Rare genital cancers  Dr Giovanni Rosti Past President of the Italian Germ cell cancer Group
Rare, but growing in incidence (0.9/100,000) Lithuania
European dis….union  Extremely rare!
Declining of sperma density: Swan et. al., Env Hlth Persp 105: 1228-1232, 1997 Bye bye spermatozoa !
Here they are ! The rare ones !
I. Germ cell neoplasms (90–95%) II.  Sex cord-stromal neoplasms (4%)  A.  Leydig cell tumor  (3%) B. Sertoli cell tumor (1...
G e rm cell tumors GONADAL EXTRAGONADAL 2-5% MEDIASTINAL RETROPERITONEAL EPIFISIS, SACRO-COCCIGAL, OTHERS Rare, but we hav...
 
SPERMATOCYTIC SEMINOMA <ul><li>Classically seen in an older age group (median age 53 yrs). </li></ul><ul><li>It accounts f...
Spermatocytic seminoma <ul><li>Not associated with criptorchidism </li></ul><ul><li>Invariably  not  associated with marke...
small 6-8µm large 15-20µm giant  50-150µm
spermatocytic seminoma   -  classical seminoma gains: vertical lines on the right side of the ideograms losses: vertical l...
 
Anaplastic variant of spermatocytic seminoma Courtesy dr Lombardi
from : Clinical Pathology of Urologic Tumors  ed. G.Mikuz Taylor-Francis, Informa, London 2007
 
 
 
CRITERIA OF MALIGNANCY <ul><li>Neoplastic  “overgrowth” </li></ul><ul><li>Stromal invasion </li></ul><ul><li>Atypical mito...
 
 
 
PROGNOSIS
 
Stage of disease at transformation and  the feasibility to perform a radical surgical removal of disease seemed to be the ...
 
PROGNOSIS Better prognosis “…  patients with TMT confined to the testis or retroperitoneum which were completely resected ...
It is not just a question of “teratoma” Carver, JCO, 2007
ECA  +  T chemotherapy ECA  + T Teratoma Growing Syndrome (Rosti, 10/05)
T 1 IN TESTIS T3 TMT arising in mediastinal primary Clinical Relevance  Incompletely  resected tumor T2 PROGNOSIS
TERATOMA:  BEYOND TRANS-DIFFERENTIATION/PLASTICITY Nothing other than cytogenetics!! Ulbright TM, 1984 – Motzer RJ, 1998 C...
HISTOLOGIC DIFFERENTIATION OF GCTs  OCT3/4  KIT  PLAP ITGCNU  ITNS  ITSE Seminoma Embryonal Carcinoma Teratoma ChorioCA YS...
CYTOGENETICS AND GENOMIC STUDIES:  GAIN OF 12p INFORMATION <ul><li>In 1982 Atkin & Baker reported an isochromosome of the ...
ARE SOME SEMINOMAS TRANSFORMING TUMORS  FROM SEMINOMA TO EMBRYONAL CARCINOMA?  Activation of pluripotency (reprogramming) ...
<ul><ul><li>108  NSGCT  pts who received chemotherapy at MSKCC with fresh frozen tissue available </li></ul></ul><ul><ul><...
What would you do ? Anterior 28-yr old man with dispnea, cough
Ex-GCT - Clinical presentation ASSOCIATED TUMORS <ul><li>Acute myeloproliferation </li></ul><ul><li>6%  of pts (17/287)  M...
I had an EGGCT too!!!!
2500 years BC described by  Egyptian fetoscopists The third foot in the midline
Mediastinal germ cell tumors 1-2 % of all germ cell tumors  20% of EGGCT Extremely rare in female Klinefelter syndrome ass...
Klinefelter Syndrome Mediastinal GCT Mediastinal GCT 8% Klinefelter s. Mediastinal GCT and Klinefelter syndrome
Gonadal   Mediastinal   Alfa FP, HCG  Markers  Alfa FP, HCG i(12p)  Genetic  i(12p) Sick   Testicular  Normal 50-60%  Semi...
Pathological diagnosis of Ex-GCT <ul><li>- FNAC or FNAB may reveal either S or NS elements but sometimes only the term “un...
<ul><li>Seminoma </li></ul><ul><li>No known prognostic factor(s) </li></ul><ul><li>Non Seminoma </li></ul><ul><li>Score: <...
Mediastinal GCT  Chemotherapy (PEB or Ifo containing regimens x  4 courses ) Surgery whenever possible High Dose chemother...
Prognostic factors at relapse October, 2010
 
Beyer et al, 2010
Beyer et al, 2010
Lorch, ASCO 2010
Other testicular tumors Von Leydig cell tumors 75% in adult patients Sometimes with gynecomastia and decreased libido 25% ...
von Leydig cell tumors In one third of cases typical Reinke’s crystals Benign disease <<10? malignant behaviour Totally ch...
The GUONO Italian study Collection among centers in North West Italy from 1988 until 2000 50 patients (52 tumors identifie...
Open questions What is a bad  von Leydig tumor ? Possibilities : size > 5 cm, infiltration of spermatic cord, VI, margins ...
Sertoli cell tumors < 1% of testicular  tumors Classic LC calcifying sclerosing
Sertoli cell tumors Association with pituitary adenomas, cardiac mixoma, pigmentaded skin, mucosal lesions. Feminilization...
Granulosa cell tumors Extremely rare disease.  Adult (no more than 30 cases in the literature) and juvanile types  Gynecom...
Thank you for your attention
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Rare Solid Cancers: An Introduction - Slide 9 - G. Rosti - Rare male genital cancers

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Rare Solid Cancers: An Introduction - Slide 9 - G. Rosti - Rare male genital cancers

  1. 1. Rare genital cancers Dr Giovanni Rosti Past President of the Italian Germ cell cancer Group
  2. 2. Rare, but growing in incidence (0.9/100,000) Lithuania
  3. 3. European dis….union Extremely rare!
  4. 4. Declining of sperma density: Swan et. al., Env Hlth Persp 105: 1228-1232, 1997 Bye bye spermatozoa !
  5. 5. Here they are ! The rare ones !
  6. 6. I. Germ cell neoplasms (90–95%) II. Sex cord-stromal neoplasms (4%) A. Leydig cell tumor (3%) B. Sertoli cell tumor (1%) C. Sertoli-Leydig cell tumor (rare) D. Granulosa cell tumors (<1%) E. Tumors in the fibroma/thecoma group (rare) F. Mixed and indeterminant (unclassified) sex cord-stromal tumors (<1%) III. Mixed germ cell-sex cord-stromal neoplasms (<1%) A. Gonadoblastoma (0.5%) B. Other mixed germ cell-sex cord-stromal tumors (rare) IV. Lymphoid and Haematopoietic tumors (<1%) A. Lymphoma (? 1% as true primary neoplasm) B. Plasmacytoma (rare) and multiple myeloma C. Granulocytic sarcoma and leukemic infiltrates (rare) D. Miscellaneous others, including metastatic tumors (1–2 %)
  7. 7. G e rm cell tumors GONADAL EXTRAGONADAL 2-5% MEDIASTINAL RETROPERITONEAL EPIFISIS, SACRO-COCCIGAL, OTHERS Rare, but we have to know them 95-98%
  8. 9. SPERMATOCYTIC SEMINOMA <ul><li>Classically seen in an older age group (median age 53 yrs). </li></ul><ul><li>It accounts for 0.6% percent of all testicular GCT. </li></ul><ul><li>1.1% of all seminomas </li></ul><ul><li>tumor marker negative </li></ul><ul><li>gross: mucoid gelatinous appearance </li></ul><ul><li>microscopy : 3 cell types, intratubular growth, no lymphocyte </li></ul><ul><li>IHC: PLAP - / + rarely </li></ul><ul><li>CK 18 / CAM 5.2 - / + dot like </li></ul><ul><li>CD 117 +++ (80% of cases) </li></ul><ul><li>genetics: gain of chromosome 9 </li></ul>
  9. 10. Spermatocytic seminoma <ul><li>Not associated with criptorchidism </li></ul><ul><li>Invariably not associated with marker(s) </li></ul><ul><li>Never in extragonadal sites </li></ul><ul><li>“ Elderly” age but not restricted to. </li></ul><ul><li>Non associated with CIS </li></ul><ul><li>Bilateral disease relatively rare </li></ul>
  10. 11. small 6-8µm large 15-20µm giant 50-150µm
  11. 12. spermatocytic seminoma - classical seminoma gains: vertical lines on the right side of the ideograms losses: vertical lines on the left side of the ideograms
  12. 14. Anaplastic variant of spermatocytic seminoma Courtesy dr Lombardi
  13. 15. from : Clinical Pathology of Urologic Tumors ed. G.Mikuz Taylor-Francis, Informa, London 2007
  14. 19. CRITERIA OF MALIGNANCY <ul><li>Neoplastic “overgrowth” </li></ul><ul><li>Stromal invasion </li></ul><ul><li>Atypical mitoses </li></ul>Davey DD, Ulbright TM, Loehrer PJ et al: The significance of atypia within teratomatous metastase after chemotherapy for malignant germ cell tumors Cancer 59: 533-539,1987
  15. 23. PROGNOSIS
  16. 25. Stage of disease at transformation and the feasibility to perform a radical surgical removal of disease seemed to be the strongest disease-related prognostic factors
  17. 27. PROGNOSIS Better prognosis “… patients with TMT confined to the testis or retroperitoneum which were completely resected experienced a longer survival than those with distant metastases…” <ul><li>Poor prognosis </li></ul><ul><li>-distant metastases </li></ul><ul><li>-TMT arising ain a mediastinal primary tumor </li></ul><ul><li>Incompletely resected tumor </li></ul><ul><li>Motzer J Urol 1998 </li></ul>
  18. 28. It is not just a question of “teratoma” Carver, JCO, 2007
  19. 29. ECA + T chemotherapy ECA + T Teratoma Growing Syndrome (Rosti, 10/05)
  20. 30. T 1 IN TESTIS T3 TMT arising in mediastinal primary Clinical Relevance Incompletely resected tumor T2 PROGNOSIS
  21. 31. TERATOMA: BEYOND TRANS-DIFFERENTIATION/PLASTICITY Nothing other than cytogenetics!! Ulbright TM, 1984 – Motzer RJ, 1998 Comiter CV, 1998 – Donadio AC, 2003 El Mesbahi O, 2007 – Malagón HD, 2007 Spiess PE, 2008
  22. 32. HISTOLOGIC DIFFERENTIATION OF GCTs OCT3/4 KIT PLAP ITGCNU ITNS ITSE Seminoma Embryonal Carcinoma Teratoma ChorioCA YST Malignant PLAP+, CD117+, CD30-, EMA- PLAP+, CD117-, CAM5.2+, CD30+ PLAP+/-, CAM5.2+, HCG+ CD117+, CAM5.2+, AFP+ 90% 60% Unusual
  23. 33. CYTOGENETICS AND GENOMIC STUDIES: GAIN OF 12p INFORMATION <ul><li>In 1982 Atkin & Baker reported an isochromosome of the short arm of the chromosome 12  i(12p)  as a marker of GCT specimen cultures metaphases </li></ul><ul><li>Extra-copies of 12p are the hallmark of this disease, occurring in nearly 100% of cases </li></ul><ul><li>(Chaganti & Houldsworth, 2000) </li></ul><ul><li>When does this gain occur during tumorigenesis? </li></ul><ul><li>What are actually the aberrant informations leading to tumorigenesis? </li></ul>
  24. 34. ARE SOME SEMINOMAS TRANSFORMING TUMORS FROM SEMINOMA TO EMBRYONAL CARCINOMA? Activation of pluripotency (reprogramming) Seminoma Embryonal Carcinoma + OCT3/4-NANOG + + SOX17 - - SOX2 + - CD30 + - HMGA2 + - DNMT1,3AB,L + - Cytokeratin 8,18,19 + - miRNA 122a, 200c, .. - - miRNA 9, 105, .. +
  25. 35. <ul><ul><li>108 NSGCT pts who received chemotherapy at MSKCC with fresh frozen tissue available </li></ul></ul><ul><ul><li>Training Set = 74 pts; Validation Set = 34 pts </li></ul></ul><ul><ul><li>Affymetrix U133A+B microarrays </li></ul></ul>Endpoints / Statistics <ul><li>5-year Overall Survival </li></ul><ul><li>Overall survival at last follow-up </li></ul>… .”We have identified two related gene sets that predict outcome (5year OS and OS) in an independent tumor cohort” KORKOLA JE, JCO 2010 - A neural differentiation genotype is associated with poor outcome (ZIC1, SOX11) - Presence of immune-related genes is associated with good outcome (IGJ, IGKC/IGKV1-5, IGL@ / IGLC1 / IGLC2 / IGLV3-25, IGKC / IGKV1-5… IGCCCG and molecular signature Time (years) Proportion surviving
  26. 36. What would you do ? Anterior 28-yr old man with dispnea, cough
  27. 37. Ex-GCT - Clinical presentation ASSOCIATED TUMORS <ul><li>Acute myeloproliferation </li></ul><ul><li>6% of pts (17/287) Med ExGCT </li></ul><ul><li>Median time from diagnosis: 6 months </li></ul><ul><li>Megacharyocitic line more interested </li></ul><ul><li>i(12p) present in 38% of the analysed cases </li></ul><ul><li>Poor-prognosis: median OS of 5 months </li></ul><ul><li>Metachronous testicular cancer </li></ul><ul><li>4% (16/635) of cases </li></ul><ul><li>Median time from diagnosis: 60 months </li></ul><ul><li>Excellent prognosis </li></ul>Hartmann, JNCI 2000 Hartmann, JNCI 2001
  28. 38. I had an EGGCT too!!!!
  29. 39. 2500 years BC described by Egyptian fetoscopists The third foot in the midline
  30. 40. Mediastinal germ cell tumors 1-2 % of all germ cell tumors 20% of EGGCT Extremely rare in female Klinefelter syndrome association
  31. 41. Klinefelter Syndrome Mediastinal GCT Mediastinal GCT 8% Klinefelter s. Mediastinal GCT and Klinefelter syndrome
  32. 42. Gonadal Mediastinal Alfa FP, HCG Markers Alfa FP, HCG i(12p) Genetic i(12p) Sick Testicular Normal 50-60% Seminoma 15-20% PEB x 3 - 4 Therapy PEB (IFO*) x 4 YES Surgery of the residuum YES 15% IGCCCG poor 100% NO Hemat. Correlated diseases Described
  33. 43. Pathological diagnosis of Ex-GCT <ul><li>- FNAC or FNAB may reveal either S or NS elements but sometimes only the term “undifferentiated carcinoma”  serum markers and IHC with specific germ cell markers (ev. i12p) </li></ul><ul><li>- 57 FNABs (47 histopathology available) both primary and metastases: </li></ul><ul><li>reliable (no problem with S and yolk sac), BUT: </li></ul><ul><li>immature teratoma and mixed GCTs  significant problem in cytology (in 37% of mixed only 1 component observed on cytology)  sampling error in needle aspiration </li></ul><ul><li>wider list of differential diagnoses for Ex-GCTs </li></ul><ul><li>A routine bilateral testicular biopsy is not indicated </li></ul>Bokemeyer et al, JCO 2002 Hartmann JT et al, JNCI 2001 Gupta R et al, Cancer 2008
  34. 44. <ul><li>Seminoma </li></ul><ul><li>No known prognostic factor(s) </li></ul><ul><li>Non Seminoma </li></ul><ul><li>Score: </li></ul><ul><li>M+ liver 1 </li></ul><ul><li>M+ brain 2 </li></ul><ul><li>M+ lung 1 </li></ul><ul><li>HCG increased 1 </li></ul><ul><li>Mediastinal location 2 </li></ul>Hartmann et al, Ann Oncol, 2002 Ex-GCT - Prognostic factors at diagnosis
  35. 45. Mediastinal GCT Chemotherapy (PEB or Ifo containing regimens x 4 courses ) Surgery whenever possible High Dose chemotherapy at the present time only an option (not EBM based)
  36. 46. Prognostic factors at relapse October, 2010
  37. 48. Beyer et al, 2010
  38. 49. Beyer et al, 2010
  39. 50. Lorch, ASCO 2010
  40. 51. Other testicular tumors Von Leydig cell tumors 75% in adult patients Sometimes with gynecomastia and decreased libido 25% in pediatric patients Sometimes with sexual pseudoprecocity No association with chryptorchidism
  41. 52. von Leydig cell tumors In one third of cases typical Reinke’s crystals Benign disease <<10? malignant behaviour Totally chemo/radio resistant disease !
  42. 53. The GUONO Italian study Collection among centers in North West Italy from 1988 until 2000 50 patients (52 tumors identified) Mean age 36 years (range 13-70) Two patients died one of metastatic diesease (age 70) Di Tonno Urologia Int ,2009
  43. 54. Open questions What is a bad von Leydig tumor ? Possibilities : size > 5 cm, infiltration of spermatic cord, VI, margins inf, necrosis , High MI, atypias RPLND? When metastatic : SURGERY whenever possible Chemotherapy is a sort of sympathetic treatment. PET/CT : who knows? Life-long follow-up ?????
  44. 55. Sertoli cell tumors < 1% of testicular tumors Classic LC calcifying sclerosing
  45. 56. Sertoli cell tumors Association with pituitary adenomas, cardiac mixoma, pigmentaded skin, mucosal lesions. Feminilization in 25% of cases Metastases to the RP only in classic type Chemotherapy and radiation totally ineffective RPLND in case of metastases (malignat potential ???? But very very rare)
  46. 57. Granulosa cell tumors Extremely rare disease. Adult (no more than 30 cases in the literature) and juvanile types Gynecomastia and estrogen production common. Juvenile forms are the most frequent stromal neoplasma in early childhood (with maldescended testes, ambiguous genitalia, abnormal karyotype)
  47. 58. Thank you for your attention

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