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PROSTATE AND TESTIS “A Coin Has Two Sides”, The Duality Of Male Pathology

• Jaime Furman, M.D. • Pathology Reference Laboratory San Antonio. • Clinical Assistant Professor Departments of Pathology and , UT Health San Antonio.

Source: http://themoderngoddess.com/blog/spring‐equinox‐balance‐in‐motion/

I am Colombian and speak English with a Spanish accent! o Shannon Alporta o Lindsey Sinn o Joe Nosito o Megan Bindseil o Kandace Michael o Savannah McDonald

Source: http://www.taringa.net/posts/humor/7967911/Sindrome‐de‐la‐ Tiza.html

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The Axial view

Base Apex

Middle

Apex Sagittal view

Reference: Vikas Kundra, M.D., Ph.D. , Surena F. Matin, M.D. , Deborah A. Kuban, M.Dhttps://clinicalgate.com/prostate‐cancer‐4/

Ultrasound‐guided following a specified grid pattern of remains the standard of care. This approach misses 21% to 28% of prostate .

JAMA. 2017;317(24):2532‐2542.

http://www.nature.com/nrurol/journal/v10/n12/abs/nrurol.2013.195.html

Prostate Pathology / Categories Adenosis, radiation, atrophy seminal vesicle Biopsy Benign

TURP HGPIN

Unsuspected is seen in 12% of Atypical IHC TURP cases. glands

Prostatectomy Subtype, Gleason, Malignant invasion, vascular invasion

Other : sarcomas, lymphomas

Benign Prostate Remember Malignant Glands Lack Basal Glands Cells

Basal cells

Secretory cells

Stroma

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Benign Prostatic Atrophy Corpora amylacea (secretions)

Seminal Vesicle Acute inflammation

GMS

Basal cell hyperplasia Basal cell hyperplasia Granulomas (BPH) (BPH) coccidiomycosis

Mimics of Prostate Carcinoma

Atrophy. Benign Carcinoma with atrophic features

Prostate Carcinoma

1. Prostate is the most common, noncutaneous cancer in men in the . 2. In 2017, approximately 160,000 men will be diagnosed with . 3. Remains the third‐leading cause of cancer death in men.

The indolent course of many tumors and the potential for adverse treatment effects have generated controversy regarding the utility of and early detection.

The diagnosis of prostate cancer is based on the microscopic evaluation of prostate tissue obtained via needle biopsy.

http://www.medscape.org/viewarticle/710056 JAMA. 2017;317(24):2532‐2542.

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Source: Source: Wikipedia How To Make The Wallpapercave Histologic Diagnosis Of Prostate Carcinoma

Low power High Prominent power nucleoli

Carcinoma involving 5% of the biopsy

The Histologic Features of Prostate Carcinoma

Architecture Small glands Sometimes large Infiltrating glands

Gland Appearance Round or angulated glands Rigid lumen Blue mucin Purple cytoplasm Basal cells absent Important to understand IHC Cytology Large nuclei and nucleoli

Tumor Invasion perineural , vascular, fat, extension and other organs

Remember in difficult lesions: 1. Levels 2. Immunohistochemical stains (IHC) ( judicious application) 3. Consultation (second opinion)

Terminology

1 1. Gland 2. Lumen 3. Nuclei 4. Nucleoli 5. Stroma

3,4

5 2

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Malignant gland Malignant invading a gland Prostate Carcinoma

Blue mucin Rigid lumen

Nerve

Common finding seen 11— 37% of biopsies

Vascular Invasion

Special Stains Are Benign Prostate Glands Helpful In a Difficult Diagnosis Cancer

Benign Basal cell stain brown. Secretory cells and stroma without staining (blue)

Stain: Pin 4 cocktail Stain: High molecular weight immunostain cytokeratin

Remember: Carcinoma lacks basal cells and The Precursor: High Grade HGPIN has basal cells Intraepithelial Neoplasia Malignant glands (HGPIN)  Incidence in biopsies 7%  Does not raise PSA  Higher risk for carcinoma if HGPIN involves HGPIN several cores

HGPIN Basal cells

The cells contain large nuclei with nucleoli similar to carcinoma

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Reporting Discontinuous Foci Of Prostate Carcinoma

Red=tumor

= mm. Option 1 + +

Option 2 = mm.

• Discontinuous involvement by prostate carcinoma is common • Two methods for measuring the discontinuous foci: 1. Adding each foci Report includes 2. Assessing discontinuous foci as a single focus a diagram • Reported as % and mm of tumor

Source: Dr. Ming Zhou, USCAP Conference. San Antonio, March 2017.

The Gleason System. The Gleason score assigned to a case of prostate cancer is an important prognostic indicator that guides therapeutic decisions. A Practical Approach Prostate carcinoma usually has > two patterns

Steps: 1 1. Confirm the histologic diagnosis of cancer 2. Match the pattern(s) with a specific Gleason grade 2 3. Decide which pattern is more common (primary pattern) and the second most common pattern (secondary pattern) 4. Add the primary and secondary pattern (Gleason score) 5. Assign the Gleason group (new) 3 Biopsy core 4 Gleason 3 (60%) Gleason 4 (40%) 5

Original (initial) Modified 2015 by Dr. Gleason

Reference: Am J Surg Pathol. 2016 Feb;40(2):244‐52. GLEASON 3+4 = GLEASON SCORE 7

Gleason Grade 3 Gleason Grade 4 Gleason Grade 5

Individual malignant glands Fusion & ragged edges Haphazardly arranged cells, individual cells, Invading between benign glands signet ring cells Gleason clinical significance Overall, Gleason scores of 6–7 with • Grade is a strong predictor of invasiveness and metastatic potential embedded pattern 3 are the most • Not reliable when used alone to predict outcome common histologic grades of prostatic • Clinically, needle biopsy Gleason grade is usually combined with other . pretreatment factors, such as serum total PSA, % free PSA, local clinical T stage, and amount of tumor in needle biopsy, to predict pathologic stage

Reference: Am J Surg Pathol. 2016 Feb;40(2):244‐52.

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Gleason Grade

Signet ring nuclei

Grade 3 Grade 5

1+1 1+2 1+3 1+4 1+5 2+1 70% Gleason grade grade 3 combinations not in use 2+2 2+3 2+4 2+5 3+1 4+1 5+1 3+2 4+2 5+2 Possible Gleason grade 3+3 3+4 3+5 4+3 combinations 4+4 4+5 5+3 5+4 5+5 Example 1 Gleason 4 3 90% 10% 4+3 Example 2 Gleason 4 3 Lower grade <5% 97% 4+4

Example 3 Gleason 3 Higher grade <5% 97% 4 3+4

Example 4 30% Gleason 3 Gleason 5 grade 4 50% 50% 5+5

Example 5 Gleason 4 100% 4+4 Final Gleason score ? Source: Dr. Ming Zhou, USCAP Conference. San Antonio, March 2017.

The new grading system is based on the modified (2005 and 2014) Gleason score groups, resulting in 5 prognostically distinct GRADE GROUPS

BEST PROGNOSIS A multi‐institutional study, based upon 2005 grading 3+3 GRADE GROUP 1 criteria was undertaken with , Memorial Sloan‐Kettering Cancer Center (MSKCC), University of Pittsburgh, Cleveland Clinic, and the Karolinska Institute to validate 3+4 GRADE GROUP 2 the new grading system. * Increased probability of recurrences 4+3 * GRADE GROUP 3 Biochemical recurrence‐free progression after Radical 4+4 GRADE GROUP 4 stratified by grade 1. Green line —Gleason score 6 [grade group1]. (best prognosis] 4+5 2. Orange—Gleason score 3+4 [grade group 2], 3. Dark blue —Gleason score 4+3 [grade group 3], GRADE GROUP 5 5+4 4. Brown—Gleason score 8[grade group 4], 5. Gray—Gleason score >9 [grade group 5] (worst prognosis) 5+5 WORST PROGNOSIS Reference: Am J Surg Pathol. 2016 Feb;40(2):244‐52.

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New Grading Grading Subjectivity System. Why? Gleason grading has an inherent level 1. Gleason scores 2 to 5 are currently no longer assigned of subjectivity, depending on individual interpretations 2. In practice, the lowest score now assigned is 6. This leads to a logical yet incorrect assumption on the part of patients of an expectation that definite treatment is always necessary.

3. Separate 3+4 V.s 4+3 Studies of intraobserver variability demonstrate agreement in up to 78% of cases; therefore, at least 22% of cases may be reread by the same pathologist as a different Gleason score. Source: Am J Surg Pathol. 2016 Feb;40(2):244‐52. Source picture: https://www.linkedin.com/pulse/violence‐mindlessness‐subjectivity‐ jayashree‐mukherjee

Multiple Biopsy Cores With Different Gleason Assign a Composite Gleason To All Grade Positive Biopsy Cores Submitted In The Same Container 3+3 3+3

APEXEX A Only 1 container with Benign 3+4 4 core biopsies

MIDD

Benign 3+4 A

BAEXSE

A B C D 3+3 4+3

Final Gleason: 4+3

E F Assign individual Gleason to different cores as long as cores are submitted in separate containers

Source: Dr. Ming Zhou, USCAP Conference. San Antonio, March 2017.

Prostatectomy With Multiple Tumor Nodules Showing Different Gleason

3+3 Dominant 4+4 nodule 4+4 3+3

o Dominant nodule is Final Gleason reported reported 3+3 and small nodule o Not necessary to report the 4+4 small nodule (3+3) o Final Gleason: 4+4 1. ALWAYS REPORT THE DOMINANT NODULE 2. Report the secondary nodule only if contains high grade Gleason grade

Source: Dr. Ming Zhou, USCAP Conference. San Antonio, March 2017.

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T1 clinically Clinical unapparent non palpable

T2 Tumor is palpable and confined within prostate

T3 Extraprostatic tumor that does not invade adjacent structures

For tumor confined to the prostate there is only 1 pathology category =pT2

T4 tumor invades adjacent Diagram reference: Vikas Kundra, M.D., Ph.D. , Surena F. structures other than seminal Matin, M.D. , Deborah A. Kuban, M.D vesicles: , bladder, pelvic https://clinicalgate.com/prostate ‐cancer‐4/ Reference: AJCC , Manual 8th Edition wall

The Stage

I

I IIA IIA IIB IIC IIIA IIIB IIIC IVA IVB

Reference: AJCC , Cancer Staging Manual 8th Edition

The Stage

Gross bladder neck • Microscopic bladder involvement involvement T4 • Presence of cancer glands within smooth bundles of bladder Reference: AJCC , Cancer Staging Manual 8th neck without benign glands Edition • Staged as pT3a no pT4

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Staging Radical Prostatectomy Source:http://www.avidphone.co m/change‐part‐i/ (AJCC 8th)

Summary Of Changes Between 7th And 8th AJCC Cancer Staging: 1. Pathologically confined disease is pT2 and no longer subclassified by extent or laterality 2. The Gleason score and grade T2 substaging. AJCC 7th NoT2 substaging in AJCC 8th group are reported 3. Stage III includes select T2a T2b T2c T2 confined disease based on PSA T2 T2 and Gleason group status

Involves more than one Involves one half of one Tumor involves both sides half of one side but not side or less Reference: AJCC , Cancer Staging Manual 8th Edition both sides

5‐10mm Submit The Entire Gland

Anterior part is rounded

Seminal vesicles insert posterior Bladder neck

Posterior part Apex is is flat cone shape

1.Review the previous biopsy history. 2.Slice 3 mm periurethral section from distal (apical) resection margin. (Serially section and submit) 3.Slice 3 mm periurethral section from proximal (basal) resection margin (Serially section and submit) 4.Serially section the remaining prostate from apex to base, in 3 mm slices perpendicular to urethral axis. 5.Identify where cancer (firm, yellow, indurated) comes closest to capsule or margins. 6.Submit every other slice in halves, quarters, sixths, or eighths, depending on the size of the cross section 7.Serially section and submit representative bilateral and vasa deferentia.

https://grosspathology‐sites.uchicago.edu/page/prostate

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Extraprostatic Extension • Ink the margins BPH EPE (T3) • Different • Prostate has no true capsule colors • At the periphery has a condensed fibromuscular layer • EPE: is defined as cancer beyond confines of prostate gland (at the level or beyond fat) • Location and extent should be documented Carcinoma (focal and non focal)

EPE: Prostate tumor in adipose tissue Source: https://grosspathology‐sites.uchicago.edu/page/prostate

• Positive margin carcinoma at ink margin • Only in

Initial biopsy with small focus of PIN stain If tumor is not seen in the sections carcinoma in 1/12 Initial biopsy from a prostatectomy, what to do? core biopsies 1. Don’t panic 2. Make sure all tissue is submitted 3. Confirm that there is no patient misidentification 1. Perform a single deep H&E recut from each block 2. Cut several levels from the positive area (left lateral apex) 3. Review the initial biopsy

3 months later PIN stain Prostatectomy with Prostatectomy small tumor (1%)

Source: https://www.aspirecqi.org/calendar

Risk Stratification Schema for Prostate Cancer

National Comprehensive Cancer Network Risk Stratification7 •Very low risk • Clinical stage of T1c, Gleason score of 6 or less, prostate‐specific antigen (PSA) level of less than 10 ng/mL, less than 3 biopsy cores with cancer presence of 50% or less in each core, and PSA density of less than 0.15 ng/mL/g •Low risk • Clinical stage of T1 to T2a, Gleason score of 6 or less, and PSA level of less than 10 ng/mL •Intermediate risk Clinical stage, Gleason PSA, % of • Clinical stage of T2b to T2c, Gleason score of 7, or PSA level of 10 to 20 ng/mL •High risk cancer in biopsies, PSA density • Clinical stage of T3a, Gleason score of 8 to 10, or PSA level greater than 20 ng/mL •Very high risk • Clinical stage of T3b to T4, primary Gleason pattern 5, or greater than 4 biopsy cores with Gleason score of 8 to 10

Prostate Cancer Nomograms •Calculates probability (0%‐100%) of extent of disease, biochemical recurrence, cancer‐specific survival based on: age, PSA level, clinical stage, Gleason score, percentage of biopsy cores involved with cancer Clinical stage, Gleason PSA, % of cancer in biopsies Cancer of the Prostate Risk Assessment •Scoring system from 0 to 10 based on age, PSA level, Gleason pattern 4 or 5, clinical stage, percentage of biopsy cores involved with cancer • Low risk score: 0‐2 Clinical stage, Gleason PSA, % of • Intermediate risk score: 3‐5 cancer in biopsies • High risk score: 6‐10

Pathologic Grading System of the International Society of Urological Pathology Groups 1 to 5 Gleason

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• Given the indolent course of many prostate cancers AS has emerged Eligible For Active as an initial management alternative. Surveillance (AS) • On AS, men avoid the side effects of prostate cancer treatment. • Under most AS strategies, patients undergo careful monitoring of the cancer, most often with PSA kinetics and serial biopsies VERY LOW RISK LOW RISK 1. cT1c (non palpable) 2. Gleason score ≤ 6 1. cT1 to cT2a 3. Serum PSA < 10ng/ml 2. Gleason score ≤ 6 4. Fewer than 3 prostate 3. Serum PSA <10ng/ml biopsy cores positive, ≤ 50% cáncer in each core

A finding of upgrading cancer on repeat biopsy commonly prompts treatment. Beyond grade, other biopsy parameters used to signify progression include an increase in the volume of prostate cancer based on the number of involved cores or the percentage of involvement within an individual biopsy core.

Most current programs use an increase in Gleason score to 7 or more as one of the criteria to recommend interventional therapy for men on AS.

Reference: Archives of Pathology & Laboratory Medicine 2014 138:10, 1387‐1405

Source: Meditation Testicular garden.net “Mediation” Pathology

Testis Anatomy

Epididymis

Hilar soft tissue Rete Testis

Source: http://knowledge.statpearls.com/chapter/nurse‐ anatomy/33979/ Contributed Illustration by Beckie Palmer

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Testicular / Adnexal Structures

Rete testis: lines spaces that drain through the efferent into the epididymis

Source diagram: : https://www.pinterest.com/pin/397090 892130231783/

Spermatogenesis

Secondary

Sperm cell

Primary Spermatocyte

Spermatogonia

Sertoli cell Source: Canadian academy Ferguson biology. SL/HL‐1 Biology (5) Ferguson

Source: http://tunisia‐surf.info/key/p/words‐pituitary‐gland‐ Sertoli and Leydig cells ‐diagram.asp

Seminiferous tubules Leydig cells FSH/LH

Sertoli cell ‐ Sertoli cells Testis (Sertoli only) + Sertoli cell Leydig cell

Leydig cells ()

Sertoli cells (sperm)

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Tunica Albuginea Testis and Vaginalis Parenchyma Epidydimis

Testis

Tunica vaginalis

Vas Deferens

The testes are wrapped by two sheets Tunica Tumor albuginea Tunica Vaginalis

1. The tunica albuginea is the fibrous covering of the testis. 2. The tunica albuginea is covered by the tunica vaginalis Tunica Vaginalis

The Testis is Opened Like a Book Grossing the Testis

There Are Two Major Categories Of Testicular Tumors Classification Germ Cell Tumors

I. Germ Cell Derived: 90—95% testicular tumors

II. Non‐germ Cell Derived : 2‐5% (in adults but 25% in children) Include: o Sex cord stromal tumors (Sertoli cell tumors, Leydig cell tumors, Granulosa cell tumors (adult and juvenile) Not discussed in o Ovarian type testicular tumors this o Hemangiomas conference o Hematolymphoid tumors o Metastatic tumors

Reference:

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World Health Organization (WHO) Classification of Germ Cell Tumors

 Germ Cell Tumors Derived From  Germ Cell Tumors Unrelated to Germ Cell Neoplasia In Situ Germ Cell Neoplasia In Situ

 Germ cell neoplasia in situ (GCNIS)  Spermatocytic tumor  Tumor one histologic type (40%)  prepubertal type   Dermoid  Epidermoid cyst  Yolk sac tumor,(YST) postpubertl  Well differentiated type  Teratoma postpubertal   Choriocarcinoma Mixed teratoma and yolk sac tumor  Tumors of more than one histologic type prepubertal (60%) Yolk sac tumor prepubertal  Mixed germ cel tumors Regressed germ cell tumors The five germ cell tumors to remember: 1.Seminoma 2.Embryonal Carcinoma 3.Yolk Sac Tumor 4.Teratoma 5.Choriocarcinoma

Epidemiology of Germ Cell Tumors Risk Factors 1. 1% of male worldwide 1. Family history 2. Most common cancer for white males between puberty and 2. Previous 40s in industrialized nations 3. Undescended testis 3. USA: incidence 6.6/100,000 (whites) , 1.2/100,000 (blacks) 4. Occupational (pesticides) 4. The incidence has increased in the last 40 years worldwide 5. Marijuana use (frequent)

CONCLUSIONS: ’The strongest association was found for non-seminoma development--for example, those using cannabis on at least a weekly basis had two and a half times greater odds of developing a non- seminoma’

Reference: Gurney et al. BMC Cancer 2015,15

http://www.medindia.net/patients/patientinfo/testicular‐cancer.htm

Embryonic Gonocyte Spermatogonia Spermatocyte Pathogenic GCNIS cells are derived from gonocytes that failed Model to differentiate into spermatogonia

Sex determination Birth Puberty Non Seminoma 1. Embryonal Normal maturation sperm carcinoma 2. Yolk sac tumor (YST) Polyploidization postpubertal 3. Teratoma 4. Choriocarcinoma

Chromosomal gain or loss Seminoma and Germ cell neoplasia in situ (GCNIS)

1. Prepubertal teratoma and yolk GCNIS unrelated sac tumor 2. Spermatocitic seminoma

Source: www. Alamy.com

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Germ Cell Neoplasia In Facts to know Situ (GCNIS) 1. Precursor to all germ cell tumors (exception The tubules contain abnormal spermatocytic seminoma cells replacing the normal cells and prepubertal teratoma) 2. Present in most germ cell tumors 3. Progression to invasive disease is 5 years (?)

References:

Germ Cell Tumors With One Histologic Type vs. More Than One Histologic Type (Mixed) More Than One Histologic Type (Mixed)

One Histologic type (Pure) 1. Seminoma 2. Embryonal carcinoma 3. Yolk sac tumor 4. Teratoma 5. Choriocarcinoma

Source: AliExpress.com Embryonal • 70% of germ cell tumors • Most common combination: embryonal carcinoma with Source: Clipart Library teratoma, seminoma and yolk sac • Most common pure tumor tumor • Any combination can be seen is seminoma • Average presentation is 30 years • Occasionally embryonal old carcinoma • Percentages of different elements • Pure postpubertal yolk sac in mixed germ cell tumors should Yolk sac tumor Teratoma very rare (0.6%) be reported

Pure 1. Seminoma Tumors

 Solid Seminoma with  Homogeneous syncitiotrophoblast  Cream coloured that produces hCG  lobulated Facts to know 1. Makes 40% of all germ cell tumors 2. Presents in the 4th decade 3. 10‐20% contain syncitiotrophoblast with mild elevation of serum HCG 4. NO AFP production

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2. Embryonal Carcinoma FACTS TO REMEMBER 1. Age: 20s‐30s 2. Rare as a pure tumor Frequently mixed with other GCT’s (40%) 3. Poorly demarcated variegated with areas of hemorrhage 4. Cells are large and hyperchromatic 5. More aggressive than seminoma (10% patients present with metastatic disease) 6. Retroperitoneal LN involvement is common

3. Yolk Sac Tumor FACTS TO REMEMBER 1. Most common testicular tumor of infants and children (up to 3 years) 2. In children has a good prognosis 3. Pediatric are predominately pure 4. In adults the pure form is rare and is frequently seen mixed with embryonal carcinoma 5. Alpha Fetoprotein elevated

FACTS TO REMEMBER 4. Teratoma 1. Contain elements derived from different Muscle embryologic origins Squamous 2. This means it can make any tissue found in epithelium the human body (cartilage, epithelium, fat , neural elements) Keratin 3. Well differentiated, are referred to as mature 4. Incompletely differentiated (fetal tissues) Gland are referred to as immature 5. Prepubertal: always benign, pure not associated with GCNIS 6. Postpubertal: always mixed, malignant and associated with GCNIS

5. Choriocarcinoma FACTS TO REMEMBER HCG stain 1. Most aggressive germ cell tumor 2. Early metastases, many to the brain 3. Elevated HCG (no AFP) 4. Pure is rare, seen in mixed tumors Positive 5. Has two types of cells: syncitiothrophoblast syncitiotrophoblasts and cytotrophoblasts Throphoblast 6. Hemorrhage background

Syncitiothrophoblast

Hemorrhage

FACTS TO REMEMBER Regressed tumor “ burn out” 1. Germ cell tumors that have undergone partial or complete regression leaving behind a nodular focus of scar 2. Less than 5% undergo regression 3. Presentation metastases or pain 4. Histology fibrotic nodule, calcifications 5. Most important differential is non neoplastic scar 6. Detection of GCNIS is crucial for the diagnosis 7. Present as high stage tumors

Fibrotic nodule

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Testis Stage AJCC 8th Edition

Remember: tumor smaller than 3 cm pT1a and larger than 3 cm pT1b Source: http://www.cap.org/

Testis Stage AJCC 8th Edition

pT1 Tumor invading the

Invasion of hilar soft tissue

Tumor limited to the testis (including rete Tumor limited to testis (including rete testis) testis invasion) without lymphovascular with lymphovascular invasion or tumor invasion. Tumor may invade into the tunica invading hilar soft tissue, epididymis albuginea (not in the tunica vaginalis)

Tumor invading the pT2

Tumor invading the external surface of the tunica albuginea with or without lymphovascular invasion

Vascular invasion (LVI)

Seminoma confined to the testis Measures 3.8 cm in maximum dimension pT1b pT1: Tumor may invade into the tunica albuginea (not in the tunica vaginalis)

Mixed germ cell tumor with embryonal carcinoma, yolk sac tumor and seminoma pT2: Tumor limited to the testis with lymphovascular invasion

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pT2: Tumor invading the Artifacts that can alter the staging of testicular tumors epidydimis True pT2 False pT2

The assessment of vascular invasion is often difficult. The problem is not whether the tumor is in a vessel, but whether it is an artifactually displaced tumor or genuine. Picture from: American Journal of Surgical Pathology . 41(6):e22‐e32, June 2017 1. Tumor in external surface of the tunica vaginalis (False positive margin, pT2?) 2. Due to dull blade and excessive force during grossing

Picture from: American Journal of Surgical Pathology . 41(6):e22‐e32, June 2017

References

Books

1. Litwin M. The Diagnosis and Treatment of Prostate CancerA Review. JAMA 2017;317(24):2532‐2542. 2. Vikas Kundra, M.D., Ph.D. , Surena F. Matin, M.D. , Deborah A. Kuban, M.D 3. https://clinicalgate.com/prostate‐cancer‐4/ 4. Epstein et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. Am J Surg Pathol. 2016 Feb;40(2):244‐52 5. Oleksandr N. Kryvenko, et al. Prostate Cancer Grading: A Decade After the 2005 Modified . Archives of Pathology & Laboratory Medicine 2016 140:10, 1140‐1152 6. M. Scott Lucia, Comparison of Classic and International Society of Urological Pathology 2005 Modified Gleason Grading Using Needle Biopsies. Archives of Pathology & Laboratory Medicine: December 2013, Vol. 137, No. 12, pp. 1740‐1746. 7. https://grosspathology‐sites.uchicago.edu/page/prostate 8. http://knowledge.statpearls.com/chapter/nurse‐anatomy/33979/. Contributed Illustration by Beckie Palmer 9. Amin, Mahul et al. Archives Pathology and Laboratory medicine. The Critical Role of the Pathologist in Determining Eligibility for Active Surveillance as a Management Option in Patients With Prostate Cancer. Archives of Pathology & Laboratory Medicine 2014 138:10, 1387‐ 1405 10. Verrill, Clare; Reporting and Staging of Testicular Germ Cell Tumors: The International Society of Urological Pathology (ISUP) Consultation Conference Recommendations. American Journal of Surgical Pathology . 41(6):e22‐e32, June 2017 11. http://www.pathologyoutlines.com 12. Vitale I, et a. Illicit survival of cancer cells during polyploidization and depolyploidization. Cell Death and Differentiation (2011) 18, 1403–1413

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