Lymphoma of the Urinary Bladder

0n 19th December 2002, she was referred to Radiation Oncology for consideration of radiation therapy to the bladder. She was assessed in Oncology clinic on 8th January 2003. Her case was presented at the Lymphoma conference. The consensus was to treat her with radical radiation therapy. The intent of the treatment was radical and the rationale was to achieve long term disease control.

Treatment Planning

Three-dimensional (3-D) radiation therapy treatment planning was used for this case. This process involved series of steps in achieving an accurate treatment delivery.

1. Simulation (January 2003): The patient was positioned supine and a footstock positioned under ankles to immobilise and support both feet. Orthogonal localisation radiographs were taken. These were needed for confirming patient position and relative isocenter placement for comparison with the digital reconstructed radiographs (DRRs).
2. CT imaging procedure (January 2003): A volumetric CT scans of slice thickness of 0.5cm and distance of 0.5cm apart was performed from the 5th lumbar vertebra to 4cm inferior to the ischial tuberosity.
3. Clinical Target (CTV), Planning Target (PTV) volumes and critical structures delineation (January 2003): CTV1 was the tissue volume that contains the bladder and subclinical malignant disease. A margin of 1 cm circumferentially except 2.0 cm superiorly was prescribed to cover CTV1 to account for variations in tissue position, size and shape as well as variations in patient and beam positions, infrafractionally and interfractionally. This defined the PTV1. CT planning procedure was repeated for phase2 at fraction 10 of Phase 1. CTV2 was delineated using these repeated CT images.CTV2 was a reduced volume and prescribed with 1cm margin added to it to define PTV2. Fig 3 (a, b).

        

               Figure 3a, showing CTV1/PTV1                   Figure3b, showing CT2/PTV2 (reduced volume)

4. Prescription: The patient was treated with two phases of radiation therapy. The phase one of the patient’s treatment was prescribed to 24Gy at the isocenter, in 12 fractions with a daily dose of 2Gy.. The phase 2 treatment was prescribed at 16Gy at the isocenter, in 8 fractions with a daily dose of 2Gy. The PTV1 and PTV2 were to be covered by the 95% isodose curve. The total prescription is 40Gy to the 100% at isocenter, in 20 fractions with a daily dose of 2Gy per fraction. The treatment was delivered once a day, five times per week for four weeks.

5.        Dosimetry:Phase1: The patient was planned with parallel opposing (anterior-posterior) fields, isocentrically using multislice CT data. The beam arrangement of almost equal weighting for this plan was simple for the large PTV1 and sparing as much of the lateral part of the pelvis and the femoral heads. The normal tissue was shielded using multi-leaf collimator (MLC). 18 MV photon was the choice of energy as the target was at a depth rather than close to skin surface. The minimum isodose 95% covered the PTV1.The clinically significant maximum dose within the PTV1 is 103%. The prescribed 100% was received at the reference point – isocenter, which is the International Commission on Radiation Units (ICRU) 50 reference point. It recommended that a value of +7% and -5% of the prescribed dose be achieved within the PTV1 Figure 4.

Figure 4 showing isodose distribution in axial, sagittal and coronal views (phase1).

Phase2: The patient was planned 3-D conformally with MLC shielding using 3 coplanar fields- anterior, right and left lateral beam arrangement. Beams and shielding placement were virtually designed by using beam’s eye view (BEV) Figure 5. 18 MV photon was used in achieving 95% isodose curve covering the PTV2 and minimising dose to the surrounding normal structures eg femoral heads and rectum. The significant maximum isodose reported was 105 % Figure 6.

Figure 5. BEVs (phase2)

Figure 6 showing isodose distribution in axial, sagittal and coronal views.

6. Plan evaluation:

The 3-D isodose distribution was evaluated with multiple views of reconstructed sections- axial, sagittal and coronal. In addition a 3-D 95% isodose surface display was used for efficient evaluation of dose distribution in terms of adequate coverage of the planning target volume and sparing the surrounding normal structures such as the femoral heads Figure 7.

Figure 7 3D display of 95% isodose

The critical structures in this plan include the rectum, right and left femoral heads, small bowels and skin. Since the total prescribed dose was 40Gy, the maximum doses received were well under the dose tolerances of these structures.

7. Plan implementation and Treatment Verification: The approved plan for Phase1 was ready for implementation on 16th January 2003. The Phase 2 treatment commenced after completion of Phase1

As per treatment protocol, on the first day of treatment, the isocenter of the plan was verified by taking orthogonal reference radiographs and compared to the original radiographs. Each treatment field was verified by taking the electronic portal imaging (EPI) in the treatment position on day 1. These images were used to verify beam placement and MLC positions by comparing to the planned fields drawn on the simulator radiographs. Skin surface distance (SSD) were taken daily and verified against values obtained from the plans. The departmental guideline for SSD tolerance for 18 MV fields is 1.5 cm for an individual field. A recalculation of monitor units is required if the SSD exceeds 1.5 cm.

      8.        Treatment Delivery and Reactions: The patient was reviewed by the doctor on a weekly basis.The nursing staff performed an initial assessment.

Phase1/Fraction3 (January, 2003): There was complaint of urinary frequency but no indication of incontinence.

Fraction 8: Patient had a few episodes of diarrhoea. She refused any medication.

Fraction 10: Patient complained about diarrhoea. She was given a prescription of immodium tablets. Her potassium level was at 3.4. She was advised to increase her intake of potassium rich food.

Phase2/Fraction 1 (February, 2003): Her diarrhoea settled with the immodium medication. Urinary frequency and nocturia was improved. There was no haematuria. Her general condition was fine.

Fraction 4: Patient tolerated RT well.

The patient completed treatment in mid February 2003.

Discussion

Literature review showed that MALT type lymphoma is the most common type of primary lymphoma of the urinary bladder (Kempton et al, 1997). Only 14 cases of primary MALT lymphoma of the urinary bladder have been reported since 1990. Because they are rare, most examples in the literature have been reported in small number of cases (Cohen et al, 2002, Wazait et al, 2000).

Incidences

The MALT lymphoma of urinary bladder was more common in elderly women (average age 58.7) Males 45%: females 55%. Several authors identified that the disease usually occurred in women (Pawade et al, 1993., Kempton et al ,1997).The higher population of females with this disease maybe reflected bt the high incidence of chronic cystitis in women (Oshawa et al,1993, cited:Wazait et al, 2001).

The case reported in our department was a female of 78 years old.

In 1983, Isaacson and Wright made the observations that certain extranodal lymphomas were related to mucosa-associated lymphoid tissue (MALT) rather than nodal lymphoid tissue. The term MALT emerged from the observation that mucosal sites such as gastrointestinal tract and bronchi harbour specialised lymphoid tissue to protect them. Peyer’s patches (unencapsulated aggregates of lymphoid cells which bear similarities to lymph nodes and contain B and T-cell areas) in the terminal ileum is the most well known example of MALT.

Lymphomas of MALT type was initially observed in the gastrointestinal tract but similar tumour were soon recognised in other sites such as salivary gland, thyroid and lung (Isaacson & Norton, 1994). These extranodal lymphomas became known as MALT lymphomas. The MALT lymphoma of the urinary bladder was first described by Kempton et al in 1990.

It is now widely accepted that MALT lymphomas represent a distinct subset of B-cell malignancy that differs from other low grade B cell lymphomas in its morphologic immunophenotypic and clinical characteristics. In 1994 the revised REAL classification MALT lymphomas is included as a distinct entity under the broader term of marginal zone B-cell lymphoma (Wazait et al, 2000).

Literature review indicated that many authors used the MALT lymphoma distinct clinical and pathological features to support their cases as MALT type of lymphoma of the urinary bladder (Bates et al, 2000, Pawade et al, 1993).

Aetiology and Clinical features

The most common symptom is gross haematuria. Other symptoms are urgency, frequency, dysuria, nocturia,, lower back pain, abdominal pain, and palpable pelvic mass.

The case reported in my department had 4 months of history of lower abdominal pain and episodes of gross haematuria.

The clinical definition of MALT lymphoma is an indolent extranodal lymphoma that tends to remain localised. It is localised at presentation and potentially curable with local therapy .Another common but not necessary required as clinical criteria is the presence of evidence of previous immunologic stimulation at the site (Helicobacter Pylori gastritis, Hashimoto thyroiditis, Sjogren syndrome or myoepithelial sialadenitis (MESA) (Harris et al, 1999).

The aetiology of primary lymphoma of the bladder is unknown Wazait et al, (2001). It is postulated that MALT was induced by inflammation secondary to infection or autoimmune disorder (Isaacson & Norton 1994). All the cases studied by authors Isaacson and Norton, (1994), showed evidence of follicular cystitis in the neighbouring mucosa representing acquired MALT. It seems that it is a necessary precursor for the development of the lymphoma. Several authors, Wazait et al, (2001), Harris et al (1999), Thieblemont et al, (2000), reasoned that MALT lymphoma in the bladder was induced by chronic inflammation following the observation of MALT lymphoma in the stomach preceded by Helicobacter Pylori infection, Sjoergen syndrome in the salivary glands and Hashimoto disease in thyroid. However it was argued against cystitis as a preceding condition by Heaney et al, 1983 (cited Cohen et al, 2002). Their finding showed that the lymphoid aggregation seen in chronic cystitis is usually on the lamina propria (cystitis follicularis), whereas most of the florid lymphomatous involvement in lymphoma is in the deeper layers of the lamina propria and muscle. (Cohen et al, 2002). On the other hand in a clinical pathological study of 11 cases of malignant lymphoma of bladder (Bates et al 2000) none of the 3 cases of MALT type lymphoma of the bladder had a documented history of cystitis but in no case had there been previous bladder biopsies, so the presence or absence of cystitis was difficult to ascertain. However the presence of lymphoepithelial lesions and reactive lymphoid follicles in each of the 3 cases supports the hypothesis that cystitis is a necessary precursor of MALT lymphoma, as experience with MALT lymphomas at other sites would suggest (Bates et al, 2000). Literature review showed that this controversial issue is still ill defined.

The case reported from our department had follicular cystitis.

Pathological features

MALT type lymphoma recapitulates the features of Peyer’s patch lymphoid tissue (Isaacson &Norton 1994, Harris et al 1999).MALT lymphomas consist of an admixture of small lymphocytes and small cells that have indented nuclei and abundant cytoplasm- centrocyte cell like (CCL) and resemble nodal monocytoid B-cell. The tumour cells are thought to be derived from cells of the marginal zone, which have the capacity to mature into monocytoid B cells and plasma cells. A main feature of MALT lymphoma is the lymphoepithelial lesion formed by invasion of individual crypt aggregates of the lymphoma cells in the epithelial tissue.

The distribution of the CCL cells in the MALT lymphoma corresponds to that of the marginal zone (MZ) cells in Peyer’s patches. The similarities of both cells give rise to similar immunophenotype CD 21+, CD35+, CD32+, and UCL4D12 +positive (Isaacson & Norton, 1994).Table 3.

The immunophenotype of MALT lymphoma is not specific. The B cells that are CD5-, CD10- and cylin D1- negative are indicated by Harris et al (1999) as possible immunophenotypic criteria for defining MALT lymphoma. The case reported by Yuille et al, (1998) had immunohistochemistry showing positive for CD20+ and lymphoma was of B-cell type. The immunophenotype result of the case described in our department reported tumour cells positive for LCA, CD20, and CD 79A confirming B-cell origin. The Ki -67 staining index within the neoplastic cell was low. BCL2 staining was negative within follicles confirming the reactive origin.

Table 3.(Isaacson & Norton, 1994).

The biologic definition is not clear. Malt type lymphoma seems to be a neoplasm of B cells that proliferate preferentially in mucosal and other extranodal sites and that have a specific interaction with epithelium and reactive germinal centres (Harris et al, 1999).

Diagnostic methods

Accurate diagnosis is important because these patients have a favourable prognosis and also may have implication for treatment.

Cystoscopy is most common procedure used in diagnosis of MALT lymphoma of the bladder. Staging of 5 out of 6 cases reported in Kempton et al (1997) study, showed MALT lymphoma occurred as a single mass and the remaining case showed multifocal involvement of the bladder.

In article by Cohen et al,(2002), the best diagnostic imaging study to make the diagnosis is CT scanning of the abdomen and pelvis although there is no defined image specific to this entity. The radiological findings of this rare tumour have not been extensively described in the literature. Most cases are reported in the pathology and urology literature. Only 7 cases have been reported in the radiology literature (Tasu et al, 2000). The report identified that the most frequent site of occurrence of this tumour was in the lateral wall of the urinary bladder – 40%. However Kempton et al (1997), reported that the common site was the trigone and dome of the bladder. Only10% had tumour in the posterior wall. 66% of the study showed as sessile masses in the CT findings.

The case reported from our department had CT for staging. which showed results of a solitary mass (11cm x 8cm) in the posterior wall and showed no lymphadenopathy.

Literature review showed no mention of using Magnetic resonance imaging scanner as a diagnostic tool. An article indicated that MR findings have reported no significant difference between lymphoma and carcinoma.

Staging

Ann Arbor staging system for Hodgkin’s Disease is used commonly for staging extranodal lymphoma.

IE (the subscript signifies an extranodal site). The lymphoma is confined to the wall of the organ. In stage 2 there is involvement of a regional but non–contiguous lymph node group. Stage 3 refers to involvement of lymph nodes of both sides of diaphragm, stage 3s the spleen. Stage 4 indicate there is dissemination to the bone marrow or other non lymphoid organs.

The case reported is diagnosed with Stage 1AE. The ‘A’ signifies absence of systemic symptoms such as weight loss, fever, or pruritis.

Management

Literature review showed that the optimal treatment approach for MALT lymphomas is still evolving because of its rarity.

Current recommended management is radical RT but in the absence of bladder symptoms, more conservative management such as antibiotic therapy might be considered.

There is evidence that the pathogenesis of MALT lymphoma of the bladder is similar to that of the acquired MALT in the form of follicular cystitis has been observed in many cases. Following the example of gastric MALT lymphoma, eradicating the cause of cystitis could be an effective treatment of the low grade B-cell MALT lymphoma of bladder. One article reported successful treatment of MALT lymphoma of the urinary bladder using Helicobacter Pylori (HP) eradication Therapy. The patient had Stage 1AE MALT lymphoma and refused RT. The patient is still in complete remission and is the first known case reported by Bosch et al (2002), of the disappearance of MALT lymphoma of the urinary bladder after treatment with HP eradication therapy. The case reported in our department was initially treated by using HP therapy as supported by other case reports reviewed by the haematologist. The treatment was abandoned as patient had severe diarrhoea and also the large size of the tumour mass would seem unlikely to benefit.

MALT lymphomas of bladder have similar clinical features of other sites in which it may remain

localised for long periods of time. This favourable clinical feature may allow adequate treatment with local RT (Pawade et al, 1993). RT should not be localised to the tumour site but should applied to the whole organ because the neoplasm often involves deeper submuscularis.

One clinical investigation conducted in Princess Margaret Hospital, 3 MALT lymphomas of bladder were treated with RT. Out of the 3 cases one was treated to 30Gy and the remaining 2 were treated to 35Gy (Tsang et al, 2001). Excellent local control-100% local control rate with stage 1 and 2.has been reported by Schecter et al (cited Tsang 2001).

A case reported by Yuille et al (1998) received RT dose of 40Gy in 20 fractions over 29 days to the bladder as planned volume and was well tolerated by 80 year female patient.

While literature supports RT as the therapeutic modality alone as the favourable treatment option to the whole bladder, there is consideration for multimodality therapy approach in some cases.

This case reported in our department had RT treatment to the whole bladder region in 2 phases. These tumours are in general very radiosensitive. We anticipated good volume reduction even with relatively small doses of RT. That was the reason for repeating CT after 10 fractions. However, she had considerably residual tumour in the repeated CT Figure 3b.

We did not achieve much volume reduction as expected. Therefore RT treatment was continued to deliver a total tumour dose of 40Gy.

Prognosis

Prognosis of MALT lymphomas confined to the bladder in common with other sites generally carry a good prognosis and little tendency to disseminate (Bates et al, 2000) Patients have a good result, with long disease free survival (Thieblemont et al 2000).

Although only a small number of cases have been reported by several authors, the prognosis of MALT-type lymphoma confined to the bladder appears to be favourable. From a study by Pawade et al, (1993) only one patient with MALT –type of the bladder has been reported to died of the disease.

One case reported by Yuille et al (1998), had quite similar presentation of the case described in our department– both patients were elderly and had large mass in the posterior wall of the bladder indicated in CT finding. Both patients received 40Gy in 20 fractions to the bladder as the planned volume. Both patients tolerated RT well

The case reported in our department is still alive and is reviewed by the radiation oncologist at interval of 3 months. Follow up CT scans and cystoscopy showed no recurrence of tumour. Patient had shown excellent response to RT treatment.

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