time felt to be consistent with a high grade leiomyosarcoma measuring 10 cm with positive margins. She thereafter underwent a TAH-BSO with all residual tumor removed and no involved lymph nodes.  FIGO Stage Ib, AJCC stage III.  She received no adjuvant therapy.  

Two years from her initial diagnosis, she recurred in the pelvis and presuming this was recurrent leiomyosarcoma, she underwent resection followed by adjuvant pelvic radiation and chemotherapy in the form of gemcitabine and docetaxel.  She developed lung nodules 1 year later.   Her pathology was reviewed at an academic center with expertise in sarcoma. Histologically, the tumor showed a trabecular and nested architecture (Image 1) and was composed of epithelioid cells with marked nuclear atypia, prominent nucleoli, clear to granular eosinophilic cytoplasm, and a high mitotic rate (Image 2). By immunohistochemistry, the tumor cells were positive for smooth muscle actin (Image 3) and desmin and the melanocytic markers HMB-45 (Image 4) and microphthalmia transcription factor (MITF; Image 5).

The original diagnosis was revised to metastatic malignant PEComa (perivascular epithelioid cell tumor).  She was subsequently started on systemic therapy.  

Type of Tumor: Malignant PEComa (perivascular epithelioid cell tumor)

Relevant Markers: TSC2  

Prior Treatment History/Response: adjuvant gemcitabine/docetaxel

Co-morbidities:  none

12016

ASCO University
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 13, 2016 9:26 AM

Discussion Questions

  1. What are the pathologic features that distinguish PEComa from the much more common leiomyosarcoma?
  2. What is the role for cytotoxic chemotherapy in the treatment of metastatic or unresectable PEComa?
  3. Are there any particular genetic targets associated with this class of malignancy for which an available therapy may be of use?  
  4. What is the role for high throughput genetic testing in these classes of tumors?

 

12041

Jason Hornick, MD, PhD
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 18, 2016 4:54 PM

Course Faculty Response

Question 1.  Whereas leiomyosarcomas are usually composed of spindle cells arranged in fascicles, PEComas are most often composed of epithelioid cells arranged in nests or trabeculae (though some PEComas are dominated by spindle cells and show a sheet-like growth pattern). However, a small subset of uterine leiomyosarcomas show epithelioid cytomorphology. Even in such instances, the nested architecture (with nests surrounded by a delicate capillary vasculature) is a helpful clue to the diagnosis of PEComa. In addition, the cytoplasmic and nuclear features are usually different (i.e., clear or granular eosinophilic cytoplasm and central, rounded nuclei in PEComa, as opposed to dense, brightly eosinophilic cytoplasm and broad, blunt-ended nuclei in leiomyosarcoma). Whereas both PEComas and leiomyosarcomas express smooth muscle markers (SMA and desmin), only PEComas are positive for melanocytic markers (most commonly HMB-45, but sometimes melan-A and microphthalmia transcription factor).

References

  1. Hornick JL, Fletcher CD. PEComa: what do we know so far? Histopathology. 2006 Jan;48(1):75-82. 
  2. Folpe AL, Kwiatkowski DJ. Perivascular epithelioid cell neoplasms: pathology and pathogenesis. Hum Pathol. 2010 Jan;41(1):1-15.

Question 3.  The majority of PEComas harbor TSC2 mutations. Inactivation of TSC2 releases the inhibition or Rheb, resulting in mTOR activation. This dominant genetic alteration is the impetus for the use of mTOR inhibitors (sirolimus, temsirolimus) in this class of tumors, which have shown significant clinical efficacy.  The majority of malignant PEComas with TSC2 mutations also harbor TP53 mutations.

References

  1. Wagner AJ, Malinowska-Kolodziej I, Morgan JA, et al. Clinical activity of mTOR inhibition with sirolimus in malignant perivascular epithelioid cell tumors: targeting the pathogenic activation of mTORC1 in tumors. J Clin Oncol. 2010 Feb 10;28(5):835-40.
  2. Dickson MA, Schwartz GK, Antonescu CR, et al. Extrarenal perivascular epithelioid cell tumors (PEComas) respond to mTOR inhibition: clinical and molecular correlates. Int J Cancer. 2013 Apr 1;132(7):1711-7.
  3. Agaram NP, Sung YS, Zhang L, et al. Dichotomy of genetic abnormalities in PEComas with therapeutic implications. Am J Surg Pathol. 2015 Jun;39(6):813-25.

12046

Victor Manuel Villalobos, MD, PhD
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 18, 2016 5:01 PM

Course Faculty Response

Question 2.  The role for chemotherapy is limited in PEComa as they often have poor responsiveness to cytotic agents.   There have been many case reports on the treatment with systemic cytotoxic chemotherapy and the results overall have thus shown limited overall benefit to this approach.  This table shows a retrospective analysis of 35 patients and their responses to different forms of therapy.  

Question 3.  The vast majority of PEComas are associated with malfunction in the TSC1/TSC2 axis (Tuberous sclerosis complex).  The most common alteration is found in tuber in (TSC2) typically as an inactivating mutation or missense mutation.  The TSC1/TSC2 heterodimer serves as an inhibitor of RHEB (Raps homolog enriched in brain protein).  When left unopposed, RHEB leads to excess activation of the MTOR pathway. See this image for further details.

There have been several case reports and small trials with patients diagnosed with PEComa receiving mTOR inhibitors in the form of sirolimus, everolimus, or temsirolimus.  There have not been any prospective trials that included more than 5 patients, but this is likely due to the rarity of these tumors.  The response rates using mTOR inhibitors has been significant, particularly compared to traditional cytotoxic agents.  In Wagner et. al.'s publication, there was a 100% response rate in the 3 patients treated despite only one patient having alterations in the TSC1/TSC2 pathway.  The retrospective analysis from Benson Et al, included 10 patients with PEComa treated with mTOR inhibition.  7 of those patients were evaluable by RECIST criteria and over 71% of those patients experienced at least a partial response.  Of note, 2 of the 10 patients progressed rapidly through therapy.  Despite the low numbers published, treatment with mTOR inhibitors has been included within the NCCN guidelines for the first line treatment of PEComas.  

References

  1. Annals of Diagnostic Pathology 19 (2015) 359–368
  2. Wagner et al JCO February 10, 2010 vol. 28 no. 5 835-840
  3. Benson et al Anticancer Res July 2014 34 (7) 3663-3668

Question 4: There may yet be a role for high throughput genetic testing of these tumors.  While many PEComas exhibit aberrations in TSC1/TSC1 or fusions in TFE3, there may be other mutations which are driving these cancers.  As genetic screening assays become more broad in their use and increase the numbers of genetic aberrations being tested, it may very well be worth while to test these tumors for other potentially actionable mutations of interest. That being said, these assays may only be valuable if they are testing for genetic aberrations relevant to particular tumor types.  This patient’s sample was tested and on the bases of not harboring a PIC3K mutation, mTOR inhibitors were classified within the agents of indeterminate benefit.  

12051

ASCO University
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 18, 2016 5:03 PM

Patient Case #1 Update

She was started on everolimus and experienced a greater than 70% response that was durable for over a year.  She subsequently developed abdominal pain and was found to have some new evidence of disease in her abdomen. She underwent tumor debulking and during the operation was found to have progressive and diffuse sarcomatosis.  The large masses were resected.  She was taken off everolimus prior to resection and during the 3 weeks after during healing when a new baseline CT revealed dramatic progression of disease.  She was restarted on everolimus with continued progression.  The patient was placed on pazopanib but continued to progress and was not well enough to receive any other chemotherapy options.  She died within 2 weeks of stopping therapy.

12056

ASCO University
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 18, 2016 5:07 PM

Patient Case #2

Age/Sex: 46-year-old male 

Medical History: Patient presented with a one year history of nasal congestion that did not respond to antibiotics or steroids. On imaging, a large right nasal sinus mass filling the nasal cavity and nasopharynx and extending to the oropharyngeal inlet was identified. A biopsy was performed.

Histologically, the tumor showed a nested growth pattern (Image 6) and was composed of epithelioid cells with central nuclei, small nucleoli, and clear cytoplasm (Image 7). By immunohistochemistry, the tumor cells were positive for HMB-45 (Image 8) and TFE3 (Image 9), whereas smooth muscle actin, desmin, and S100 protein were negative.

Fluorescence in situ hybridization (FISH) was positive for a TFE3 rearrangement.

Type of Tumor: PEComa (perivascular epithelioid cell tumor) 

Relevant Markers:  TFE3  

Prior Treatment History/Response: none

Co-morbidities:  none

12061

ASCO University
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 18, 2016 5:08 PM

Discussion Questions

  1. What other tumor types are associated with TFE3 gene rearrangements? 
  2. Are there any genetic targets associated with this tumor type for which an available (or experimental) therapy may be of use?  

 

12066

Anis Toumeh, MD
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 18, 2016 5:31 PM

There are some rare cases of renal cell carcinoma with TFE3 gene rearrangement at Xp11.2 which is a distinct subtype usually with an indolent course in children, but might take a more aggressive one in adults. Also TFE3 can be rearranged in alveolar soft part sarcoma.

12071

Tony Philip, MD
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 19, 2016 5:51 PM

Question 2 - I agree with Dr. Villalobos that cytotoxic chemotherapy unfortunately has lmited use nin the treatment of metastatic or unresectable PEComa but there can be occasioanl responses to mTOR inhibition.

Question4 -  high throughput genetic testing may help us understand more about this difficult to treat tumors by better understanding if any other mutations are presents other than TSC.  Maybe no actionable mutations but better understanding its biology

12096

Jason Hornick, MD, PhD
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 20, 2016 5:18 PM

Course Faculty Response

Thank you Dr. Philip for your comments.  Indeed high-throughput genomic testing may reveal biologically interesting findings in rare tumor types, even when the clinical relevance of such alterations is unclear.

12101

Jason Hornick, MD, PhD
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 22, 2016 9:26 AM

Course Faculty Response

Question 1.  Although TSC2 mutations are the most common genetic alterations in PEComa, a large subset of PEComas lack TSC2 mutations; the majority of such PEComas instead harbor TFE3 gene rearrangements. This subset of PEComas often lack expression of smooth muscle markers. TFE3 gene rearrangements were first identified in alveolar soft part sarcoma [a consequence of the translocation t(X;17)], an aggressive soft tissue sarcoma associated with a high rate of metastasis to lung, lymph nodes, bone, and brain. TFE3 gene rearrangements also define an uncommon variant of renal cell carcinoma with a predilection for children and young adults, referred to as Xp11 translocation carcinoma. Most recently, TFE3 gene fusions were identified in a small subset of epithelioid hemangioendotheliomas.

References

  1. Argani P, Aulmann S, Illei PB, et al. A distinctive subset of PEComas harbors TFE3 gene fusions. Am J Surg Pathol. 2010 Oct;34(10):1395-406.
  2. Agaram NP, Sung YS, Zhang L, et al. Dichotomy of genetic abnormalities in PEComas with therapeutic implications. Am J Surg Pathol. 2015 Jun;39(6):813-25.

12106

Victor Manuel Villalobos, MD, PhD
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 22, 2016 9:32 AM

Course Faculty Response

Question 2.  Targeting TFE3 fusions may be difficult since this pathway is still not fully elucidated and is quite complex.  The pathway shown below displays potential therapeutic targets.  TFE3 gene fusions have shown some responsiveness to mTOR inhibitors.  MET may seem to be a likely target.  Wagner, et al describes a clinical trial using tevantinib ( a selective noncompetitive MET inhibitor)  in 47 patients with MIT associated cancers that showed a 60% disease stabilization rate.  (Cancer. 2012 Dec 1;118(23):5894-902). MiT tumors all exhibit dysregulated expression of a family of homologous transcription factors including TFE3, TFEB, TFEC, and MITF.  These data could presumably apply to PEComa which have a TFE3 fusion. Clearly other potential options would be mTOR inhibitors, CDK4/6 inhibitors, vs TGFbeta inhibitors such as imatinib.  See image for further details.

Reference

  1. Kauffman, E. C. et al. Nat. Rev. Urol. 11, 465–475 (2014)

 

12116

Jason Hornick, MD, PhD
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 27, 2016 10:44 AM

Course Faculty Case Summary

The first case illustrates the problem in diagnosis of rare sarcoma types. Sarcomas are a diverse group of malignant neoplasms, many of which show significant pathologic overlap; awareness of the existence of particularly rare tumor types, and their distinctive histologic, immunophenotypic, and molecular features can help pathologists avoid misdiagnosis. PEComas (perivascular epithelioid cell neoplasms) show overlap with smooth muscle neoplasms (i.e., leiomyosarcoma) but also co-express melanocytic markers. Immunohistochemistry can therefore facilitate proper diagnosis.

Recent studies have identified TSC2 mutations as the most common pathogenetic driver of PEComas. As loss of TSC2 results in mTOR activation, mTOR inhibitors may be used to treat patients with metastatic malignant PEComa. Some PEComas lacking TSC2 mutations instead harbor gene fusions, most commonly involving TFE3 (the same gene involved in translocations in alveolar soft part sarcoma). PEComas with TFE3 rearrangements usually have clear cytoplasm and lack expression of smooth muscle markers, as seen in the second case. Appropriate systemic therapy for this other class of PEComas remains uncertain. The diversity of genetic alterations underlying the pathogenesis of PEComa suggests the potential utility of high-throughput genomic methods to distinguish among these genetic groups of PEComa in order to select proper therapy.

12121

Victor Manuel Villalobos, MD, PhD
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 27, 2016 10:46 AM

Course Faculty Case Summary

As Dr. Hornick has nicely summarized, there is no way to emphasize enough the importance of accurate pathologic diagnoses in rare tumor subtypes.  In this case, treatment with a directed inhibitor against a driver pathway led to disease response and stabilization in a tumor type that is rarely known for response to traditional cytotoxic agents. Mesenchymal tumors in particular frequently have relatively simple genomics that are driving tumor development and growth. Around 30% of sarcoma subtypes (though a much smaller proportion of actual cases) are associated with genetic translocations, fusions or mutations, and more are being discovered every year.  The use of of genome sequencing and genetic panels will likely increase with time and the number of genes that can be tested simultaneously also continues to grow.  While we are not yet sure if different therapeutic targets respond the same way in different histologies (see BRAF in melanoma vs colon), these are good places to start, particularly in the rare tumors population.

12126

ASCO University
Re: PEComa (January 2016): Molecular Oncology Tumor Boards
Jan 27, 2016 10:48 AM

Thank you to Drs. Hornick and Villalobos leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments but users have the opportunity to claim credit on ASCO University by clicking here.

Please check back in mid-February for a new case in this series related to breast cancer.   

 


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