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A VIPoma is an endocrine tumor, usually originating in the pancreas, which produces a vasoactive intestinal peptide and is believed to cause profound cardiovascular and electrolyte changes with vasodilatory hypotension, watery diarrhea, hypokalemia, and dehydration.

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A 35-year-old woman with asthma and polycystic lung disease - pulmonary and critical care pearls
From CHEST, 1/1/02 by Octavian C. Ioachimescu

(CHEST 2002; 121:256-260)

A 35-year-old white woman with a history of asthma since childhood went to her primary-care physician with symptoms of fever, cough, and yellowish sputum of 2 days in duration. A chest radiograph showed a right upper lobe infiltrate and multiple thin-walled cysts scattered over both lung fields (Fig 1), and findings were confirmed on a CT scan (Fig 2). The upper lobe infiltrate resolved after 10 days of antibiotic treatment. Because of persistent polycystic lung disease, the patient was referred to a pulmonologist for further investigation and treatment.

[FIGURES 1-2 OMITTED]

The most severe asthmatic exacerbations the patient experienced were during menses, while receiving birth control pills (for uncomplicated uterine leiomyoma), and during pregnancy. Her asthma was relatively stable over the last years, with intermittent use of albuterol as rescue inhaler.

Other significant medical history consisted of four episodes of pneumonia (localized in different lobes, without any other pulmonary lesions on the chest radiographs). A rash reaction was documented to sulfa drugs in the past; no aspirin or other nonsteroidal anti-inflammatory drug sensitivity was noted.

The family history included hypertension and diabetes mellitus (father), vipoma (mother), juvenile rheumatoid arthritis (brother), systemic lupus erythematosus (maternal aunt), and reactive arthritis (one daughter). There was no family history of asthma or other allergic conditions.

On physical examination, she was an alert, young woman in no acute distress. Her weight was 70 kg and her height was 162 cm. She had a BP of 120/70 mm Hg; heart rate, 60 beats/rain and regular; respiratory rate, 16 breaths/min; temperature, 38.8 [degrees] C; and pulse oximetry, 96% on room air. The head, eyes, ears, nose, and throat were normal; the neck was supple, without any masses, lymph nodes, thyroidomegaly, or jugular venous distension. The lung examination revealed scattered rhonchi and no wheezes or crackles. The cardiac examination was unremarkable; she had no clubbing, cyanosis, rashes, or alopecia. The remainder of the examination was normal.

Laboratory Findings

The CBC count, chemistry panel, liver function tests, total proteins, albumin, and urinalysis results were all normal. The serum protein electrophoresis showed a discrete band in the mid-[gamma] region, and by immunofixation, a biclonal IgG-type [lambda] gammapathy. The serum IgG and IgM 400 were slightly elevated, with a mild increase of [lambda] chains. No IgG subclass deficiencies were identified. The thyroid-stimulating hormone was within normal limits. The rheumatoid factor was mildly elevated to 45 IU/mL (normal < 16 IU/mL), antinuclear antibody and Sjogren's syndrome antigens A and B serologies were negative, and [[alpha].sub.1]-antitrypsin level was normal (in a reference laboratory).

The pulmonary function test results showed a mild obstructive ventilatory defect, nonreversible to inhaled bronchodilator: FE[V.sub.1], 1.90 L (74% of predicted); FVC, 2.94 L (84% of predicted); FE[V.sub.1]/FVC ratio, 65%; residual volume, 3.26 L (168% of predicted); total lung capacity, 6.37 L (108% of predicted); residual volume/total lung capacity, 51%; functional residual capacity, 3.84 L (117% of predicted); and diffusing capacity of the lung for carbon monoxide, 22.2 mL/mm Hg/min (85% of predicted). Arterial blood gas values were normal.

The chest radiograph showed pectus excavatum and polycystic lung disease with bilateral abnormal linear densities, particularly in the mid and lower lung zones, occupying more than two thirds of the lung parenchyma (Fig 1). The high-resolution CT scan revealed multiple thin-walled cysts superimposed on a background of normal lung, and multiple pulmonary nodules measuring < 1 cm in diameter. No intrathoracic lymph node enlargements were appreciated (Fig 2). The patient underwent a thoracoscopic wedge resection biopsy from the left lower lobe without any complications.

What is the likely diagnosis?

Diagnosis: Low-grade B-cell lymphoma of bronchial-associated lymphoid tissue; follicular bronchiolitis

DISCUSSION

In the lungs, between the blood vessels and the lymphatic vessels/nodes, the lymphocytes reside in one of the following pools: at the epithelium surface of the bronchi and alveoli; within aggregates associated with the epithelium, the so-called bronchial-associated lymphoid tissue (BALT); and in the interstitium. Each compartment has a distinct phenotypic and functional repertoire.

The lymphoproliferative disorders of the lung can be classified as benign and malignant. The benign lesions can be either diffuse--like follicular bronchitis/ bronchiolitis, diffuse lymphoid hyperplasia, and lymphoid interstitial pneumonitis--or localized nodular lesions, such as plasma cell granuloma, hyalinizing granuloma, or Castleman's disease. The malignant lesions can be subclassified in Hodgkin's disease and non-Hodgkin's lymphoma, which could be either B-cell, T-cell, or natural-killer cell neoplasms. The current classification of the primary pulmonary lymphoproliferative disorders includes BALT lymphoma, large cell B-cell lymphoma, primary pulmonary Hodgkin's disease, posttransplant lymphoproliferative disorders, HIV-related lymphoma, lymphomatoid granulomatosis, extramedullary plasmacytoma, and primary pulmonary Langerhans' cell histiocytosis.

Diffuse lymphoid hyperplasia of the BALT system is characterized by expansion of the lymphatic routes by nodular aggregates of small lymphocytes, which compress adjacent alveolae but do not extend into alveolar septa. Follicular bronchiolitis is a hyperplasia of the lymphoid tissue in the bronchial and bronchiolar submucosa and peribronchial connective tissue only. Both are considered to be nonspecific proliferative response of the BALT to chronic airway infection (viruses or Mycoplasma), chronic bronchial obstruction, asthma, COPD, or cystic fibrosis. In the absence of these conditions, other diseases should be ruled out, such as adult or juvenile rheumatoid arthritis, Sjogren's syndrome, HIV infection, and hypersensitivity conditions.

The clinical picture of follicular bronchiolitis includes an onset of disease in patients from 1 to 70 years old, with a slight female preponderance, with the main complaint being, in the majority of cases, exertional dyspnea. The most frequently encountered radiologic appearance is that of bilateral reticulonodular infiltrates; the main CT scan findings are bilateral centrilobular and peribronchial nodules with ground-glass opacities in 75% of cases. The treatment consists of steroids and chemotherapy; only a few cases are chemoresistant.

In patients with lymphoid interstitial pneumonitis (LIP), there is a marked infiltration of alveolar septa and extra-alveolar interstitial space with lymphocytes, plasma cells, and histiocytes. The feature distinguishing LIP from lymphoid hyperplasia or follicular bronchiolitis is a diffuse involvement of the alveolar septa. The lymphocytes are generally small sized, with minimal atypia, of B-cell type, sometimes associated with T-helper cells. LIP has about the same clinical associations as follicular bronchiolitis. The radiologic picture is that of diffuse reticular or reticulonodular infiltrates, mostly at the bases, with possible progression to interstitial fibrosis and honeycombing. The CT findings are ground-glass opacities with poorly defined centrilobular nodules plus/minus subpleural small nodules, cystic lesions, and lymph node enlargement. The management is the same as that of follicular bronchiolitis.

Low-grade, small B-cell BALT lymphomas represent up to 90% of primary pulmonary non-Hodgkin's lymphoma and are frequently associated with underlying systemic immune disorders, including Sjogren's syndrome. They are slow growing, and thus were initially considered benign and called pseudolymphoma by Saltzenstein. Clinically, they have an indolent course, and localized forms can be cured by surgical removal. Immunohistochemical and genetic techniques have shown that they are monoclonal B-cell proliferations and that pseudolymphomas are actually low-grade BALT lymphoma. Macroscopically, the lesions may be unicentric or multicentric, unilateral or bilateral. The neoplastic cells are small, dense lymphocytes with minimal atypia. Infiltration of the bronchial mucosa may cause luminal narrowing with associated obstructive pneumonia, atelectasis, or possibly air trapping with secondary cyst formation. Demonstration of light-chain restriction or clonal Ig gene rearrangements is helpful in differentiating low-grade BALT lymphoma from reactive lymphoid proliferations. The small B-cell BALT lymphomas express monotypic Ig- and B-cell-associated antigens; they do not express T-cell markers such as CD5 or CD10; furthermore, they do not have bcl 1 or bcl 2 gene rearrangements.

The clinical presentation of low-grade BALT lymphomas generally occurs in patients from 25 to 85 years of age, with a peak incidence in the sixth decade; there is no gender preponderance. The diagnosis can be incidental on chest radiograph, or the patients may present with cough, dyspnea, hemoptysis, crackles plus/minus fever, weight loss, and night sweats, the latter manifestations as markers of extrathoracic involvement. The pulmonary function test results usually show an obstructive ventilatory defect. The serologic studies may show a monoclonal gammapathy (most often IgM) and in some cases free [kappa] or [lambda] chains. In a few patients, the BAL can show a monoclonal population of small lymphocytes. The treatment is surgical removal if amenable, or chemotherapy and radiation if the patient is symptomatic and/or if surgical treatment is not possible. Close follow-up is necessary because of the possibility of transformation into a high-grade B-cell lymphoma.

The high-grade B-cell lymphoma, with its attendant prognosis, can be classified into large noncleaved cell and immunoblastic cell types; some of them develop from lesions of low-grade BALT lymphoma. These forms usually have constitutional symptoms, and the pulmonary function test results reveal a restrictive ventilatory defect. The CT scan of the chest often shows diffuse pneumonic infiltrates with air bronchograms and nodules, bubble-like radiolucencies, ground-glass attenuation, and also diffuse air trapping. The bubble-like radiolucencies were consistent with bronchiolar/distal bronchi dilatation or small cysts in the periphery of the lung parenchyma. In LIP, lung cyst formation is a well-known phenomenon and its mechanism is thought to be partial bronchiolar obstruction with air trapping due to peribronchiolar lymphocytic infiltration. This phenomenon has been described either in low-grade BALT lymphoma or in follicular bronchiolitis.

In our case, the imaging studies revealed multiple thin-walled cysts, with larger diameters than the bubble-like radiolucencies described in previous reports. The radiographic differential diagnosis of lung cysts in a young woman includes lymphangioleiomyomatosis, tuberous sclerosis complex, eosinophilic granuloma of the lung (or Langerhans' cell histiocytosis), congenital polycystic lung disease, and infectious/postinfectious. [[alpha].sub.1]-Antitrypsin deficiency was excluded in our patient by demonstrating normal serum enzyme activity measured in a reference laboratory.

Pathologic Findings

Hematoxylin-eosin-stained sections of the lung biopsy showed features of follicular bronchiolitis, characterized by reactive lymphoid follicles, some of which were seen to compress bronchioles and sheets of atypical small lymphocytes, admixed with plasma cells, scattered histiocytes, and eosinophils (Fig 3, 4). Immunostains showed that the majority of the cells of both follicular bronchiolitis and lymphomatous lesions were CD20 positive (B cells) and only scattered UCHL1 positive (T cells); they were S100 negative (Langerhans' cell marker) and HMB45 negative (marker for myoid cells of lymphangiomyomatosis). The stains for [kappa] and [lambda] light chains revealed a polyclonal staining pattern of the accompanying plasma cells. Polymerase chain reaction-based DNA testing for Ig heavy and T-cell gene rearrangements showed a single rearranged band in the heavy-chain region. This result was consistent with a monoclonal B-lymphocyte population.

[FIGURES 3-4 OMITTED]

Our case presents the interesting feature of combined pathologic findings of a benign condition (follicular bronchiolitis), and a low-grade B-cell lymphoma of BALT. Either pathologic findings could be encountered in Sjogren's syndrome, and this scenario cannot be ruled out completely, even though for the time being there is neither clinical nor laboratory data to support the diagnosis of Sjogren's syndrome. The family history positive for different connective tissue disorders may anticipate future progression to a collagen vascular disorder.

Follow-up: The patient was administered a full course of pulse steroids for 2 months, every other week, and then a 6-week course of rituximab, a monoclonal antibody against CD20-positive cells. She tolerated the treatment very well, with an Eastern Cooperative Oncology Group performance status of 0, but no significant radiologic or functional improvement at 2 months after the completion of the treatment.

Clinical Pearls

1. In young patients with diffuse polycystic-bullous lung disease, lesions of follicular bronchiolitis or low-grade BALT lymphoma can be pathogenically responsible for air trapping, by a valve mechanism.

2. The coexistence of a malignant disorder cannot be excluded in the presence of a polycystic lung disease; the lung biopsy is crucial in establishing the diagnosis.

3. Sjogren's syndrome is often associated with pulmonary lesions of lymphocytic alveolitis, LIP, follicular bronchiolitis, or BALT lymphoma.

4. Low-grade B-cell lymphomas of BALT can be discovered incidentally in asymptomatic patients; treatment with corticosteroids and other immunosuppressants should be advocated in the case of impending complications and/or surgical unresectability. The role of rituximab and other monoclonal antibodies in this setting remain to be established.