Testicular Tumors Including Secondary and Unusual Tumors of the Testis

Testicular Tumors Including Secondary and Unusual Tumors of the Testis Milton W. Datta Partner, Hospital Pathology Associates University of Minnesota Minneapolis, MN

Topics Review Features of Germ Cell Tumors Differential diagnosis Discuss staging issues Presence of Lymphatic/vascular invasion Serum markers Examine the use of immunohistochemistry Appropriate and judicial use

Testicular Tumors Germ Cell Tumors 88% Non-Germ Cell Tumors 12% Sertoli Cell Tumor Leydig Cell Tumor Sex Cord Stromal Tumor Spermatiocytic Seminoma Granulosa Cell Tumor Small Cell Carcinoma Carcinoid Lymphoma Secondary Tumors Other

Age related Younger male Germ cell tumors Older Male Lymphoma Secondary tumors

Younger Age Distribution Older 10 years 20 years 30 years 40 years 50 years 60 years Yolk Sac Teratoma Embryonal Carcinoma Seminoma Choriocarcinoma Sarcomatous degeneration Mixed Germ Cell Spermatocytic Seminoma Lymphoma Secondary tumors Granulosa Cell Tumor Granulosa Cell Tumor Large cell calcifying Sertoli cell tumor Dermoid cyst Sertoli Cell Tumor Leydig Cell Tumor Carcinoid Tumor Sex Cord Stromal Tumor

Testis Tumors Germ Cell Tumors 88% Seminoma 26% Embryonal Carcinoma 1% Yolk Sac Tumor < 1% Teratoma < 1% Choriocarcinoma < 1% Mixed 60% Non-Germ Cell Tumors 12%

Germ Cell Tumor Component Percentages Poor inter-pathologist agreement in percent of germ cell components Key elements that effect prognosis: Predominant Embryonal carcinoma Presence of Choriocarcinoma Presence of mature teratoma Presence of yolk sac tumor Pan-staining of tumors to determine percentages in not necessary

Need for Immunohistochemistry ISUP Recommendations Less than 5% of testicular tumor cases need immunohistochemistry Germ cell: SALL4, PLAP Embryonal carcinoma: Oct 3/4, CD30 Seminoma: Oct 3/4, CD117 Yolk Sac tumor: AFP, Glypican 3 Choriocarcinoma: bhcg, Glypican 3 1: Amin MB, et al. Best practices recommendations in the application of immunohistochemistry in urologic pathology: report from the International Society of Urological Pathology consensus conference. Am J Surg Pathol. 2014 Aug;38(8):1017-22. PubMed PMID: 25025364. 2: Ulbright TM, et al. Best practices recommendations in the application of immunohistochemistry in testicular tumors: report from the International Society of Urological Pathology consensus conference. Am J Surg Pathol. 2014 Aug;38(8):e50-9. PubMed PMID: 24832161.

Testis Cancer Staging : pt Key primary tumor staging; 1. Diffuse lymphatic/vascular invasion by tumor 2. Distinction between tunica albuginea and tunica vaginalis 3. Direct extension into spermatic cord 4. Scrotal wall 5. Tumor extension into rete testis (seminoma - radiation oncology) ptx Primary tumor cannot be assessed. pt0 No evidence of primary tumor (e.g., histologic scar in testis). ptis Intratubular germ cell neoplasia (carcinoma in situ). pt1 Tumor limited to the testis and epididymis without vascular/lymphatic invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis. pt2 Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis. pt3 Tumor invades the spermatic cord with or without vascular/lymphatic invasion. pt4 Tumor invades the scrotum with or without vascular/lymphatic invasion.

http://www.ansci.wisc.edu/jjp1/ansci_repro/lab/lab2/boar_tract/tunica_vaginalis.html http://faculty.une.edu/com/abell/histo/histolab3f.htm

Testis Cancer Staging : pn,m Lymph Node Metastasis determined by number of positive nodes (5 nodes) and metastasis size (2 cm, 5 cm) pnx Regional lymph nodes cannot be assessed. pn0 No regional lymph node metastasis. pn1 Metastasis with a lymph node mass 2 cm in greatest dimension and 5 nodes positive, none >2 cm in greatest dimension. pn2 Metastasis with a lymph node mass >2 cm but not >5 cm in greatest dimension; or >5 nodes positive, none >5 cm; or evidence of extranodal extension of tumor. pn3 Metastasis with a lymph node mass >5 cm in greatest dimension. Metastasis determined by site (distant lymph nodes, pulmonary metastasis) M0 No distant metastasis. M1 Distant metastasis. M1a Nonregional nodal or pulmonary metastasis. M1b Distant metastasis other than to nonregional lymph nodes and lung.

Testis Cancer Staging : ps - Key focus is residual disease (tumor spread/burden) implied by sustained serum marker elevation - Need serum marker values 30 days AFTER orchiectomy - Serum AFP half life: 4-5 days - Serum bhcg half life: 24-36 hours - Serum LDH half life: 10 hrs 3 days (isozymes, LDH-1) - Stratify into stage 1S (most cases) SX Marker studies not available or not performed. S0 Marker study levels within normal limits. S1 LDH <1.5 normal, and hcg (miu/ml) <5,000 and AFP (ng/ml) <1,000. S2 LDH 1.5 10 normal or hcg (miu/ml) 5,000 50,000 or AFP (ng/ml) 1,000 10,000. S3 LDH >10 normal or hcg (miu/ml) >50,000 or AFP (ng/ml) >10,000. 1. International germ cell cancer collaborative group. International germ cell consensus classification: A prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol. 1997;15:594 603.

Tumors by Histology Germ Cell Tumor Histology Seminomatous pattern Embryonal carcinoma pattern Mature Teratoma pattern Non-Germ Cell Tumor Histology Leydig pattern Sertoli pattern Granulosa cell pattern Lymphoma pattern Spindle cell pattern

Seminoma Mean 40.5 years, wide age range Sheets of cells Broad fibrous bands Lymphocytes, Tumor cells Large cells Clear to eosinophillic cytoplasm Large nuclei, open chromatin Prominent pink nucleolus

Variant features Pleomorphic anaplastic nuclei Limited inflammatory components

Seminoma pattern Melanoma

Secondary tumors of the testicle Uncommon, but present, over 350 cases reported. Majority are surgical specimens 2/3 cases this was the only metastasis 21 cases was the presenting finding Long intervals, up to 16 years Not always bilateral (5%) Wide age range (8 months to 89 years, mean 57.4 years) Colonic (mean 52 years, 18-76) Prostatic (mean 69 years, 47-89)

Melanoma 47 years (28-78) Cases as presentation Many amelanotic. Melanospermia Outcome up to 12 months 1: Datta MW, Young RH. Malignant Melanoma Metastatic to the Testis: A Report of Three Cases with Clinically Significant Manifestations. Int J Surg Pathol. 2000 Jan;8(1):49-57. PubMed PMID: 11493964.

Seminoma Pattern Renal cell carcinoma

Renal Cell Carcinoma Age 35 87 yrs. Second most common as an initial presentation All unilateral Clear cell type Survival up to 2 years 1: Datta MW, Ulbright TM, Young RH. Renal cell carcinoma metastatic to the testis and its adnexa: a report of five cases including three that accounted for the initial clinical presentation. Int J Surg Pathol. 2001 Jan;9(1):49-56. PubMed PMID: 11469344.

Metastasis: Tools for Separation Seminoma / Melanoma / Renal Cell Carcinoma IGCNU Any pigment? (Melanoma / Leydig) Lace-like vascular network (RCC) Stains Oct 3/4, C-kit, PLAP S100, Melan A, MART-1 Pax-8 (Renal cell carcinoma) Inhibin (Sertoli)

Embryonal Carcinoma Sheets and Glands Interspersed loose to embryonic stroma Limited inflammatory infiltrate Dirty Necrosis Large cells, single cell necrosis Poorly defined cytoplasmic borders Pleomorphic overlapping nuclei

Embryonal Carcinoma Pattern Gastric CA

Gastric Carcinoma 11 cases Mean 42 yrs (12-62) Grey-white masses Fibrotic Survivial 1-12 months Peritoneal carcinomatosis 1: Qazi HA, Manikandan R, Foster CS, Fordham MV. Testicular metastasis from gastric carcinoma. Urology. 2006 Oct;68(4):890.e7-8. PubMed PMID: 17070383. 2: Muir GH, Fisher C. Gastric carcinoma presenting with testicular metastasis. Br J Urol. 1994 Jun;73(6):713-4. PubMed PMID: 8032845. 3: Haupt HM, Mann RB, Trump DL, Abeloff MD. Metastatic carcinoma involving the testis. Clinical and pathologic distinction from primary testicular neoplasms. Cancer. 1984 Aug 15;54(4):709-14. PubMed PMID: 6204734.

Carcinomas in Teratoma? Ovary: Dedifferentiation into carcinomas Squamous cell carcinoma Adenocarcinoma Testis: Dedifferentiation into Carcinomas Rare 31 cases described (32 year period at Indiana Univ) Poor response to chemotherapy Histology stage, grade did not affect outcome 1: Rice KR, et al. Management of Germ Cell Tumors with Somatic Type Malignancy: Pathological Features, Prognostic Factors and Survival Outcomes. J Urol. 2014 Jun 18. PubMed PMID: 24952240.

Embryonal Carcinoma Pattern Choriocarcinoma

Embryonal Carcinoma Pattern Angiosarcoma

EC vs Angiosarcoma 1: Steele GS, Clancy TE, Datta MW, Weinstein M, Richie JP. Angiosarcoma arising in a testicular teratoma. J Urol. 2000 Jun;163(6):1872-3. PubMed PMID: 10799210.

Sarcomatoid Degeneration Present in 3-4 percent of germ cell tumors 12-41 years Types Rhabdomyosarcoma Chondrosarcoma Osteosarcoma Angiosarcoma Clinical: Definitive surgery is the best hope 1: Motzer RJ, et al. Teratoma with malignant transformation: diverse malignant histologies arising in men with germ cell tumors. J Urol. 1998 Jan;159(1):133-8. PubMed PMID: 9400455. 2: Donadio AC, et al. Chemotherapy for teratoma with malignant transformation. J Clin Oncol. 2003 Dec 1;21(23):4285-91. PubMed PMID: 14645417.

Rhabdomyosarcoma

Sarcoma: Tools for Separation Sarcomatous differentiation Defined sarcomatous elements Areas of residual mature teratoma, germ cell tumor Rhabdomyosarcomatous Desmin

Immature Teratoma? Primitive Neuroectodermal tumor only Important in the ovary (4 HPF) drops prognosis from 95% to 80% post treatment survival NOT important in the testis Does not affect survival or response to treatment 1: Ulbright TM. Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol. 2005 Feb;18 Suppl 2:S61-79. Review. PubMed PMID: 15761467. 2: Ulbright TM. Gonadal teratomas: a review and speculation. Adv Anat Pathol. 2004 Jan;11(1):10-23. Review. PubMed PMID: 14676637.

Late Recurrence in Germ Cell Tumors Indiana University two years after initial treatment (91 cases) 22% teratoma alone (best outcome) 40% teratoma + germ cell tumor 20% pure non-teratoma germ cell components; embryonal carcinoma, yolk sac tumor 18% non-germ cell tumor; sarcoma, carcinoma Worse prognosis: Pure non-teratoma, Non-germ cell tumor 83% w/disease, 37% alive at 4.7 years avg 1: Michael H, Lucia J, Foster RS, Ulbright TM. The pathology of late recurrence of testicular germ cell tumors. Am J Surg Pathol. 2000 Feb;24(2):257-73. PubMed PMID: 10680894.

Epidermoid Cyst 2 nd -4 th decades Isolated epithelial features Epidermal elements Fibrous stroma No IGCNU Teratoma PLAP, p53, Oct 3/4 https://www.radiology.wisc.edu/cow/imagevault/cow167-2.jpg

Epidermoid Cyst

Mature Teratoma in MMGCT

Leydig Cell Tumor 1-3% testis tumors Any age Gynecomastia (15%) Interstitial tumor Uniform small cells Eosinophillic cytoplasm Uniform nuclei Small nucleoli Inhibin

Leydig pattern

Malignancy in Leydig cell tumors No clear-cut indicators of malignancy besides metastatic spread Features more often associated with malignancy: Infiltrative tumor borders Vascular invasion by tumor Nuclear atypia Tumor necrosis High mitotic rate Lack of lipofuscin pigment. 1: Al-Agha OM, Axiotis CA. An in-depth look at Leydig cell tumor of the testis. Arch Pathol Lab Med. 2007 Feb;131(2):311-7. Review. PubMed PMID: 17284120.

Malignant Leydig 15% Prostate cancer

Most common metastasis to testis Therapeutic orchiectomy Mean 69 yrs Range 47-89 10% bilateral Survival 6-18 months Prostate Cancer

Variant features Glandular formation Gleason progression Nuclear pleomorphism Two-cell component Leydig cells tumor cells Nkx3.1, PSA, PAP Leydig: Inhibin 1: Benchekroun A, et al.[testicular metastasis of prostatic adenocarcinoma. Report of a case]. Ann Urol (Paris). 2001 Jul;35(4):234-6. Review. French. PubMed PMID: 11496601.

Sertoli Cell Tumor (NOS) All ages (mean 46 yrs) Solid to hollow tubules, nests Scant fibrous stroma Sclerosing Large cell Calcifying Clear (lipid) to eosinophillic cytoplasm Mild nuclear pleomorphism 1: Young RH. Sex cord-stromal tumors of the ovary and testis: their similarities and differences with consideration of selected problems. Mod Pathol. 2005 Feb;18 Suppl 2:S81-98. Review. PubMed PMID: 15502809.

Sertoli Cell Pattern Sertoli cell tumor Carcinoid

Carcinoid Tumor 35% teratomatous 65% pure Mean 36 yrs (12-65) Carcinoid syndrome rare Overall benign (4.3 yrs f/u) NSE, Chromogranin, Synaptophysin 1: Wang WP, et al. Primary carcinoid tumors of the testis: a clinicopathologic study of 29 cases. Am J Surg Pathol. 2010 Apr;34(4):519-24. PubMed PMID: 20351489.

Granulosa Cell Tumor Rare, 45 cases Mean 40 years (14-87 yrs) Gynecomastia Microfollicles, Sheets Small, uniform cells Nuclear grooves Minimal cytoplasm Discohesive 1 sarcomatous degeneration, 1 metastasis (4.1 yr f/u) 1: Cornejo KM, Young RH. Adult granulosa cell tumors of the testis: a report of 32 cases. Am J Surg Pathol. 2014 Sep;38(9):1242-50. PubMed PMID: 24705318. 2: Schubert TE, et al. Adult type granulosa cell tumor of the testis with a heterologous sarcomatous component: case report and review of the literature. Diagn Pathol. 2014 Jun 3;9:107. PubMed PMID: 24894598

Granulosa Cell Pattern Granulosa cell tumor Small Cell Carcinoma

Small Cell Carcinoma Mean 55 yrs Range 47-73 yrs Lung, esophagus, stomach, Merkel cell Changes chemotheraputic options 1: Rosser CJ, Gerrard E. Metastatic small cell carcinoma to the testis. South Med J. 2000 Jan;93(1):72-3. PubMed PMID: 10653072. 2: Kravitz JR, Ridlen MS. Imaging of an oat cell metastasis to the testicle: case report and review of the literature. J Clin Ultrasound. 1990 Feb;18(2):121-3. Review. PubMed PMID: 2156905.

Lymphoma 5% of all testis tumors Mean 58 yrs (46-76 yrs) 38% bilateral Diffuse large B-cell type Median survival 36 mo 1: Lokesh KN, et al. Primary Diffuse large B-Cell lymphoma of testis: A single centre experience and review of literature. Urol Ann. 2014 Jul;6(3):231-4. PubMed PMID: 25125896

Lymphoma pattern leukemia

Leukemia Associated with Acute (64%) and chronic (22%) leukemias Can be a sign of recurrence (ALL) Overlaps with plasmacytic tumors 1: McIlwain L, et al. Acute myeloid leukemia mimicking primary testicular neoplasm. Presentation of a case with review of literature. Eur J Haematol. 2003 Apr;70(4):242-5. Review. PubMed PMID: 12656749.

Spermatocytic Seminoma Often over 50 yrs, rare under 30 Lack of uniform cells Three cell types large, medium, small Spermatogonia, primary spermatocytes, No inflammatory infiltrate (LCA) Oct3/4, PLAP, Glypican 3 negative Testicular tumors, R.H.Young, ASCP Press

Testicular tumors, R.H.Young, ASCP Press

Splenogonadal Fusion Left testis mass, upper pole Continuous, discontinuous Undescended testis or hernia operation

Spindle Cell Pattern Rare in the testis Testicular fibroma Sex cord stromal tumors Fasicles, broad bands Spindled morphology Mild to moderate nuclear pleomorphism Seen in melanoma, renal cell carcinoma

Spindle cell pattern Spindle sertoli cell Spindle RCC

Acknowledgements Robert Young, Mass. General Hospital Tom Ulbright, Indiana Univ Mahul Amin, Cedars Sinai Medical Center Michael Whittaker, Community Memorial Hospital Doug Chausow, Community Memorial Hospital