Benign Lymphoproliferative Disorders of the Lung (Benign intraparenchymal lymph nodes, Nodular lymphoid hyperplasia, Follicular bronchiolitis, Lymphoid interstitial pneumonitis, IgG4 sclerosing disease)

What every physician needs to know:

Benign lymphoproliferative disorders of the lung include:

• Benign intraparenchymal lymph nodes

• Nodular lymphoid hyperplasia

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• Follicular bronchiolitis

• Lymphocytic interstitial pneumonia (LIP)

• IgG4-related sclerosing disease

These conditions represent distinct histologic patterns that are characterized by hyperplasia of the bronchial-associated lymphoid tissue (BALT). LIP and follicular bronchiolitis often present as diffuse parenchymal lung diseases, mimicking interstitial lung disease. Intraparenchymal lymph node and nodular lymphoid hyperplasia commonly present as pulmonary nodules, mimicking malignancy.

Benign nodular hyperplasia, follicular bronchiolitis, and LIP overlap histologically, differing in the extent and location of lymphoid hyperplasia. Surgical biopsy is required for definitive diagnosis. Molecular and immunohistochemical analysis of resected tissue is required to exclude neoplastic lymphoproliferative disorders.

IgG4 sclerosing disease is a steroid-responsive systemic sclerosing disease that may involve thoracic structures with or without extrathoracic organ involvement. The lung may be involved diffusely as in interstitial lung disease or focally as a mass lesion. Mediastinal fibrosis and pleural effusion have been reported as well. Diagnosis requires histology that demonstrates a plasmalymphocytic infiltrate with abundant IgG4-positive plasma cells in an appropriate clinical setting.

Classification:

Benign lymphoproliferative disorders include:

• Intraparenchymal lymph nodes

• Follicular bronchiolitis

• Lymphoid interstitial pneumonitis

• Nodular lymphoid hyperplasia

• IgG4-related sclerosing disease

Are you sure your patient has a benign lymphoproliferative disorder of the lung? What should you expect to find?

Intraparenchymal lymph nodes

Intrapulmonary lymph nodes are often identified incidentally during imaging performed for the workup of other disorders since patients are usually asymptomatic. While CT imaging routinely identifies hilar and mediastinal lymphadenopathy, intraparenchymal lymph nodes are identified less frequently. Intraparenchymal lymph nodes are clinically important because they mimic carcinoma and biopsy may be necessary to exclude malignancy.

Follicular bronchiolitis

Individuals with follicular bronchiolitis are typically adults (median age is 44) although children may be affected as well. Patients present with cough and dyspnea and less commonly with fever, weight loss, and fatigue. Recurrent respiratory tract infection is common. Spirometry may show an obstructive, restrictive or mixed pattern.

Several conditions are associated with development of follicular bronchiolitis:

• Connective tissue disease, most commonly Sjögren’s syndrome and rheumatoid arthritis

• HIV infection

• Common variable immune deficiency: these individuals may develop follicular bronchiolitis as part of the syndrome of granulomatous lymphocytic interstitial lung disease (GLILD) in which LIP, follicular bronchiolitis, and poorly formed granulomas are seen histologically.

Follicular bronchiolitis may occur without associated diseases (idiopathic), or as a secondary pathologic finding in other lung diseases.

Lymphocytic interstitial pneumonia (LIP)

The majority of patients with LIP have symptoms of dry cough and dyspnea. Fever, sweats, and weight loss occur infrequently. LIP is a chronic disease with signs and symptoms developing over months to years. Autoimmune disease (most commonly Sjögren’s Syndrome) and immunodeficiency (HIV, common variable immune deficiency) are the primary risks for LIP, though idiopathic cases clearly occur. While the typical age of onset is between forty and seventy, LIP has been described in the elderly and in children (typically presenting at age one to two). When the disease is not associated with HIV infection, women are affected twice as often as men are, and patients of either gender are most often Caucasian.

Nodular lymphoid hyperplasia

Nodular lymphoid hyperplasia is a new term referring to cases formerly known as “pseudolymphoma”. In contrast to LIP and follicular bronchiolitis, nodular lymphoid hyperplasia is considered to represent a localized form of lymphoid hyperplasia. Chest imaging typically reveals single or multiple pulmonary nodules or masses. Men and women are affected equally, and the median age at diagnosis is sixty-five. Most patients are asymptomatic although cough, dyspnea, and pleuritic chest pain may occur.

IgG4-related sclerosing disease

IgG4-related sclerosing disease is a systemic disease that was first described in 2001 as a cause of autoimmune pancreatitis. This disorder may also cause inflammatory sclerosing disease of the biliary tract, salivary glands, and the orbit, in addition to lacrimal glands, lymph nodes, kidney, and retroperitoneal structures. Lung involvement may be the first manifestation of IgG4 sclerosing disease, but disease at other locations is often already present.

Within the lung, IgG4 sclerosing disease may cause diffuse parenchymal involvement that mimics interstitial lung disease or presents as one or more masses or nodules. Less commonly, IgG4 sclerosing disease may cause pleural effusion, hilar and mediastinal lymphadenopathy, or mediastinal fibrosis.

Patients may be asymptomatic or may present with cough, dyspnea, hemoptysis, or chest pain. Most patients are adults (age range 40-77), and males are affected more often than females by a ratio between 2:1 and 4:1. Elevated serum IgG4 is common but is not specific for IgG4 sclerosing disease. Although follow-up data is limited, the prognosis for lung disease is excellent given responsiveness to oral corticosteroids.

Diagnosis requires histology that demonstrates a lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells in the appropriate clinical setting. The classic histologic triad also includes vasculitis-like lesions and fibrosis.

What imaging studies will be helpful in making or excluding the diagnosis of benign lymphoproliferative disorders of the lung?

Intraparenchymal lymph node

Chest CT will show single or multiple well circumscribed nodules present in a subpleural or paraseptal location. The nodules are typically well circumscribed but may show ill-defined borders and spiculation. The majority of intraparenchymal lymph nodes (72% in one study) are present in the lower lobes.

The classic description of an intraparenchymal lymph node is a solid subcentimeter polygonally shaped subpleural or paraseptal nodule. When an intraparenchymal lymph node abuts the pleural, the node may appear as a semicircle. Intraparenchymal lymph nodes are typically too small to be seen on chest x-ray. (Figure 1)

Figure 1.

Follicular bronchiolitis

Bilateral reticular or reticulonodular infiltrates are usually present on chest X-ray. A high-resolution CT scan demonstrates subcentimeter centrilobular and occasionally peribronchial nodules. Areas of ground-glass opacity are present in the majority of cases (Figure 2). These radiographic findings have been described as a “tree in bud” pattern. Mosaicism from air trapping may be present.

Figure 2.

Lymphocytic interstitial pneumonia (LIP)

Chest X-ray shows patchy or diffuse reticulonodular infiltrates. High-resolution chest CT demonstrates bilateral, diffuse, or patchy, ground-glass opacities; centrilobular or subpleural nodules; thickened bronchovascular bundles; and interlobular septal thickening.

Lung cysts of varying sizes may be present in about 68 percent of cases. In the right clinical context, these cysts suggest a diagnosis of LIP. Fibrosis and honeycombing are rare but may complicate advanced disease.

Nodular lymphoid hyperplasia

Chest x-ray or CT will reveal a single or multiple pulmonary nodules or masses. Approximately a third of patients may have multiple lesions that may have ill-defined borders or be well-demarcated on CT. Both solid lesions and ground-glass opacities are seen. Lesions are typically subpleural. Regional lymphadenopathy may occur, but it is most often absent. (Figure 3)

Figure 3.

IgG4-related sclerosing disease

Radiographic features of IgG4-related sclerosing disease are varied. These features include the following non-specific CT patterns:

• One or more solid nodules or masses within the lung

• One or more focal ground-glass opacities within the lung

• Diffuse alveolar-interstitial pattern that is often suggestive of non-specific interstitial pneumonitis (NSIP)

• Thickening of bronchovascular bundles and interlobular septa.

Beware: there are other diseases that can mimic benign lymphoproliferative disorders of the lung:

Intraparenchymal lymph node – differential diagnosis

The differential diagnosis of an intraparenchymal lymph node is the same as that for a solitary pulmonary nodule, including a wide array of neoplastic, infectious, and non-infectious inflammatory etiologies. Primary or metastatic carcinoma is often the principal concern.

Follicular bronchiolitis – differential diagnosis

• LIP

• Hypersensitivity pneumonitis

• Respiratory bronchiolitis – ILD (RBILD)

In practice, there is radiographic and histologic overlap between LIP and follicular bronchiolitis. Hypersensitivity pneumonitis, RBILD, and follicular bronchiolitis have clinical overlap and share radiographic features, but they are easily distinguished histologically.

Lymphocytic interstitial pneumonia (LIP) – differential diagnosis

• Low-grade lymphoma of BALT

• Pulmonary involvement by chronic lymphocytic leukemia

• Follicular bronchiolitis

• Hypersensitivity pneumonitis

• Nonspecific interstitial pneumonitis (cellular NSIP)

• Usual interstitial pneumonia (UIP) – (in chronic, advanced forms of LIP)

These disorders can mimic LIP both radiographically and histologically. In chronic LIP, the histologic features may mimic UIP.

Nodular lymphoid hyperplasia

The differential diagnosis of an intraparenchymal lymph node is the same as that for a solitary pulmonary nodule. The diagnosis includes a wide array of neoplastic, infectious, and non-infectious inflammatory etiologies. Primary or metastatic carcinoma is often the principal concern.

The histologic differential diagnosis of nodular lymphoid hyperplasia includes:

• Low grade lymphoma of BALT

• Inflammatory pseudotumor (inflammatory myofibroblastic tumor)

• IgG4 Related Sclerosing Disease

The distinction between nodular lymphoid hyperplasia and low-grade lymphoma of BALT requires sophisticated molecular and immunohistochemical studies to establish polyclonality or monoclonality. With the advent of such testing, many cases formerly considered lymphoid hyperplasia have proven to be low-grade lymphomas. A subset of cases of nodular lymphoid hyperplasia may show an increase in IgG4 positive plasma cells greater than 50 / hpf with an IgG4/IgG ratio of greater than 40%. However, reported cases have not been associated with other manifestations of IgG4 positive sclerosing disease or elevations in serum levels of IgG4.

IgG4-related sclerosing disease – differential diagnosis

• Lymphoproliferative disease, especially grade I lymphomatoid granulomatosis

• Non-specific interstitial pneumonitis (NSIP)

• Inflammatory myofibroblastic tumor

With growing recognition of IgG4-related sclerosing disease, some cases previously diagnosed as grade I lymphomatoid granulomatos, cellular NSIP, or inflammatory pseudotumor are now identified as IgG4-related sclerosing disease.

How and/or why did the patient develop a benign lymphoproliferative disorder of the lung?

Intraparenchymal lymph node

The etiology of intraparenchymal lymph nodes is unknown, but it is presumably no different from development of reactive lymphadenopathy elsewhere. Some authors have postulated that they develop in response to antigenic stimulation presumably from inhaled dust. The ubiquity of CT imaging and improved resolution of modern scanners has led to increased identification of pulmonary nodules, some of which are intraparenchymall ymph nodes. In two published series, histologic examination showed that 18-46 percent of small, well circumscribed peripheral pulmonary nodules identified by CT imaging were benign intrapulmonary lymph nodes.

Follicular bronchiolitis

Several conditions are associated with development of follicular bronchiolitis:

• Connective tissue disease, most commonly Sjögren’s syndrome and rheumatoid arthritis

• HIV infection

• Common variable immune deficiency: these individuals develop LIP as part of the spectrum of granulomatous lymphocytic interstitial lung disease (GLILD) in which LIP, follicular bronchiolitis, and poorly formed granulomas develop.

Follicular bronchiolitis may occur without associated diseases (idiopathic) or as a secondary pathologic finding in other lung diseases.

Lymphocytic interstitial pneumonia (LIP)

The age range for LIP diagnosis is similar to that for follicular bronchiolitis. Most affected patients are adults, with a mean age in the mid-50s. LIP is sometimes associated with viral infection, including HIV and Ebstein-Barr virus. LIP may occur in the following settings:

• Sjögren’s syndrome. Sjögren’s syndrome is the most common autoimmune disease associated with LIP, occurring in 25 percent of cases.

• Other autoimmune disorders. Other autoimmune disorders associated with LIP include rheumatoid arthritis, systemic lupus erythematosus (SLE), autoimmune thyroiditis and hepatitis, primary biliary cirrhosis, hemolytic anemia, celiac sprue, pernicious anemia, and myasthenia gravis.

• Following allogeneic bone marrow transplantation

• Drug reactions

• HIV infection. LIP has been reported to occur in 1-2 percent of HIV-infected patients, although the incidence is decreasing with development of highly active anti-retroviral therapy. In children under age thirteen, LIP is strongly associated with progression to AIDS and is considered an AIDS-defining illness. The majority of adults with HIV-associated LIP in the United States are African American.

• Common variable immune deficiency. These individuals may develop LIP as part of the syndrome of granulomatous lymphocytic interstitial lung disease (GLILD) in which LIP, follicular bronchiolitis, and poorly formed granulomas develop.

Nodular lymphoid hyperplasia

The etiology of nodular lymphoid hyperplasia is unknown. Unlike several other benign lymphoproliferative diseases, nodular lymphoid hyperplasia is not associated with autoimmune disease or immune deficiency states.

IgG4 related sclerosing disease

IgG4 sclerosing disease is a systemic disease of unclear etiology that most commonly causes autoimmune pancreatitis. Lung involvement may herald onset of this disease or may develop with a background of autoimmune or idiopathic disease in other organs. Other organs that may be affected by this disease include the biliary tract (sclerosing cholangitis), the mediastinum (sclerosing mediastinitis), the gallbladder (acalculous cholecystitis), the salivary glands (sclerosing sialadenitis), the thyroid, and the orbit (presenting as a mass lesion), in addition to lacrimal glands, lymph nodes, kidney (interstitial nephritis), and retroperitoneal structures (retroperitoneal fibrosis).

Which individuals are at greatest risk of developing a benign lymphoproliferative disorder of the lung?

Intraparenchymal lymph node

Intraparenchymal lymph nodes occur more often in patients who are smokers than in those who are not.

Follicular bronchiolitis

Several conditions are associated with development of follicular bronchiolitis:

• Connective tissue disease, most commonly Sjögren’s syndrome and rheumatoid arthritis

• HIV infection

• Common variable immune deficiency: these individuals develop LIP as part of the spectrum of granulomatous lymphocytic interstitial lung disease (GLILD) in which LIP, follicular bronchiolitis, and poorly formed granulomas develop.

Idiopathic follicular bronchiolitis: Follicular bronchiolitis may occur in isolation. The diagnosis of follicular bronchiolitis should not be dismissed if an autoimmune or immune deficiency is absent.

Follicular bronchiolitis may found as a secondary histologic finding in other lung diseases, such as bronchiectasis and asthma.

Lymphocytic interstitial pneumonia (LIP)

LIP is most likely to develop in middle-aged individuals with autoimmune disease (most commonly Sjögren’s syndrome), in HIV-infected individuals (including children), and in those with common variable immune deficiency.

Nodular lymphoid hyperplasia

Although one case of nodular lymphoid hyperplasia has been described in a patient with Sjögren’s syndrome, most cases are not associated with an underlying disease or with specific risk factors.

IgG4-related sclerosing disease

Autoimmune or idiopathic sclerotic disease in extrathoracic locations, particularly the pancreas, is commonly present when the lungs become involved. When compatible pulmonary findings develop, the presence of sclerosing disease in other organs should raise suspicion for IgG4-related sclerosing disease.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Intraparenchymal lymph node

Other than imaging and biopsy, laboratory studies are unhelpful in the diagnosis of intrapulmonary lymph nodes.

Follicular bronchiolitis

Patients should be assessed for HIV infection, connective tissue disease, and dysproteinemia

• HIV serology

• Serologic evaluation for connective tissue disease, including rheumatoid factor, antibodies to citrullinated proteins (anti-CCP), and anti-Ro/SS-A and anti-La/SS

• Immunoglobulin levels

Lymphocytic interstitial pneumonia (LIP)

Patients should be assessed for HIV infection, connective tissue disease, and dysproteinemia.

• HIV serology

• Serologic evaluation for connective tissue disease should include ANA, rheumatoid factor, antibodies to citrullinated proteins (anti-CCP), and anti-Ro/SS-A and anti-La/SS-B.

• Dysproteinemia (present in 80% of patients with LIP) should be evaluated with serum protein electropheresis. (Dysproteinemia is usually a polyclonal hypergammaglobulinemia but may include hypogammaglobulinemia.)

Nodular lymphoid hyperplasia

• Molecular and immunohistochemical studies of resected lesions are necessary to establish polyclonality, thereby excluding a low-grade lymphoma of BALT.

• Serum IgG4 may be helpful in distinguishing this entity from localized IgG4 sclerosing disease.

IgG4-related sclerosing disease

• Serum IgG4 levels are elevated in most patients. Serial serum IgG4 levels have been suggested as a way to assess response to therapy. However, the value of this practice is unclear.

• Serologic markers of connective tissue disease, such as ANA and rheumatoid factor, are usually negative or present in low titre.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of a benign lymphoproliferative disorder of the lung?

Intraparenchymal lymph node

• Gas exchange and pulmonary function are normal.

• Other than imaging and biopsy, pulmonary diagnostic studies are not helpful in the diagnosis of intrapulmonary lymph nodes.

Follicular bronchiolitis

• Pulmonary function studies may be normal or show a restrictive pattern. Airflow obstruction is less commonly seen.

• A decrease in the diffusion capacity for carbon monoxide is also common.

• Sputum cultures should be obtained to evaluate for infection.

Lymphocytic interstitial pneumonia (LIP)

• Pulmonary function studies most often show a restrictive pattern but are non-specific.

Nodular lymphoid hyperplasia

• Gas exchange and pulmonary function are normal.

• Other than imaging and biopsy, pulmonary diagnostic studies are not helpful in the diagnosis of nodular lymphoid hyperplasia.

IgG4-related sclerosing disease

• When lung involvement is diffuse, pulmonary function studies show a restrictive defect.

• Preliminary data suggest the diffusion capacity for carbon monoxide (DLCO) may decrease out of proportion to changes in spirometry because of frequent vascular involvement by the fibroinflammatory infiltrate.

What diagnostic procedures will be helpful in making or excluding the diagnosis of a benign lymphoproliferative disorder of the lung?

Intraparenchymal lymph node

• When the suspicion of malignancy is low based on clinical setting, nodule size, and imaging characteristics, observation with serial chest imaging is recommended.

• When the suspicion of malignancy is high, biopsy and/or surgical resection is recommended.

Follicular bronchiolitis

• Surgical lung biopsy is required for definitive diagnosis of follicular bronchiolitis.

• BAL lymphocytosis is supportive but not specific.

• Transbronchial biopsies may show follicular bronchiolitis but do not provide adequate tissue to exclude another primary histologic finding present elsewhere.

• High-resolution chest CT findings may be suggestive in an at-risk individual but are not specific enough to be diagnostic.

Lymphocytic interstitial pneumonia (LIP)

• LIP may be considered or suspected in the appropriate clinical context (e.g., underlying connective tissue disease, HIV infection)

• Definitive diagnosis of LIP in adults, however, requires surgical biopsy.

• Transbronchial biopsies are typically not adequate because their small size leads to sampling error. However, transbronchial biopsies may be helpful in detecting other conditions (e.g., CMV infection) within the clinical differential diagnosis of LIP.

• BAL lymphocytosis is typically present but is non-specific.

• Clinical-radiographic diagnosis without surgical lung biopsy: In a highly suggestive clinical setting (e.g., known Sjögren’s syndrome, HRCT with ground-glass opacities and characteristic lung cysts, bronchoscopic findings suggestive of LIP, no reason to suspect other cystic lung disease), surgical lung biopsy may not be clinically necessary.

Nodular lymphoid hyperplasia

• When the suspicion of malignancy is low, based on clinical setting, nodule size, and imaging characteristics, observation with serial chest imaging is recommended.

• When the suspicion of malignancy is high, biopsy or wedge resection is recommended. Incomplete sampling of the lesion via needle or forceps biopsy is inadequate to exclude a low-grade lymphoma of BALT. Therefore, complete excision is necessary for a confident diagnosis.

• Once the lesion is resected, molecular and immunohistochemical studies are necessary to exclude monoclonality associated with the more common low-grade lymphoma of BALT.

IgG4-related sclerosing disease

• Histologic analysis is necessary for diagnosis.

• Smaller tissue samples may suggest the diagnosis, as may an elevated serum IgG4. Surgical lung biopsy is typically necessary for definitive diagnosis.

What pathology / cytology / genetic studies will be helpful in making or excluding the diagnosis of a benign lymphoproliferative disorder of the lung?

Intraparenchymal lymph node

In general, intraparenchymal lymph nodes are circumscribed, round or oval nodules in a subpleural or paraseptal distribution. Nodules are typically 1 cm or less in diameter. Histologically, intraparenchymal lymph nodes are similar to nodes in other parts of the body that contain reactive primary and secondary follicles and sinuses. (Figure 4)

Figure 4.

Follicular bronchiolitis

The principle histologic finding in follicular bronchiolitis consists of numerous hyperplastic lymphoid follicles with associated reactive germinal centers distributed along bronchovascular bundles. The follicles may compress adjacent bronchioles. Lymphocytes may extend into and permeate the underlying bronchial or bronchiolar epithelium. In a minority of cases (20%), a mild interstitial inflammatory infiltrate is present in adjacent alveolar septa. In these cases, the features overlap with LIP.

The reactive lymphoid follicles stain positively with markers of B-cells (CD-20 and CD-79a), whereas the interstitial component, when present, stains positively with T-cell markers (CD-3). The follicles stain negatively for BCL-2. Although not necessary for diagnosis, PCR analysis for IgH chain gene rearrangements typically shows a polyclonal pattern.

Follicular bronchiolitis can occur as a minor or secondary histologic finding in a variety of lung diseases, in which case the clinical-radiologic presentation, as well as the approach to management, are dictated by the primary lung disorder. (Figure 5) (Figure 6)

Figure 5.

Figure 6.

Lymphocytic interstitial pneumonia (LIP)

LIP shows a dense polymorphous inflammatory infiltrate consisting of variable numbers of lymphocytes, histiocytes and plasma cells which expands the alveolar interstitium. There is considerable histologic overlap with cellular non-specific interstitial pneumonitis. In contrast to NSIP, the infiltrate in LIP is more marked expanding and distorting alveolar septa. A component of follicular bronchiolitis, consisting of reactive lymphoid follicles adjacent to airways, often accompanies these findings. In about 20 percent of cases, there is overlap in the histologic features between LIP and follicular bronchiolitis. As in follicular bronchiolitis, lymphocytes may permeate the bronchial epithelium.

Variable nonspecific findings include focal lymphocytic infiltration of vessel walls, occasional isolated giant cells, foci of amyloid, and varying degrees of interstitial fibrosis. Immunohistochemical stains show that the majority of lymphocytes are T-cells and are positive for CD-3. Areas of follicular bronchiolitis stain positively for B-cell markers (CD-20 and CD-79a). Associated plasma cells show a polyclonal pattern of staining for kappa and lambda on immunohistochemistry. Although not necessary for diagnosis, a polyclonal pattern is present on PCR analysis for IgH chain gene rearrangements. (See Figure 7, Figure 8, Figure 9)

Figure 7.

Figure 8.

Figure 9.

Nodular lymphoid hyperplasia

Gross features of nodular lymphoid hyperplasia reflect radiographic findings. One or more well circumscribed gray to white tan nodules are present in a subpleural or peribronchial distribution. Histologically, nodules consist of numerous reactive germinal centers with variable amounts of interfollicular fibrosis and sheets of interfollicular plasma cells. Occasional scattered giant cells may rarely be present. Dutcher bodies, bronchial cartilage invasion, or plaque-like involvement of the pleura are notably absent.

The diagnosis of nodular lymphoid hyperplasia pathologically is one of exclusion. Accordingly, additional immunohistochemical and genetic studies to exclude lymphoma are usually necessary.

On immunohistochemistry, reactive lymphoid follicles stain positively for B-cells (CD-20 and CD-79a), whereas interfollicular lymphocytes stain positively for T-cells (CD-3, CD-43 and CD-5). In contrast to many cases of low grade B-cell lymphoma of BALT, co-expression of CD43 and CD-20 is not identified. Germinal centers lack expression of BCL-2, which is restricted to the mantle zone and interfollicular lymphocytes.

Immunohistochemical staining for kappa and lambda light chains shows a polyclonal pattern of expression, and PCR analysis for IgH chain gene rearrangements also shows a polyclonal pattern. (Figure 10,) (Figure 11, ) (Figure 12)

Figure 10.

Figure 11.

Figure 12.

A subset of cases of nodular lymphoid hyperplasia may show an increase in IgG4 positive plasma cells. However, reported cases have not been associated with other manifestations of IgG4 positive sclerosing disease or elevations in serum levels of IgG4.

IgG4-related sclerosing disease

Pathologic manifestations of IgG4 sclerosing disease involving the lung consist of several different patterns. Fibroinflammatory masses associated with IgG4-related sclerosing disease have a characteristic morphology consisting of a plasma-cell-rich lymphohistiocytic infiltrate with fibrosis in a lymphangitic distribution. There is involvement of arteries and veins by intimal endothelial inflammation and increased numbers of IgG4-positive plasma cells on immunohistochemistry (range 24-229 in three high-power fields), as well as an increased IgG4 to IgG plasma cell ratio (range 16%-71%). A recent consensus statement has suggested that, in the appropriate clinical setting, lung biopsies showing >50 IgG4 positive plasma cells per high power field in conjunction with an IgG4+/IgG+ plasma cell ratio of greater than or equal to 0.4 is highly suggestive of IgG4 related sclerosing disease.

Plasma-cell-rich variants of inflammatory pseudotumor associated with IgG4-related sclerosing disease consist of a fibroinflammatory mass composed of a mixture of fibrosis and inflammatory cells, including lymphocytes and plasma cells. Obliterative phlebitis and arteritis may be present. The number of IgG4-positive plasma cells and the ratio of IgG4-positive to IgG-positive plasma cells are increased.

An interstitial pneumonia pattern resembling nonspecific interstitial pneumonia (NSIP) may be present in some patients with IgG4-related sclerosing disease. Biopsies show a diffuse interstitial lymphoplasmacytic infiltrate, which expands alveolar septa, is present along bronchovascular bundles and may involve the pleura. The infiltrate also involves small arterioles and venules that may show obliterative arteritis and phlebitis. Abundant IgG4-positive plasma cells will be present on immunohistochemical staining.

Some, if not most, cases formerly considered grade I lymphomatoid granulomatosis are actually pulmonary manifestations of IgG4-related sclerosing disease. These cases consist of fibroinflammatory nodules or interstitially lymphoplasmacytic infiltrates associated with arteritis and venulitis. The pathologic features of these processes would probably fit within the spectrum of other “fibroinflammatory masses” described in this disorder. Similar to the other patterns, there is a marked increase in IgG4-positive plasma cells on immunohistochemistry. (Figure 13) (Figure 14) (Figure 15) (Figure 16) (Figure 17) (Figure 18)

Figure 13.

Figure 14.

Figure 15.

Figure 16.

Figure 17.

Figure 18.

If you decide the patient has a benign lymphoproliferative disorder of the lung, how should the patient be managed?

Intraparenchymal lymph node

Once identified as a lymph node, no further treatment is necessary.

Follicular bronchiolitis

Oral corticosteroids are generally effective. Treatment is usually given for months, but there is little published data to guide treatment decisions. Azathioprine and methotrexate have been used in some cases with unclear benefit. Macrolide antibiotics are an intriguing strategy based on a single case report in this entity and effectiveness in other inflammatory airway diseases.

Lymphocytic interstitial pneumonia (LIP)

No controlled trials are available to guide treatment decisions. Anti-retroviral therapy may be effective in HIV-infected individuals, and it is preferable to immunosuppresive agents as an initial treatment. Not all patients need to be treated, given the variable natural history of LIP. Factors like age, co-morbidities, severity of disease, and the longitudinal course of the disease should inform the decision to treat.

It is unclear whether treatment alters the natural history of LIP. If treatment is necessary, prednisone alone or with a cytotoxic agent like azathioprine may be used. Cyclosporin A may be particularly effective in CVID-associated LIP. Typical prednisone dosing is 0.5 – 1.0 mg/kg/day with a taper beginning at 8-12 weeks, with adjustments made based on patient tolerance of treatment, rapidity of response, use of a cytotoxic, and so on. Prophylaxis for pneumocystis should be considered for individuals who will remain on doses of prednisone of 20 mg/day or more for an extended period of time.

Nodular lymphoid hyperplasia

Surgical excision is generally the only treatment. Spontaneous regression of unresected lesions has occurred when multifocal disease was present.

IgG4-related sclerosing disease

Treatment should be considered for lung, pleural, or mediastinal disease that is associated with symptoms, physiologic impairment, or progression over time. Focal lesions that have been resected do not require additional treatment. The role of post-resection surveillance is unclear. Small focal pulmonary lesions may be observed for progression.

When treatment is needed, limited data from the lung and more extensive experience in extrathoracic organs suggests that oral corticosteroids are effective. Improvement or resolution of radiographic abnormalities is commonly reported.

Cytotoxic agents are generally not needed because of the typically excellent response to corticosteroids. For interstitial lung disease, corticosteroid dosing regimens similar to those used for organizing pneumonia or NSIP have been employed. New information is likely to emerge over the next few years that informs duration and dosing.

Pulmonary function testing and chest imaging are typically performed prior to initiating treatment. Other physiologic tests such as the six-minute walk test and arterial blood gases may be appropriate. Pulmonary function testing should be performed in follow-up every 3-6 months initially, with chest imaging performed less frequently based on clinical need.

What is the prognosis for patients managed in the recommended ways?

Intraparenchymal lymph node

Aside from the risk associated with biopsy, prognosis is excellent.

Follicular bronchiolitis

The prognosis for patients with follicular bronchiolitis is generally good. Most patients will respond to prednisone, but relapses are common when treatment is tapered or stopped.

Lymphocytic interstitial pneumonia (LIP)

The natural history and response to treatment is variable. Resolution of disease, stabilization, and progression to end-stage fibrosis all may occur. Survival is decreased in patients with a diagnosis of LIP; the reported survival rate has varied from 33 percent to 50 percent at five years for a median survival of 11.5 years. Deaths in LIP are typically due to infection, end-stage lung disease, or conversion to lymphoma, but progression to lymphoma is uncommon.

Nodular lymphoid hyperplasia

The prognosis for patients with nodular lymphoid hyperplasia is excellent, although long-term follow-up of published cases has been poor. Nodular lymphoid hyperplasia does not generally result in significant symptoms or lung dysfunction, and surgical excision is generally curative. If a low-grade lymphoma of BALT is properly excluded by the pathologist at the time of diagnosis, subsequent malignant transformation has not been reported.

IgG4-related sclerosing disease

The prognosis for patients with pulmonary involvement that is due to IgG4-related sclerosing disease is favorable, given the excellent response to oral corticosteroids. There is a risk of disease recurrence or progression within the lung, as well as multi-system involvement over time. However, the natural history of untreated disease is not well defined.

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