Genitourinary involvement of lymphomas on FDG-PET.

Primary extranodal lymphomatous involvement of the genitourinary tract is rare and secondary extranodal involvement in disseminated disease occurs more frequently. Imaging of metabolic activity with 2-(fluorine-18) fluoro-2-deoxy-d-glucose (FDG) used in PET facilitates the identification of these extranodal sites of disease, particularly in the absence of structural lesions on conventional imaging modalities. Primary extranodal lymphoma affecting the genitourinary system is often caused by high-grade Non-Hodgkin’s Lymphoma (NHL) with the most common subtype being diffuse large B-cell lymphoma (DLBCL). Although rare, the incidence of extranodal lymphoproliferative disease is increasing and a delay in diagnosis holds a poor prognosis. Familiarity with benign and physiological causes of FDG uptake, particularly due to the urinary tracer excretion is crucial in identifying sites of lymphomatous involvement in the genitourinary system. Additionally, non-lymphomatous malignancies are usually treated surgically, whereas lymphoma is primarily treated with chemotherapy and/or radiotherapy. Therefore, accurate identification and staging together with histological confirmation significantly impacts management of these patients. This article serves to review and illustrate the imaging findings on FDG-PET/CT of primary extranodal lymphoma affecting the genitourinary system.

Extranodal lymphoma (ENL) describes lymphomatous proliferation from sites other than native lymph nodes or lymphoid tissue.1 Primary ENL is confined to one organ with or without closely adjacent lymph nodes. Secondary extranodal involvement is more common, occurring in cases of disseminated disease.1 The incidence of ENL is increasing due to the increasing prevalence of immunosuppression (e.g., HIV/AIDS, immunosuppressive therapies) and due to increased detection from advances in novel imaging and laboratory diagnostic techniques.1 PET is a functional imaging modality using radiolabelled isotopes to identify biological processes such as glucose metabolism, serving as a surrogate biomarker for malignancy. The most widely used tracer is 2-(fluorine-18) fluoro-2-deoxy-d-glucose (FDG) for Hodgkin’s lymphoma (HL) and Non-Hodgkin’s lymphoma (NHL).1 PET-CT is incorporated in the management of lymphoma and is superior than conventional imaging at staging, therapy monitoring and prognostication,1 identifying metabolic changes prior to structural changes. Detection of extranodal involvement is critical, often leading to treatment escalation.1, 2 Bone marrow involvement is the most common extranodal site and recent evidence suggests PET could obviate the need for bone marrow biopsy in high-grade lymphoma.2 Lymphomas demonstrate variable FDG avidity especially in low-grade disease such as mucosa associated lymphoid tissue (MALT) lymphoma, where the absence of structural abnormalities makes detection challenging.3 Most genitourinary (GU) lymphomas are high-grade demonstrating intense FDG avidity. Aggressive lymphomas have been shown to be more FDG avid compared with indolent subtypes with a maximum standardised uptake value (SUVmax) > 10.4 Unlike glucose, FDG is not reabsorbed in the kidneys and in the absence of structural abnormalities, intense physiological accumulation or hold-up in the urinary tract can obscure disease detection in the GU system. Bladder catheterisation/lavage or delayed post-void imaging with or without administering a diuretic can decrease urinary FDG concentration.3 FDG accumulation can occur in infection and inflammation [e.g. following surgery or radiotherapy (RT)], granulomatous disorders, uterine fibroids, and part of the normal menstrual cycle,3 (Figure 1) and PET should be scheduled accordingly to minimise false positive results.2 While GU lymphoma is rare, early detection is vital in order to assign an accurate stage and appropriate treatment regimen. This article describes and illustrates its features on FDG-PET (Table 1). Table 1. | Case | Figure | Age | Sex | Subtype | Treatment given | Response | | Diffuse renal | 2a | 44 | F | DLBCL | Chemotherapy | Remission | | Multifocal renal | 2b | 59 | F | Follicular | Chemotherapy | Remission for 7 months, relapse and poor response to ongoing therapy | | Unilateral renal | 2c | 59 | M | DLBCL | Chemotherapy | Remission | | Ureteric | 4a | 63 | M | DLBCL | Chemotherapy, systemic methotrexate | Remission | | Focal ureteric | 4b | 82 | F | DLBCL | Chemotherapy | Remission for 14 months, para-aortic relapse, poor response to secondary chemotherapy, disease progression, passed away | | Bladder | 5 | 63 | M | MALT | Chemotherapy | Remission, developed transitional cell carcinoma which was treated with radical cystectomy and ileal conduit. | | Adrenal | 7 | 64 | F | DLBCL | Chemotherapy | Remission | | Uterus | 8 | F | Mantle cell | Chemotherapy, radiotherapy | Remission | | | Cervix and uterus | 9 | 82 | F | DLBCL | Chemotherapy. | Remission, central nervous system relapse 5 months later, passed away | | Uterus and left ovary | 10 | 59 | F | Follicular | Chemotherapy, radiotherapy | Remission | | Vaginal | 11 | 64 | F | DLCBL | Chemotherapy, radiotherapy | Remission | | Vulval | 12 | 64 | F | DLBCL | Chemotherapy | Unknown, Lost to follow up | | Prostate | 14 | 87 | M | DLBCL | Chemotherapy | Remission, relapsed 2 years later, undergoing further treatment | | Prostate | 14 | 60 | M | Marginal zone | Chemotherapy | Remission | | Seminal vesicle | 15 | 74 | M | DLBCL | Chemotherapy | Remission | | Bilateral testicular | 18a | 76 | M | DLBCL | Chemotherapy, intrathecal methotrexate | Remission for 5 years, CNS and testicular relapse, passed away | | Unilateral testicular | 18b | 74 | M | DLBCL | Chemotherapy, intrathecal methotrexate, planned radiotherapy | Passed away prior to planned radiotherapy | | Relapsed testicular | 18c | 78 | M | DLBCL | Right orchidectomy, chemotherapy, radiotherapy to the left testis and CNS prophylaxis with intrathecal methotrexate | Remission for 5 months, relapse left testicle, declined further treatment, palliated | | Spermatic cord | 19 | 52 | M | DLBCL | Chemotherapy, bilateral testicular radiation and intrathecal methotrexate | Remission, 12 months later relapsed in spermatic cord, salvage chemotherapy and autologous BMT | | Penile | 20 | 89 | M | DLBCL | Declined chemotherapy | Passed away 5 months following diagnosis | BMT, bone marrow transplant; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; MALT, mucosa-associated lymphoid tissue. Renal Primary renal lymphoma (PRL) accounts for less than 1% of ENL as renal parenchyma is normally devoid of lymphoid tissue.5 Occurring in middle aged or older, PRL, typically caused by B-cell NHL, are often bilateral but can be unilateral with solitary or multiple lesions, or diffuse infiltration5 (Figures 2–4). FDG excretion is typically evident in the pelvicalyceal system, therefore any focal or diffuse hypermetabolism within the cortices would be concerning for lymphoma. PRL is usually asymptomatic, but can present as acute renal injury5 (Figures 2–4). The prognosis is poor with a median survival of less than a year. Early detection and initiation of chemotherapy has resulted in a good response5 and rapid improvement of renal function. Renal cell carcinomas (RCCs) have a lower level of metabolic activity when compared to high-grade lymphomas (Figure 5) and PET-CT can be useful in its differentiation. In one series, lymphomas demonstrated an SUVmax >5.98 g ml–1, whereas RCC had an SUVmax <5.26 g ml–1 with no significant difference in renal size.6 Ureteric Reported cases7 noted a male predominance with the median age of presentation as 56 years, the majority being asymptomatic. Conventional imaging often demonstrates hydronephrosis with no other specific imaging characteristics.7 Lymphomas affecting the proximal and distal ureter are usually caused by para-aortic and iliac adenopathy respectively (Figures 6 and 7). Documented subtypes included diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), small lymphocytic lymphoma (SLL), MALT and HL.7 Due to its rarity, treatment guidelines have not been established with variable outcomes. Bladder Primary bladder lymphomas are frequently caused by MALT.8 Secondary involvement commonly arises from DLBCL.8 Typically affecting adults above 60 years, 75% are women with associated chronic cystitis. Initial symptoms include haematuria, dysuria, abdominal or back pain.8 Radiologically, 70% are solitary bladder masses, 20% multiple masses and 10% have diffuse wall thickening.8 Due to physiological FDG accumulation, lesions are obscured, and the main role of PET was to identify other disease sites (Figure 8). Prognosis varies and depends on histological subtype with MALT having an excellent prognosis. Recurrent bladder lymphoma is associated with disseminated disease and poor prognosis.8 Urethra Primary urethral NHL was first reported in 1972 and first described in 1987.9 All documented cases have been in older patients with a female predominance9 commonly presenting with a mass at the urethral meatus.9 Urethral lymphoma has not been reported in the PET literature to date. Due to physiological excretion, it would be difficult to differentiate between focal lesions and urinary activity. Moreover, in men who have undergone transurethral procedures, tracer pooling is often seen in a dilated prostatic urethra (Figure 9) and clinical history could prevent this pitfall. Adrenal Accounting for less than 1% of all NHL and 3% of primary ENL, primary adrenal lymphoma (PAL) affects elderly men with a mean age of 62 and a male:female ratio of 1, 8:1.8 Often presenting with B symptoms or adrenal insufficiency, PAL can be bilateral (75%) or unilateral.8 Common subtypes include DLBCL and T-cell Lymphoma and cases of MALT, mantle cell, anaplastic large cell lymphoma and HL have also been documented.10 Prognosis is poor with a 12-month survival of 20% and those with DLBCL are likely to develop central nervous system (CNS) involvement.10 Adrenal lymphoma is intensely FDG avid (Figure 10) similar to that seen in adrenal cortical carcinomas and metastases which may be indistinguishable. Female genitourinary organs Cervix/uterus The median age of diagnosis of cervical/uterine lymphoma in pre-menopausal women is fourth to fifth decade who can present with dysfunctional uterine bleeding, a pelvic/cervical mass and associated pain, however, symptoms may be absent in the initial stages. DLBCL is most common and a recent study demonstrated uterine and not ovarian lymphoma to be associated with secondary CNS involvement and poor prognosis.11 Cases of FL and endometrial primary marginal zone lymphoma have also been recorded.12 Both the cervix and uterine body are usually involved with diffuse uterine enlargement and FDG avidity (Figure 11), a large lobulated (Figure 12)/exophytic mass or nodules.12 While submucosal leiomyomas are similar in appearance on conventional imaging12 the hypermetabolism in lymphoma on PET is a distinguishing feature. Fallopian tube Patients can be asymptomatic or experience pelvic pain.12 Secondary involvement is described in cases of ovarian lymphoma.13 Primary fallopian tube lymphoma can be unilateral or bilateral, with variable presentations—associated with chronic inflammation (tubo-ovarian abscess/endometriosis), a pelvic mass or an incidental finding during surgery.14 Documented subtypes include FL, MALT and T-cell.13 As far as we know, the appearance on PET has not been reported. Ovarian Burkitt’s lymphoma and DLBCL are most common of both primary and secondary ovarian lymphoma.12 FL (Figure 13) and small lymphocytic lymphoma also occur, more so in older women.14 Primary ovarian lymphoma accounts for 1.5% of all ovarian neoplasms and has a wide age range with peak incidence in the 30s to 40ss, commonly presenting with abdominal or pelvic pain, often with an elevated CA-125.8, 14 Involvement can be unilateral or bilateral and ascites is infrequent despite the larger size of the lesion when compared with other ovarian malignancies.12 Less than 50% of cases demonstrate peritoneal involvement and extension often occurs through the pelvic and para-aortic lymph nodes.12 In premenopausal women, benign physiological FDG uptake of the ovaries and endometrium varies cyclically and occurs at both ovulation and during the menses (Figure 1). Corpus luteal cysts can also have increased tracer uptake.3 In post-menopausal women, FDG accumulation is abnormal, however, benign aetiologies can mimic malignancy on PET such as fibroids and endometrial polyps.1 Treatment often involves oophorectomy to aid diagnosis and chemotherapy. Prognosis is poor with a 5-year survival of 57%.8 Vaginal Primary vaginal lymphoma (Figure 14) is exceedingly rare with a mean age of diagnosis in the fifth decade, typically presenting with perineal discomfort or vaginal discharge/bleeding.12 Approximately, 50% are diagnosed at autopsy due to the lack of solid lesions that could otherwise be identified by conventional imaging. FDG-PET can potentially prevent a delay in diagnosis and treatment as the mean 5-year survival is 80% for early stages and 30% in advanced stages.15 Vulval Accounting for 4% of pelvic NHL,16 the mean age is 60, often presenting with a nodule, induration, a mass in the region of Bartholin’s gland or a clitoral mass.14 The most common histological subtype is DLBCL and others include T-Cell and Burkitt’s.16 PET-CT demonstrates high sensitivity as an intensely FDG avid mass (Figure 15). Squamous cell carcinoma (SCC) can appear similar on PET making it indistinguishable (Figure 16). Where surgery is a treatment option for vulval SCC, chemotherapy and RT are used in NHL. Male genitourinary organs Prostate Primary prostate lymphoma (PPL) has been documented in 0.1% of NHL (DLBCL being the most common) and 0.09% of prostate malignancies, with a 5-year survival rate of 33%.8, 17 It can mimic benign prostatic hypertrophy or carcinoma as it occurs in elderly men who present with urinary obstruction or retention, however, the PSA level is usually normal17 (Figure 17). In contrast to prostate adenocarcinoma, which generally has low FDG avidity, PPL is intensely avid. Prostatitis also demonstrates intense FDG avidity. PET plays a role in initial staging, treatment response and prognostication, however, due to its rarity, experience is limited. Seminal vesicle Due to the lack of symptoms and rarity of primary seminal vesicle malignancies,18 identification and early diagnosis is challenging. Transrectal ultrasound and CT have previously reported large masses at the seminal vesicles in primary seminal vesicle DLBCL.18 We illustrate a case of relapsed DLBCL affecting the left seminal vesicle without any structural abnormality on conventional imaging (Figure 18), highlighting the superiority of PET. Testicular Testicular lymphoma, affecting 0.26 in 100,000 people annually, is the most common primary testicular malignancy in males over 60 years,19 significantly different to that of germ cell tumours (GCT) who present at 15–35 years of age.8 DLBCL is the most common subtype with reported cases including immunoblastic, plasmablastic and Burkitt-like lymphoma.8 Primary testicular lymphoma (PTL) is intensely avid on FDG-PET. Orchitis demonstrates intense FDG uptake and can be indistinguishable (Figure 19) whereas GCT are less metabolically active (Figure 20). We describe four patterns of FDG avid PTL [(focal or multifocal, diffuse asymmetrical or symmetrical uptake19 (Figures 21–23)]. The testis is an occult sanctuary site with a high rate of relapse in the contralateral testis and CNS, with a median survival between 12 and 24 months.19 Inguinal orchidectomy and RT along with prophylactic intrathecal chemotherapy, CNS irradiation, and adjuvant RT to the contralateral testis can improve survival.19 Spermatic cord Primary spermatic cord lymphoma accounts for 1.6% of all primary spermatic cord tumours affecting patients with a mean age of 60 years, who typically present with a mass in the inguinoscrotal region.20 DLBCL (Figure 24) is most common, however, cases of FL, MALT and Burkitt’s lymphoma have been documented.20 Overall prognosis is poor with a median survival of 12.2 months.20 Penile Penile lymphoma, whilst rare is a diagnosis to consider for patients presenting with painless nodules, non-healing ulcers, or diffuse penile swelling,21 most commonly affecting the shaft followed by the glans penis.21 DLBCL is most common (Figure 25) with reported cases of T-cell and lymphoblastic lymphoma,22 and a wide age range (3–77 years).22 Malignant differential diagnoses also avid on FDG-PET include SCC or sarcoma.21 Contributor Information Nikita Naik, Email: [email protected]. Michael Lin, Email: [email protected]. Peter Lin, Email: [email protected].

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