Testicular Cancer

Risk Factors

• White race
• HIV
• Family history — brother 8–12× | father 2–4×
• GCNIS/IGCN — ~50% develop GCT within 5 years
• Personal history of testicular cancer: 12×
• CHEK2 mutation: 4×
• Infertility: 2×
• Undescended testis (UDT) — 4–6× | reduced to 2–3× if orchidopexy pre-puberty
• Marijuana use — 3.5-fold more common among GCT patients than controls
• Pesticide exposure — higher levels found in men with testis cancer, and in their mothers
• SNP in KITLG — homozygosity for the dominant allele is associated with up to a 4.5-fold increase in the risk of GCT
• Disorders of sex development — variable risk, depending on the specific disorder
• A history of extragonadal GCT also increases the risk of a metachronous testicular GCT

Not risk factors: microlithiasis, testicular atrophy, trauma

Klinefelter syndrome is a risk factor for mediastinal primary NSGCT — not for testicular GCT (see Special Notes).

Most common genetic abnormality: extra copy of short arm chromosome 12 (i12p)

---

Tumor Classification

A. Germ Cell Tumors (~95%)

All adult GCT subtypes arise from GCNIS EXCEPT the spermatocytic tumour — embryonal carcinoma, choriocarcinoma, classic seminoma and teratoma all do.

1. Seminoma (52–56%)

• Age 20–30 (actually 4th–5th decade — older than NSGCT)
• 15% have ↑ β-hCG
• Chemo- and radiosensitive
• Histology: clear cytoplasm ("fried egg")
• Arises from GCNIS

2. NSGCT (44–48%)

Subtype	Markers	Histology / Key
Yolk sac	↑ AFP	Schiller-Duval bodies; infant; chemo-sensitive
Embryonal carcinoma	↑ AFP ± β-hCG	Papillary; aggressive; totipotent → can differentiate into other NSGCT subtypes
Choriocarcinoma	↑ β-hCG (>10,000)	Syncytiotrophoblasts; haematogenous spread → brain mets
Teratoma	Usually negative	Cystic germ layer elements; chemo-resistant; can transform to somatic malignancy

→ Pure seminoma + ↑ AFP → treat as NSGCT

Comparison of germ cell tumours

Tumour	Usual age	AFP	β-hCG	Radiation	Chemo	Pathology
Yolk sac	< 10	Maybe	Maybe	Resistant	Sensitive	Schiller-Duval bodies, embryoid bodies, hyaline globules
Choriocarcinoma	20–30	Never	Always	Resistant	Sensitive	Syncytiotrophoblasts, cytotrophoblasts, central haemorrhage
Embryonal	25–35	Maybe	Maybe	Resistant	Sensitive	Papillary projections
Teratoma	25–35	Maybe	Never	Resistant	Resistant	Multiple germ cell layers, often cystic
Typical seminoma	30–40	Never	Maybe	Sensitive	Sensitive	Clear cytoplasm, distinct cell borders, "fried egg" nucleus

• Syncytiotrophoblastic cells are present in choriocarcinoma, seminoma AND embryonal carcinoma — not choriocarcinoma alone

Choriocarcinoma

• Rare — pure < 1%, 10% as a mixed component
• Haematogenous spread — lung, liver and brain
• Prone to haemorrhage — spontaneously or after chemotherapy

Teratoma

• The pure form produces neither AFP nor β-hCG; pure teratoma is rare in adults
• Chemoresistant AND radioresistant
• Benign but unpredictable behaviour — local growth and malignant transformation

Embryonal carcinoma

• Poorly differentiated, with the ability to differentiate into other NSGCT subtypes
• Aggressive, with a high rate of metastasis
• Syncytiotrophoblastic cells are scattered throughout the tumour

Yolk sac

• Schiller-Duval bodies are the classic pathognomonic finding
• Cytoplasmic and extracellular eosinophilic hyaline globules are present in up to 84% of cases
• The most common testicular tumour in infants and children

Teratocarcinoma — a mixed tumour producing both AFP and β-hCG

3. GCNIS

• High risk of progression to invasive GCT
• Management options (3): orchiectomy | low-dose RT (18–20 Gy) | surveillance
• → Preserve fertility → surveillance
• → ↓ cancer risk → orchiectomy or testicular RT
  • RT advantage: Leydig cells radioresistant (less hypogonadism — 40% need TRT)
  • RT disadvantage: scatter to contralateral testis impairs spermatogenesis

Option	Outcome
Observation	50% develop cancer within 5 years
Orchiectomy	100% cure
Radiotherapy 18–20 Gy	97% cure — testosterone replacement usually needed
Chemotherapy	66% cure

B. Sex Cord–Stromal Tumors (~90% benign)

• Leydig cell — testosterone, gynecomastia; 10% bilateral; 40% need TRT post-op
• Sertoli cell — testosterone, estrogen; assoc. Peutz–Jeghers
• Gonadoblastoma — gonadal dysgenesis/intersex; bilateral orchiectomy (40% bilateral)

C. Non-Germ Cell

• Spermatocytic tumor — elderly; benign; no GCNIS, no i(12p), no cryptorchidism link

D. Secondary

• Lymphoma (most common testis tumor in men >50; 35% bilateral)
• Leukaemia — usually appears in the testis after the patient is in remission; diagnosed by biopsy. Orchiectomy should NOT be done. Local control is radiotherapy 20 Gy, and the contralateral testis is included in the radiation field
• Mets: prostate, lung, melanoma, colon, kidney

E. Paratesticular Tumours

• Adenomatoid tumour — of mesothelial origin; the most common paratesticular tumour
• Mesothelioma — arises from the tunica vaginalis; treated by orchiectomy and hemiscrotectomy

Sarcoma

• Usually arises from the cord. Do an MRI ± inguinal biopsy before wide-margin orchiectomy with high ligation of the cord. Some advocate local radiotherapy
• Systemic chemotherapy for retroperitoneal or distant metastases

When the metastatic workup is negative:

• Liposarcoma of the cord → radiotherapy

• Other sarcomas (rhabdomyosarcoma, malignant fibrous histiocytoma, angiosarcoma) and mesothelioma → RPLND, with post-operative chemotherapy if the retroperitoneal nodes are involved

• In sarcoma the primary pattern of failure is LOCAL, particularly for liposarcoma — some advocate post-operative radiotherapy for all paratesticular sarcomas

---

Special Notes

• 5% of GCTs are extragonadal (midline)
  • Retroperitoneum
  • Mediastinum — Klinefelter syndrome is a risk factor for mediastinal primary NSGCT, not for testicular GCT; poor prognosis, chemo-resistant
• UDT patients: age 19–50 → orchiectomy | >50 → no surgery
• Orchitis → re-evaluate 2–4 weeks after antibiotics

---

Metastatic Spread

• Lymphatic (70–80%)
  • Right testis → interaortocaval nodes
  • Left testis → para-aortic nodes
• Inguinal nodes only if:
  • Prior inguinal/scrotal surgery
  • Tunica vaginalis invasion
• Exception: choriocarcinoma = haematogenous → lung, brain
• Mets at diagnosis: 33% NSGCT | 15% seminoma

---

Tumor Markers & Half-Life

Marker	Size (daltons)	Half-life	Normal range	Produced by
AFP	70,000	5–7 days	< 40 µg/L	Yolk sac, EC, teratoma (NOT seminoma or chorio)
β-hCG	38,000	24–36 hours	< 5 IU/L	Seminoma (15%), EC, choriocarcinoma
LDH	134,000	Varies (~1 day)	1.5–3.2 µkat/L	Non-specific; used for S-stage

• Repeat markers after 5 half-lives post-orchiectomy
• False ↑ β-hCG — hCG immunoassays are directed at the beta subunit, so there is cross-reactivity with LH. This causes false-positive elevations in primary hypogonadism (including alcoholics and the anorchid) — they normalise within 48–72 hours of giving testosterone
• Marijuana use and hypogonadism cause a persistently high β-hCG
• Liver damage causes a persistently high AFP

---

Work-Up

• History & physical exam
• Scrotal ultrasound (both testes — 2% bilateral) — high-frequency transducer (5–10 MHz)
  • In the landing zone, a 5 mm node is suspicious. In other zones, 10 mm is the cut-off.
• Tumor markers + LFTs + hormones
• CT chest / abdomen / pelvis (CXR acceptable for CS I seminoma)
• Brain imaging if:
  • Neurologic symptoms
  • β-hCG >5,000
  • AFP >10,000
  • Extensive lung mets
  • Non-pulmonary visceral mets
• Use MRI with and without contrast. A CT brain is also warranted with a highly elevated β-hCG (> 10,000 mIU/mL), since those levels are often associated with metastatic choriocarcinoma
• Contraindicated: testicular biopsy, trans-scrotal orchiectomy (scrotal violation ↑ local recurrence)

Contralateral biopsy is indicated when (the patient has already had a unilateral orchiectomy)

• History of undescended testis
• Atrophic contralateral testis
• Patient under 40
• Suspicious ultrasound finding

---

Fertility Considerations

• At diagnosis: 50% oligospermic | 10% azoospermic
• All patients become azoospermic after chemotherapy. Of those with normal semen parameters at diagnosis, 50% resume baseline at 2 years and 80% at 5 years
• Radiotherapy for seminoma affects spermatogenesis — recovery may take 2–3 years
• RPLND can cause ejaculatory dysfunction
• → Sperm bank before chemo/RT

---

Testis-Sparing Surgery (Selective)

• Solitary testis
• Synchronous bilateral tumors
• Tumor <1 cm, <30% testicular volume, non-palpable, normal markers
• 50–80% have concomitant GCNIS in ipsilateral testis
• Obtain a frozen section
• Biopsy the adjacent tissue for GCNIS — if positive, give radiotherapy 20 Gy
  • Fertility will be impaired, and testosterone will decline gradually — up to 40% will need testosterone replacement
  • If the patient already has a low testosterone, go for radical orchiectomy instead

---

Pathologic Risk Factors for Relapse (CS IA/IB )

Seminoma (2)

• Tumor size >4 cm
• Rete testis invasion

NSGCT (5)

• LVI (most important)
• Stage pT2 or higher
• > 40% embryonal cell carcinoma
• Proliferation rate > 70% on MIB-1
• Absence of yolk sac tumour

---

TNM Staging (AJCC 8th)

T Stage (pathologic — assigned after radical orchiectomy)

Stage	Definition
pTis	Intratubular germ cell neoplasia (carcinoma in situ)
pT1	Limited to testis and epididymis, no LVI; may invade tunica albuginea but not tunica vaginalis
pT2	Limited to testis and epididymis with LVI, or extending through tunica albuginea with involvement of tunica vaginalis
pT3	Invades the spermatic cord, with or without LVI
pT4	Invades the scrotum, with or without LVI

N Stage

Clinical	Pathologic
N1 — mass ≤ 2 cm, or multiple nodes none > 2 cm	pN1 — mass ≤ 2 cm and ≤ 5 nodes positive, none > 2 cm
N2 — mass > 2 cm but ≤ 5 cm, or multiple nodes any one > 2 cm but ≤ 5 cm	pN2 — mass > 2 cm but ≤ 5 cm; or > 5 nodes positive, none > 5 cm; or extranodal extension
N3 — mass > 5 cm	pN3 — mass > 5 cm

• Regional nodes are the abdominal nodes: pre-aortic, para-aortic, retro-aortic, interaortocaval, pre-caval, para-caval, retro-caval, and along the spermatic vein
• Pelvic and inguinal nodes are NOT regional — unless there was scrotal violation

M Stage

• M1a: non-regional nodes or lung
• M1b: non-lung visceral mets

S Stage

	LDH	AFP	β-hCG
S1	<1.5×	<1,000	<5,000
S2	1.5–10×	1,000–10,000	5,000–50,000
S3	>10×	>10,000	>50,000

---

Stage Grouping

Stage I (N0, M0)

• IA: T1, S0
• IB: T2–T4, S0
• IS: Any T, S1–S3 (marker-positive post-orchiectomy)

Stage II (N+, M0, S0–1)

• IIA: N1
• IIB: N2
• IIC: N3

Stage III (Any N, M1 and/or higher S)

• IIIA: M1a, S0–S1
• IIIB: N1–3 + M0–M1a + S2
• IIIC: N1–3 + M0–M1a + S3, OR M1b any S

The short version

• Stage I — local tumour, no regional nodes, markers negative

• Stage II — regional nodes, markers negative, no metastases

• Stage III — metastases or markers positive

• S2 → IIIB · S3 → IIIC

---

Risk Stratification (IGCCCG)

Risk	Non-seminoma (ALL of)	Seminoma (ALL of)
Good	Testicular or retroperitoneal primary · M0 or M1a · S0 or S1	Any primary site · M0 or M1a · normal AFP
Intermediate	Testicular or retroperitoneal primary · M0 or M1a · S2	Any primary site · M1b · normal AFP
Poor	Any of: mediastinal primary · M1b · S3	No patients are classified as poor risk

• For IGCCCG risk, S stage is determined on the first day of chemotherapy — not at orchiectomy

---

Management

Pure Seminoma

Stage I (CS IA/IB Seminoma)

Option	Relapse rate	Usual relapse site
Surveillance (preferred if compliant)	15–20%	Retroperitoneal nodes
XRT — para-aortic RPLN below the diaphragm ± ipsilateral iliac nodes, 20 Gy	3%	Thorax
Carboplatin ×1–2 cycles	3%	Retroperitoneal nodes

Advantages of surveillance

• Avoids over-treating 80% of patients
• Avoids the toxicity of radiotherapy and chemotherapy
• Same cure rate

When to avoid XRT

• Inflammatory bowel disease · prior abdominal radiation · a kidney in the radiation field (horseshoe kidney, ectopic kidney, adenopathy near the kidney)
• Shield the contralateral testis if it is not involved
• With scrotal violation, include the ipsilateral iliac and inguinal nodes in the field
• When the ipsilateral iliac nodes are not radiated, follow-up must include pelvic nodal imaging — the iliac nodes are then a common relapse site

Surveillance schedule — CS I seminoma

	Years 1–2	Years 3–5	> Year 5
History, physical, CT abdomen ± pelvis	Every 4–6 months	Every 6–12 months	If clinically indicated

Stage II and beyond

• Stage IIA → XRT to para-aortic RPLN + ipsilateral iliac nodes, 30 Gy — relapse ~10%, usually in the thorax
• Stage IIB → 36 Gy if the RPLN mass is ≤ 3 cm; BEP ×3 or EP ×4 if > 3 cm
• Stage IIC / III
  • Good risk → BEP ×3 or EP ×4
  • Intermediate → BEP ×4

Residual Masses Post-Chemo (Seminoma)

• 60–80% have radiologically detectable residuum
• Histology: necrosis or fibrosis 80–90% · malignancy 10–20% · pure teratoma (rare)
• → <3 cm: observe
• → >3 cm: FDG-PET
  • Positive → post-chemo surgery
  • Negative → observe
• Perform the PET scan ≥ 6 weeks after chemotherapy — this reduces false positives. If indeterminate, repeat in 6–8 weeks
• Granulomatous disease (e.g. sarcoid) can cause a false-positive PET
• Malignancy is rare in residual masses ≤ 3 cm, but is present in 30–50% of residual masses > 3 cm
• Template RPLND is difficult here — chemotherapy for seminoma causes a desmoplastic reaction that obscures the tissue planes, so resection or biopsy of the residual mass is often performed instead
• For FDG-PET-positive residual masses > 3 cm, give strong consideration to PC-RPLND — particularly after second-line chemotherapy

Post-chemotherapy relapse

• Early — could contain teratoma. If markers are normal, biopsy first; if there is no teratoma, give second-line chemotherapy
• Late — better prognosis. Treatment is chemotherapy (remember they probably had carboplatin). Biopsy first is not really needed — teratoma in late relapse is rare
• Radiotherapy has no role in a post-chemotherapy residual mass

---

Non-Seminoma

• Stage I
  • Surveillance (compliant T1 only)
  • RPLND (unilateral) — preferred if teratoma in pathology
  • Chemo BEP ×2

Stage	Surveillance relapse rate
IA	15–20%
IB	50%

• 60% of relapses occur in the retroperitoneum
• Non-compliant IA → nerve-sparing RPLND (modified or full bilateral template) or BEP ×1
• Non-compliant IB → nerve-sparing RPLND or BEP ×2

Surveillance schedule — CS I NSGCT

	Year 1	Year 2	Year 3	Year 4	Year 5	> Year 5
History, physical, markers	q2–3 mo	q2–4 mo	q4–6 mo	q6–12 mo	q6–12 mo	If indicated
CXR + CT abdomen ± pelvis	q3–6 mo	q4–12 mo	Once	Once	Once	If indicated

• Stage IIA/B — RPLND (bilateral) only if S0; otherwise chemo BEP ×3
• Stage IS → BEP ×3
• Stage IIC / III
  • Good risk → BEP ×3 or EP×4
  • Poor risk → BEP ×4
  • Substitute VIP×4 if compromised pulmonary function or extensive chest surgery expected

---

Post-RPLND (pre-chemo)

Pathologic stage	Management
pN0	Observe
pN1	Compliant → observe (preferred); non-compliant → EP ×2 or BEP ×2
pN2	Compliant → observe; non-compliant → EP ×2 or BEP ×2 (preferred)
pN3	EP ×4 or BEP ×3

Relapse after primary RPLND, by pathologic stage

Stage	Relapse
pN0	~10%
pN1	25%
pN2	50%
pN3	> 90%

• Most relapses occur OUTSIDE the retroperitoneum — primarily in the lungs

Residual Masses Post-Chemo (NSGCT)

Four response categories after chemotherapy

1. Complete response — markers normalise and radiographic disease resolves (residual masses < 1 cm)
2. Partial remission, marker negative — markers normalise but radiographic tumour persists
3. Partial remission, marker positive
4. Disease progression

• 5–15% fall into categories 3 and 4 and are managed with second-line (salvage) chemotherapy
• 38–68% have residual masses > 1 cm after first-line chemotherapy — clear consensus that these should undergo post-chemotherapy surgery

	After PC-RPLND (induction)	After salvage chemotherapy
Necrosis / fibrosis	40%	10%
Teratoma	45%	40%
Viable cancer	15%	50%

• Markers elevated: salvage chemo
• Markers normal:
  • >1 cm: → resection (full bilateral template PC-RPLND if RP)
  • < 1 cm after primary chemotherapy — surveillance carries a 9% recurrence rate, but only 4% recur in the retroperitoneum. If every patient with a sub-centimetre residual mass had an RPLND, 96% would undergo unnecessary surgery
  • After SALVAGE chemotherapy the risk of residual malignancy is much higher — resection of a residual retroperitoneal mass is recommended regardless of size
• → Multiple sites → RPLND first (highest probability of residual; predicts other sites)
• PC-RPLND histology:
  • Necrosis/teratoma → surveillance
  • Viable disease → 2 cycles chemo (EP, TIP, VIP, or VeIP)
• FDG-PET has NO role in NSGCT residual masses

Parameters predicting fibrosis in the retroperitoneum after platinum-based chemotherapy

1. No teratoma in the primary tumour
2. 90% reduction in the size of the mass on CT
3. Pure embryonal cell carcinoma in the primary tumour
4. Size of the lymph node post-chemotherapy

• Post-chemotherapy, if a residual liver mass has shrunk (e.g. 5 cm → 2.5 cm) and the retroperitoneal nodes have nearly resolved (3 cm → 2 mm) with normalised markers → do the LIVER resection only. Adding an RPLND results in a high incidence of chylous ascites

---

RPLND

Not only therapeutic — it gives accurate pathologic staging. Up to 30% of clinical stage I NSGCT have occult metastases, and up to 35% of clinical stage IIA are downstaged to stage I.

Type	When
Primary RPLND	After orchiectomy, for high-risk CS I or low-volume CS II (N1) NSGCT with normal markers
PC-RPLND	After induction chemotherapy — residual mass > 1 cm with normal post-chemotherapy markers
Salvage PC-RPLND	After both induction and salvage chemotherapy
Desperation PC-RPLND	After chemotherapy where the markers are elevated
Re-operative RPLND	After a prior RPLND
Resection of late relapse	Relapse > 24 months after a complete response to primary chemotherapy

• The standard of care for PC-RPLND is a full, bilateral infrahilar retroperitoneal dissection with nerve sparing where technically feasible
• A predominance of teratoma in the orchiectomy specimen favours RPLND over chemotherapy — it increases the risk of teratoma in the retroperitoneum

Surgical Considerations

• Contralateral nodal involvement is more common in RIGHT-sided primary tumours — following right-to-left lymphatic drainage
• The sympathetic trunks are bilateral paravertebral chains giving rise to postganglionic fibres posterior to the IC, anterior to the aorta, coalescing at the inferior hypogastric plexus caudal to the IMA
• For optimal preservation of ejaculation in a RIGHT-sided nerve-sparing RPLND, preserve the postganglionic sympathetic fibres POSTERIOR TO THE VENA CAVA
• The most common site of sympathetic nerve injury during RPLND is the hypogastric plexus anterior to the aortic bifurcation
• Postoperative tachycardia is common and is caused by sympathetic discharge

Steps

1. Midline incision
2. Find the caecum
3. Open the retroperitoneum
4. Dissect the white line of Toldt as far as the second part of the duodenum (from behind), then come from anterior-inferior and go superiorly to release the third part of the duodenum
5. Reflect the bowel into the bag

Auxiliary Procedures

• Nephrectomy is the commonest — usually the left
• There is a common discordance between liver/thoracic pathology and retroperitoneal nodal pathology — one does not predict the other
• Thoracic masses should be managed AFTER the RPLND is completed. Masses > 1 cm should be considered for resection unless the retroperitoneum harboured only fibrosis

Complications

IVC injury

• If > 25% narrowing is expected, consider patch venoplasty or an interposition graft
• (Note the divergence: in the renal setting, 50% narrowing of the IVC lumen is accepted.)

Aortic injury

• Most common with subadventitial dissection of densely adherent masses, requiring aortic replacement with a PTFE or Dacron graft

Lymphocele

• A thin-walled cystic lesion in the resection bed
• Air within the lymphocele and/or a rim of enhancement raises concern for infection
• Percutaneous drainage for symptomatic or infected lymphoceles; antibiotics only if perceived to be infected

Anejaculation

• Seminal emission and prostatic secretion, plus bladder neck closure, rely on postganglionic sympathetic fibres from L1 to L4, which coalesce at or below the IMA in the hypogastric plexus before travelling caudally in the interiliac space at the sacral promontory

Chylous ascites

• 0.2–2% in primary RPLND; 2–7% after post-chemotherapy RPLND
• Diagnosis — suspicion, CT abdomen, and paracentesis showing high protein (> 3 g/dL) and a triglyceride level 2–8× that of serum
• If symptomatic, escalate in this order:
  1. Paracentesis with no drain
  2. If it reaccumulates quickly, leave a drain and cap it off at intervals
  3. Very low fat, high protein diet with medium-chain triglyceride replacement
  4. IM octreotide
  5. NPO and TPN
  6. Observation or invasive intervention

Also: VTE, mortality

---

Special Scenarios

Growing Teratoma Syndrome

• ↓ markers + ↑ mass during chemo
• → Complete chemo course, then resect

Brain Mets (choriocarcinoma)

• High hCG → bleed risk on chemo (death 4–10% ICH)
• → BEP ×4 → resection ± RT

Post-Chemotherapy Relapse (NSGCT)

Early (< 2 years)

• Second-line salvage chemotherapy — TIP, VIP or VeIP ×4; third line is high-dose chemotherapy
• If a residual mass remains after salvage chemotherapy → surgical resection; 50% contain viable cancer

Late (> 2 years)

• Biopsy first
• Yolk sac is the most common histology; the majority are in the retroperitoneal nodes
• Generally chemoresistant — surgery is the better option
• The best chemotherapy is TIP

Scrotal Violation

Scrotal violation alters the normal lymphatic drainage, redirecting it to the superficial inguinal nodes.

Optimal treatment is unclear, but consider:

• Stage T4 suspected at the time of orchiectomy → orchiectomy + en bloc excision of the involved portion of the scrotum
• After a trans-scrotal biopsy → radical inguinal orchiectomy + en bloc excision of the biopsy tract and the scrotal scar
• After a trans-scrotal orchiectomy — adjunctive therapy "may rarely be considered… for local control" [AUA]
• Seminoma with scrotal violation going to radiation → modify the field to include the ipsilateral iliac and inguinal nodes

Bleomycin + RPLND

• Risk of post-op respiratory distress
• Obtain PFTs pre-operatively; the anaesthetic team should be aware of bleomycin's pulmonary fibrosis risk
• → Low FiO₂ + conservative fluids

Chemotherapy — Agent-Specific Toxicity

Agent	Toxicity
Cisplatin	Nephrotoxicity and ototoxicity
Carboplatin	Myelosuppression
Bleomycin	Pulmonary toxicity
Etoposide	Hypotension
Ifosfamide	Haemorrhagic cystitis and neurotoxicity