TRANSITIONAL CELL CARCINOMA UPPER TRACT

Dr Jaynil A. Bagawade

MS, DNB Urology

Introduction Etiology Clinical Features Imaging Diagnosis Confirmatory Diagnosis Staging Risk stratification Treatment Guidelines Radical Nephroureterectomy Management of Bladder Cuff Lymphadenectomy Conservative Surgical Approaches Mx of upper tract positive cytology/CIS Adjuvant Therapy Treatment of Metastaic Disease Follow up protocol

Transitional Cell Carcinoma

Originates from Transitional epithelium of urinary tract.

Most common in urinary bladder, then in renal

pelvis, least in ureter(125:2.5:1) 5-10% of upper urinary tract neoplasms. Renal TCC most common --extrarenal part of the

pelvis, followed by the infundibulocaliceal region 2%–4% ---bilaterally.

Relation with Bladder TCC

Upper tract TCC after bladder TCC- 2-

4%

Bladder TCC after Upper tract TCC- 15-

75%

ETIOLOGY

Genetic› Hereditary UTUC is associated with hereditary

nonpolyposis colorectal carcinoma (HNPCC), or Lynch syndrome.

Environmental› Balkan Nephropathy/ Chinese herb nephropathy:

Aristolochic acid, which is found in plants Aristolochia fangchi and Aristolochia clematitis, has a mutagenic action on codon 139 of p53 gene.

› Smoking: Aromatic amines.› Analgesic abuse

Phenacetin- 2yrs latent phase Acetoaminophin- 20 yrs latent phase.

› Arsenic exposure› Occupational

7 yrs of contact/inhalation to aromatic amines.

Clinical features most common in 7th decade, rare in childhood

males 3 times > female

Clinical features Hematuria- gross/ microscopic- 56-

95% flank pain or acute renal colic(clots)

discovered incidentally at radiologic examination- 15%

IMAGING MODALITIES

INTRAVENOUS UROGRAPHY

Supplanted by CT-IVU

detailed anatomy of the pelvicalyceal system and ureters.

a filling defect within the contrast-enhanced collecting system, single or multiple & smooth, irregular or stippled

Stipple sign---tracking of contrast material into the interstices of a papillary lesion

Tumor-filled, distended calyces --“oncocalyces.”

If these fail to opacify with contrast-- “phantom calyces.”

 TCC of the renal pelvis in a 60-year-old man with painless hematuria. Fifteen-minute IVU image shows a large irregular filling defect (arrow) involving the right renal pelvis and extending into the lower pole calyceal system

 TCC of the renal pelvis in a 65-year-old man. Fifteen-minute IVU image shows a large stippled filling defect involving the collecting system of the right kidney.

  TCC of the upper pole collecting system in a 55-year-old woman. Fifteen-minute IVU image shows amputation of the upper pole calyx secondary to TCC.

  Ureteric TCC in a 68-year-old woman. RP image shows a long irregular stricture of the left distal ureter with proximal hydroureter and “shouldering” .

Ultrasonography a central soft-tissue mass in the echogenic renal

sinus, with or without hydronephrosis.

TCC is usually slightly hyperechoic relative to surrounding renal parenchyma; occasionally, areas of mixed echogenicity.

typically TCC is infiltrative and does not distort the renal contour.

  Renal TCC in a 59-year-old woman. Sagittal US scan shows a well defined hyerechoic mass in the upper pole. Tumor tissue is more echogenic than the surrounding renal cortex but less echogenic than renal sinus fat.

Renal TCC in a 65-year-old woman. Sagittal US scan shows a large mass of mixed echogenicity (arrows) involving the upper pole and overlying renal parenchyma.

US has a limited role in the evaluation of ureteric TCC

If visualized, these tumors are typically intraluminal soft-tissue masses with proximal distention of the ureter

US also allows limited assessment of periureteric tissues.

May 2, 2023 17

Computed Tomography CT is well established in the preoperative staging and

assessment of upper tract TCC- 100% sensitivity and 60%specificity.

CT urography

single breath-hold coverage of the entire urinary tract, has improved resolution has the ability to capture multiple phases of contrast

material excretion

Urothelial cancers - sessile filling defect - range of 10 to 70 HU ( average 46 HU) – Early enhancement on arterial phase.› This is in contrast to an average of 100 HU

seen in radiolucent uric acid stones (range, 80 to 250 HU).

› Blood clots- Higher HU- 50-75 HU ( Smith endour)

› Sloughed off papilla and fungal ball- Do not enhance

Pelvicaliceal irregularity, focal or diffuse mural thickening, oncocalyx, and focally obstructed calyces.

Advanced TCC extends into the renal parenchyma in an infiltrating pattern --- distorts normal architecture

However, reniform shape is typically preserved

(unlike in renal cell carcinoma)

enhances poorly after IV contrast ( Less than RCC)

Hydronephrosis and hydroureter

Ureteric TCC-- Ureteric wall thickening (eccentric or circumferential), luminal narrowing, or an infiltrating mass.

A thickened enhancing ureteric wall with periureteric fat stranding -- suggestive of extramural spread

 TCC of the renal pelvis in a 43-year-old man with flank pain and hematuria. Axial nonenhanced CT scan shows a mass in the right renal pelvis. The mass is slightly hyperdense relative to the urine and renal parenchyma.

Post contrast image shows characteristic early enhancement of the mass, which is less than that of the surrounding renal parenchyma.

 Renal TCC in a 53-year-old man. Axial nephrographic phase CT scan shows a well defined heterogenous hypodense lesion in the left kidney with preservation of its reniform contour

 Bilateral ureteric TCC in a 57-year-old woman. Coronal T2-weighted MR image show low-signal-intensity tumors in the distal right and distal left ureters.

Renal TCC in a 68-year-old woman. Coronal gadolinium-enhanced MR angiogram shows a moderately enhancing TCC in the upper pole of the right kidney

Pre-op Confirmation Cystoscopy – Mandatory to rule out

concurrent bladder tumor. Ureteroscopy

› Reserved for doubtful cases ( On radiology)

› Brush or punch biospy› Staging not accurate as depth of tumor

not well assesed› Risks of tumor seeding, extravasation,

and dissemination- Low but present

Retrograde Pyelography

75% Sensitivity in inadequately excreting kidneys,

in cases of contrast allergy.

facilitates ureterorendoscopy with biopsy or brushing & cytology of urine

an intraluminal filling defect,-- smooth, irregular, or stippled.

An “apple core” appearance-- eccentric or encircling ureteric lesions

localized ureteric dilatation around and distal to the filling defect may give rise to the “goblet” sign.

EUA Guidelines

Cytology and Tumor Markers

Sensitivity› 20% for grade 1 tumors › 45% for grade 2 › 75% for grade 3 tumors

If a voided cytology specimen is abnormal in a patient with an upper tract filling defect- › Ureteral catheterization › Washings from ureter more accurate › Brush biopsy- Sensitivity in the 90%

Massive hemorrhage Perforation of the urinary tract with extravasation

FISH in TCC- Upper and Lower

FISH probes were used for chromosomes 3, 7, 17, and the CDKN2A (9p21) gene, overall sensitivity of FISH was significantly higher than that of cytology and specificity for both was 100%

Staging

Histologically TCC- Most common Variant Histology

› Squamous- Ch. Infection, inflamation or analgesic abuse

› Glandular› Sarcomatoid› Neuroendocrine› Micropapillary- Aggressive and poor

prognosis

Tumor spreads by mucosal extension

local

Hematogenous

lymphatic invasion

The most common sites for metastases are the lungs, liver, bones, and regional lymph nodes.

Prognostic Factors

Age- ??

Pelvic tumors better

Risk Stratification

EUA GUIDELINES

Treatment

Site Specific

Radical Nephroureterectomy

Open Radical Nephroureterectomy Dissection outside

gerota’s Adrenal removed only if

found involved on pre-op imaging or intra-operatively.

Management of Distal Ureter and Bladder Cuff› The entire distal

ureter, including the intramural portion and the ureteral orifice, has to be removed

Management of Distal Ureter and Bladder Cuff

Importance of Complete Resection

The risk of tumor recurrence in a remaining ureteral stump is 30% to 75%

Traditional Open Distal Ureterectomy

Extravesical ApproachIntravesical Approach

Transvesical Ligation and Detachment Technique

Low lithotomy position Cystoscopy- bladder filled. One or two 5-mm trocars are

placed intravesically from the suprapubic area.

Endoloop is placed around the ureteral orifice, and a ureteral catheter is advanced into the ureter through the Endoloop.

With a Collins knife the bladder cuff is incised, and this incision is carried into the extravesical space.

Retraction is provided by the grasper through one of the trocars.

Once the ureter is freed, the Endoloop is cinched around the ureter as the catheter is removed.

Transurethral Resection of the Ureteral Orifice/ “Pluck” technique Abandoned

› Tumor seeding of the extravesical space

› Potential for leaving incompletely resected ureter

Intussusception (Stripping) Technique

Ureteral catheter- Placed at the beginning of the case.

After nephrectomy the ureter is divided and the catheter is secured to the distal portion of the ureter.

The patient is moved to the lithotomy position, and the ureter is intussuscepted into the bladder with retrograde traction.

A resectoscope is used to excise the attached orifice.

Problems:› Incomplete intramural ureter

excision› Failure rate-18.7% - disruption

of the ureter during manipulation – requiring additional incision.

Total Laparoscopic Technique Initial cystoscopy - Placement

of a ureteral catheter and incision of an intramural tunnel at the 12 o’clock position Ureteral orifice is cauterized

After nephrectomy the distal ureter is traced to detrusor muscle. The detrusor muscle is split and the ureter retracted in antegrade direction. The endovascular stapler is then used to place a staple line as distally as possible.

A fulguration mark helps serve as an identifier of the bladder cuff

Potential for leaving ureter mucosa within the staple line – Contraindicated in distal ureteral tumors.

Lymphadenectomy

The role and extent of lymphadenectomy Limited or regional

lymphadenectomy is included withradical nephroureterectomy

For renal pelvis- Ipsilateral hilar nodes + › Right-sided tumors -

paracaval, retrocaval, and interaortocaval lymph nodes

› For left sided tumors- para-aortic lymph nodes

› The inferior mesenteric artery marks the inferior boundary of the template.

For upper two thirds of the ureter- Template is extended to the level of bifurcation of aorta

For distal ureter- Ipsilateral common, external and internal iliac, obturator, and presacral nodes.

Conservative Approaches

Open Nephron-Sparing Surgery for Renal Pelvis Tumors The risk of

recurrence after conservative surgery› Grade 1 - less than

10% › Grade 2- 28%› Grade 3 - 60%

Open Segmental Ureterectomy Ureteroureterostomy

› Proximal ureter or mid-ureter

› 1-2 cm margin proximally and distally

Distal Ureterectomy and Direct Neocystostomy or Ureteroneocystostomy with a Bladder Psoas Muscle Hitch or a Boari Flap

Ileal Ureteral Replacement

Renal autotransplantation

Segmental ureterectomy is offered for low-grade, non–muscle-invasive disease of the proximal ureter or mid-ureter that is not amenable to complete ablation by endoscopic means because of tumor size or multiplicity.

Distal ureterectomy and neocystostomy may be offered for low-grade, low-stage, or in select cases, high-grade, locally invasive tumors of the distal ureter when renal preservation is necessary.

Open v/s Endoscopic Management

The advantage of a ureteroscopic approach is lower morbidity than that of the percutaneous and open surgical counterparts, with the maintenance of a closed system.

With a closed system, nonurothelial surfaces are not exposed to the possibility of tumor seeding.

Endoscopic Management Indications

› Unifocal Disease› Low Grade tumor› Low volume tumor < 1cm› Non invasive on CT- IVU› Abnormal kidney – Opposite

Bilateral tumor CKD Higher risk for CKD

› Poor surgical risk

Antegrade v/s Retrograde Mx

Retrograde› Smaller instruments - smaller field of view and

working channel- Removal of bulky tumors not possible

› Difficulty in accessing the lower pole› Difficult in patients with prior urinary diversion.

Percutaneous › Large volume tumor can be resected› Higher morbidity › Better in complicated calyceal and lower pole

calyx› Nephrostomy tract can be maintained for

immediate postoperative nephroscopy and administration of topical adjuvant therapy

Endoscopic Resection

Management of Positive Upper Tract Urinary Cytology or Carcinoma in Situ

Adjuvant Therapy

After Organ-Sparing Therapy› Instillation Therapy

Immunotherapeutic Agent Chemotherapeutic Agent

After Complete Excision› Radiation Therapy› Systemic Chemotherapy

After Organ-Sparing Therapy Instillation Therapy- Primary

treatment for CIS and as adjuvant therapy after endoscopic or organ-sparing therapy.› Thiotepa› Mitomycin › BCG › Gemcitabine alternative to BCG

with fewer side effects. Brachytherapy- To nephrostomy

tract through iridium wire or delivery system- described by Patel and coworkers (1996) and Nurse and colleagues (1989). No recurrences. Complication- Cutaneous fistula formation requiring nephroureterectomy.

1: Nephrostomy tube2: Ureteric catheter3: Ureteral stent orby iatrogenically created vesicoureteral reflux- Not reliable

After Complete Excision

Radiation Therap› For Stage T3 to T4, N+› Radical nephroureterectomy alone provides a

high rate of local control. Adjuvant radiation without chemotherapy for high-stage disease does not protect against a high rate of distant failure.

› There may be a role for combined radiation-chemotherapy regimens in patients with advanced disease with adverse features; however, the current evidence supporting this is small and retrospective in nature.

Systemic Chemotherapy Neo-adjuvant:

› MVAC (methotrexate, vinblastine, Adriamycin, and cisplatin), › MEC (methotrexate, etoposide, and cisplatin)› MVEC (methotrexate, vinblastine, epirubicin, and cisplatin)› gemcitabine-paclitaxel-doxorubicin [GTA] › Cisplatin-gemcitabine[GC]

Adjuvant Chemotherapy Lack of controlled trials that establish the efficacy of either

neoadjuvant or adjuvant chemotherapy in this UTUC. However, given the significant influence of renal function on eligibility to receive effective chemotherapy, the focus is shifting toward a neoadjuvant approach, with several trials underway.

Further studies are needed to aid in providing recommendations in this setting.

Follow up protocol for Low Risk Disease

Follow up protocol for High Risk Disease

Treatment of Metastatic Disease

When there is evidence of regional lymph node metastases, initial chemotherapy should be given as the primary therapy, and surgery should be withheld until a good—ideally a complete—radiographic response is seen. At that time, consolidative surgery can be offered.

Paclitaxel, cisplatin, and gemcitabine (PCG) versus gemcitabine and cisplatin (GC)- Bettter survival with addition of paclitaxel

Carboplatin is frequently substituted for cisplatin because of either limitations of renal function or concerns over toxicity with the latter, but the results with carboplatin remain inferior.

Upcoming molecule- Cabozantinib, the inhibitor of MET and VEGF pathways

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