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Clinical Meetings at RH Year 2012

2012 - An unusual answer to a common scenario

Drs LH SHEK and CK CHOW; Department of Medicine and Geriatrics, Caritas Medical Center

Case History
A 59 years old gentleman was referred to our Endocrine clinic for work up of hypo-pituitarism after pituitary adenomectomy performed in year 2010 for benign pituitary tumour. He had secondary hypothyroidism and was put on thyroxin replacement by the Oncology Team. He had enjoyed good past health otherwise.

He complained of polyuria, dry mouth and generalized malaise after he had received the operation. He had no chest symptoms all along. On physical examination, he was afebrile and Body Mass Index was 18.4. General examination was unremarkable with no pallor, finger clubbing or palpable lymph nodes. Chest auscultation revealed right basal crepitations. Figure 1. Routine CXR in Endocrine Clinic 10/2010. Right Lower Zone Consolidation




He was admitted to our ward at the end of October 2010 for work up of his hormonal profile and the incidental finding of the right lower zone shadow detected on the routine chest X-ray. He had adrenal insufficiency proven by Short Synacthen Test and was put on hydrocortisone replacement.

He was afebrile and had no chest symptoms. Blood tests including complete blood count, liver and renal functions were normal. His LDH level and Albumin/globulin level were normal. Sputum culture and AFB smear were negative. He was given Augmentin for one week empirically; and he performed private CT thorax with contrast in the same month.



Bronchoscopy was performed in October 2012. There was no endo-bronchial lesion, and the bronchial aspirate yielded no malignant cells. Trans-bronchial biopsy obtained at right lower lobe was: Extra-nodal marginal zone B-CELL LYMPHOMA of mucosa-associated lymphoid tissue (MALT lymphoma).

He received further investigations:
- serum protein electrophoresis : abnormal band detected in mid-gamma region measuring 3g/L
- immunofixation electrophoresis: IgM-kappa paraprotein detected
- IgG, IgA level were normal; slight increased in IgM 357 (55-307 mg/dl)
- Hepatitis B & C serology were negative
- HIV was negative
- Bone marrow examination showed no evidence of lymphoma involvement.

He was referred to Oncology and Cardiothoracic Team. Surgical resection (lobectomy) was suggested but the patient refused the operation and defaulted further follow up visit until the end of February 2012. CT scan was repeated in February, which showed the same right lower lobe consolidation and some new small subcarinal lymph nodes of less than 1 cm.

He received right thoracotomy with right middle and lower lobe lobectomy at the end of March 2012. The pathology confirmed pulmonary MALT lymphoma. The stapled margin showed focal involvement and the subcarinal, hilar, lobar and right paratracheal lymph nodes were also involved.

He was followed up in Oncology Team post-operatively. Oncology team repeated bone marrow examination which was normal, and contrast CT scan from nasopharynx to pelvis showed no abnormal lymph nodes. He is waiting for next follow up visit to see if further treatment is required.

Discussion
Marginal zone lymphoma was formally reported as monocytoid B-cell lymphoma and immunocytoma. It was first recognized as a separate clinical pathological entity by Isaacson and Wright in 1983. It is classified under the non-Hodgkin lymphoma of marginal zone lymphoma subtype (REAL/WHO classification systems). Together with nodal marginal zone B cell lymphoma and splenic marginal zone cell lymphoma, they are classified under this category as they appear to arise from the same germinal center and share a similar immuno-phenotype.

Extra-nodal marginal-zone lymphoma of MALT type encompasses 5-8% of all non-Hodgkin lymphoma. The commonest primary extra-nodal site is stomach, accounting for 60% of all extra-nodal marginal-zone lymphoma of MALT type and pulmonary MALT lymphoma accounts for 15% of cases. (1, 2)

Pathogenesis
(I) Genome instability: Somatic hyper-mutation is a key component to the affinity maturation of the humoral immune response, which introduces point mutations and small deletions to the immunoglobulin heavy chain genes of the germinal center B cells. Gene translocation at this juncture leads to lymphomagenesis. The commonest gene translocation is API2-MALT1 Fusion, which was detected in 40% cases of pulmonary MALT lymphoma. Patients with this fusion gene present a more indolent disease and are histologically more typical of the pulmonary MALT lymphoma (3)

(II) Antigen Driven: The second theory was the antigen driven chronic inflammation leading to the accumulation and proliferation of antigen-dependent B cells. The origin of the antigens could be self (autoimmune) or external (pathogen).

-Autoimmune: Sjogren Syndrome was associated with 30 fold risk of developing Marginal-zone lymphoma in a report studying over 700 patients with Marginal-zone lymphoma(4). For pulmonary lymphoma, a report in European Respiratory Journal (1), reported 10 out of 63 patients had history of autoimmune disease, 5 had Sjogren Syndrome, 1 had Rheumatoid Arthritis and 4 had undifferentiated connective tissue disease.

-Pathogens: Primary gastric MALT lymphoma is well reported to be causally related to H. pylori infection and the treatment of H. pylori is crucial in management of gastric MALT lymphoma. Other reported correlations were Campylobacter jejuni with colonic MALT lymphoma and C. psittaci with ocular adnexal MALT lymphoma. For pulmonary MALT lymphoma, it is controversial. Chlamydia and Mycoplasma could lead to chronic inflammation but there were no sufficient evidence to show their correlation to pulmonary MALT lymphoma. A report in 2007 in British Journal of Cancer showed no significant causative relationship(5); but a conflicting report in 2011 showed Chlamydia psittaci DNA was detected in 5 out of 5 patients with pulmonary MALT lymphoma’s lung biopsy in contrast to none detected in normal lung biopsy.(6) Pulmonary Tuberculosis was not correlated to pulmonary MALT lymphoma.(7)

Presentation and Diagnosis
Patients are usually asymptomatic but with radiological abnormality. Some of the patients may present with B symptoms (fever, weight loss and night sweating) and various chest symptoms including haemoptysis, cough and chest pain. (1)

Diagnosis is based on morphologic, immunophenotypic and genetic analysis of the biopsy material. The tissue could be obtained by bronchoscopy but the diagnostic yield was relatively low at 30-40%. Bronchial alveolar lavage (BAL) may aid the diagnosis by detection of MALT1 gene rearrangement. (10) Open surgical or VATS lung biopsy could yield more than 90% (8, 9)

The investigation and work up should go in line with all non-Hodgkin lymphoma, aim to establish the precise histologic subtype, the extent and site of disease. Physical examination should include lymphoid survey to look for any lymph node enlargement and hepatosplenmegaly. Besides routine blood tests, other blood tests such as serum calcium, LDH, uric acid, serum protein electrophoresis, Beta-2 microglobulin levels, HIV, hepatitis B and C serology are helpful. Autoimmune markers are indicated if autoimmune disease is suspected. Bone marrow examination should be done in all cases as 13% of non-gastric MALT lymphoma develops bone marrow involvement.

The X-ray and CT features are non-specific, ranging from consolidation, lung mass to nodules; but interestingly, it seldom presents with pleural effusion. CT scan is useful in staging for detection of any enlargement of non-palpable lymph nodes. Pulmonary MALT lymphoma is not a typically FDG avid lymphoma; therefore PET scan would not add information to the diagnosis or staging of the disease.

Non-gastric MALT lymphoma was more likely to disseminate, 35% were found disseminated at time of diagnosis. There were several studies showing the significance of gastric involvement in patients with pulmonary MALT lymphoma (11, 12). These results suggest that routine evaluation of stomach with Oesophagogastroduodenoscopy (OGD) should be a part of the initial staging procedures.

Treatment
There is no guideline or protocol specific for the treatment of pulmonary MALT lymphoma. The reported treatment options:
- Surgery
- Radiotherapy
- Chemotherapy
- Immunotherapy
- Combination of the above
- Antibiotics?
- Watchful waiting

It is generally agreed that localized/regional treatment like surgical resection or radiotherapy for patients with stage I-II (Ann Arbor Pulmonary Lymphoma Staging); systemic treatment i.e. chemotherapy for stage III-IV disease. The treatment options did not affect the overall survival.

Rituximab, an anti-CD20 monoclonal antibody is logically useful treatment modality as 100% of MALT lymphoma expresses CD20. A recent Korean research reported a case with complete remission with 6 weeks course of Rituximab as single agent first line therapy. (13)

There was a case report in CHEST 2010, reporting 2 patients who were refractory to conventional treatment; they were treated with long term Clarithromycin 200mg daily and attained complete remission of disease. (14) Although many pulmonary MALT lymphoma cases were related to Helicobacter pylori infection, treatment of H. pylori was ineffective for the treatment of non-gastric MALT lymphoma. (15)

The prognosis of pulmonary MALT lymphoma is generally good, with 10-year survival over 70% and 10-year progress free survival of 36% (1). Watchful waiting might be an acceptable alterative as retrospective study showed that overall survival did not differ in patients with or without active treatment. (16)

Summary

Pulmonary MALT lymphoma is an indolent disease with good prognosis in general. It is a rare form of lung cancer encompassing less than 1% of all lung cancers. There is a role for OGD in the initial work up for pulmonary MALT lymphoma. Although there were no typical radiological features, hopefully when you come across an asymptomatic patient with a large lung mass without pleural effusion; pulmonary MALT lymphoma shall be one of your top differentials.

References
  1. Borie et al. Clinical characteristics and prognostic factors of pulmonary MALT lymphoma. Eur Respir J 2009; 34 1408-1416.
  2. Cohen et al. Non-Hodgkin's lymphoma of mucosa-associated lymphoid tissue. Oncologist. 2006 Nov-Dec;11(10):1100-17.Oncologist. 2006 Nov-Dec;11(10):1100-17
  3. Okabe et al. API2-MALT1 Fusion Defines a Distinctive Clinicopathologic Subtype in Pulmonary Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue. American Journal of Pathology, Vol.162, No.4, April 2003; 1113-1122
  4. EKSTRO ̈ M SMEDBY et al. Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. Blood, 15 April 2008;VOLUME 111, Number 8
  5. E Chanudet et al. Chlamydiae and Mycoplasma infections in pulmonary MALT lymphoma. British Journal of Cancer 2007 97; 949-51
  6. AigelsreiterA,GerlzaT,DeutschAJA,etal.Chlamydia psittaci Infection in nongastrointestinal extranodal MALT lymphomas and their precursor lesions. Am J Clin Pathol. 2011;135:70-75.
  7. Tom-Oliver et al Bronchus-Associated Lymphoid Tissue Lymphoma and Mycobacterium tuberculosis Infection: An Unusual Case and a Review of the Literature. Respiratory Care, June 200; Number 6
  8. Kim JH, Lee SH, Park J, Kim HY, Lee SI, Park JO, Kim K, Kim WS, Jung CW, Park YS, Im YH, Kang WK, Lee MH, Park K, Han JH, Ko YH. Primary pulmonary non-Hodgkin's lymphoma. Jpn J Clin Oncol. 2004;34:510–514
  9. Tamura A et al. Primary pulmonary lymphoma: relationship between clinical features and pathologic findings in 24 cases. The Japan National Chest Hospital Study Group for Lung Cancer. .Jpn J Clin Oncol 1995 25(4);140-52
  10. Takashi Kido et al. Detection of MALT1 Gene Rearrangements in BAL Fluid Cells for the Diagnosis of Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma. Chest January 2012 141:1 176-182
  11. Raderer M, Wohrer S, Streubel B, Troch M, Turetschek K, Jager U, et al. Assessment of disease dissemination in gastric compared with extragastric mucosa-associated lymphoid tissue lymphoma using extensive staging: a single-center experience. J Clin Oncol. 2006;24(19):3136-41.
  12. Dabaja BS, Ha CS, Wilder RB, Pro B, McLaughlin P, Cabanillas F, Cox JD et al.Importance of esophagogastroduodenoscopy in the evaluation of non-gastrointestinal mucosa-associated lymphoid tissue lymphoma. Cancer J. 2003;9(4):321.
  13. Bilici A et al. Pulmonary BALT Lymphoma Successfully Treated with Eight Cycles Weekly Rituximab: Report of First Case and F-18 FDG PET/CT ImagesJ Korean Med Sci. 2011 April; 26(4): 574–576.
  14. Yuji Ishimatsu et al. Two Cases with Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma Successfully Treated with Clarithromycin. CHEST 2010;138(3);730-733
  15. Gru ̈ nberger et al. Antibiotic Treatment Is Not Effective in Patients Infected With Helicobacter pylori Suffering From Extragastric MALT Lymphoma. J Clin Oncol 24: 1370-1375 2006
  16. Troch et al. Does MALT Lymphoma of the Lung Require Immediate Treatment? An Analysis of 11 Untreated Cases with Long-term Follow up. Anticancer Research 27: 3633-3638 (2007)
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