MALIGNANT LYMPHOID LESIONS

LOW-GRADE MARGINAL ZONE B-CELL LYMPHOMA OF MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALToma)

Primary non-Hodgkin lymphomas of lung are generally defined as monoclonal lymphoid proliferations that affect one or both lungs or bronchi in an individual who has no evidence of extra-pulmonary tumor at time of diagnosis or for three months thereafter.⁸  Primary pulmonary lymphomas represent 3-4% of extra-nodal lymphomas, but they are really quite infrequent, for they compose only 0.5-1% of primary malignancies of the lung.^4,8  Still, they have presented diagnostic problems to pathologists, chiefly because of the frequency of low-grade lesions and the problem of distinguishing them from reactive processes. Specifically, several large clinicopathologic studies of lymphomas presenting in lung have shown that most pulmonary lymphomas (approximately 58-87%) are of low histological grade.^{1, 4, 8, 33, 35-37}  Further, these lymphomas often contain reactive germinal centers. Also, they have a surprisingly good clinical prognosis, and they tend to recur in lung or unusual extranodal sites, such as salivary gland or gastrointestinal tract.³⁵ 

Isaacson and colleagues were the first to link both the microscopical appearance and clinical behavior of these low-grade pulmonary lymphomas to those of lymphomas occurring in other mucosal sites, termed malignant lymphomas of mucosa-associated lymphoid tissue (MALT).^{1, 23, 24, 26}  These studies suggested the concept that low-grade pulmonary lymphomas, despite their apparent cellular diversity, were best considered originating from a single putative progenitor B-cell, a centrocyte-like or marginal zone cell, of the bronchus- or mucosa-associated lymphoid tissue (BALT or MALT). In the WHO classification, these lymphomas are identified as extra-nodal marginal zone B-cell lymphomas of MALT (MALT lymphoma, MALToma) and they are linked to similar tumors in the gastrointestinal tract and in other organs.²⁸  MALT lymphomas are the most common form of primary pulmonary lymphoma.⁷  Several large series have been been studied.^{16, 36, 39} 

Clinical Features: Women seem to predominate,^{33, 35, 36, 39}  although there is some uncertainty about this.⁸  On the mean, the patients are in the sixth decade. The disease can also occur in HIV-positive children.⁵⁹  One-third to one-half of the patients have asymptomatic solitary nodules or masses, usually less than 5 cm in diameter, and they often show air bronchograms.^{16, 35, 36, 39}  Multiple nodules or infiltrates are often present by CT scan, but less than 10% of patients show bilateral reticulonodular infiltrates.⁸  Hilar lymphadenopathy and cavitation are infrequent.^{33, 35}  Symptoms include cough, dyspnea, hemoptysis and chest pain.^{36, 39}  A minority has constitutional symptoms such as fever, weight loss and night sweats.

Laboratory findings are suggestive or helpful in only a minority of cases. Lymphocytic leukemia is typically absent.³³  Tumor involves bone marrow in only 16% of patients who undergo biopsy, and a monoclonal immunoglobulin spike (typically IgM or IgA, rarely IgG) is seen in 23-40% of patients^{33, 36}  When serum immunoglobulin is present, it matches the immunohistochemical profile of the tumor cells.³⁶  There are also rare reports of paraneoplastic syndromes, including peripheral neuropathy, cerebellar ataxia and transverse myelitis.³⁶  A variety of autoimmunue diseases have been reported in the setting of these tumors and HIV infection may be present (Table 1). The pathogenetic significance of these conditions is discussed below.

Bronchoalveolar lavage has not been systematically studied as a diagnostic tool for these tumors. Increased B-cell levels (>10%) in bronchoalveolar lavage sediments can be present in these pulmonary lymphomas, and molecular biologic methods may provide a diagnosis in some cases.⁸ 

Hilar lymph nodes were involved by tumor in only 0-30% of cases in two early series ,^{33, 35}  but in a recent series, as many as 44% of patients had regional nodal involvement.³⁶  Of interest, this finding did not adversely affect prognosis.³⁶ 

The important clinical feature of pulmonary MALTomas is that, like their counterparts in other sites, they tend to remain localized for prolonged periods and therefore show a relatively good prognosis. One hypothesis is that the lymphoma remains localized because it requires continued antigenic stimulation from a local site for its devlopment.

Recurrences occur in a high proportion of patients with pulmonary MALTomas - nearly 50% after 2 years.⁸  They most often involve lung or other mucosal sites such as gastrointestinal tract or salivary gland,³⁵  a behavior similar to that of MALT lymphomas of the gut, but the disease-free interval is shorter in pulmonary as opposed to gastic MALTomas. However, the frequency of simultaneous recurrence in more than one mucosal site in extra-gastric tumors is surprisingly high – 55%.⁵¹  What this means that limited surgery should only be used if extensive staging evaluation of other mucosal sites is done.⁵¹  It is believed that some of these unusual locations for recurrence could be due to the homing capabilities of MALT lymphocytes. These lymphocytes can home to mucosal sites by binding of the surface receptor a4ß7 to high endothelial venules in the mucosa.^{5, 27}  How often the malignant lymphomas derived from MALT lymphocytes contain these binding molecules, termed addressins, is unclear.

The outcome of low-grade B-cell lymphomas is generally good, with 5- and 10-year survivals of 84-88%.³⁵  Kennedy and associates ³³ found that a median survival had not yet been reached after 217 months. However, a recent series reported a lymphoma-specific survival of only 72% at 10 years.³⁶  Survival is not statistically impacted by any of a large number of factors, including bilateral disease, use of chemotherapy alone, positive lymph nodes, TNM stage, adjuvant chemotherapy, and presence of monoclonal gammopathy.³⁶  Adverse indicators are few: pleural effusions and the presence of amyloid within the tumor. A multivariate analysis found that elevated ß2 microglobulin was a prognostic factor.⁶⁰ 

Five-18% of these lymphomas can have concurrent or develop subsequent large B cell lymphomas, but it is not clear whether this adversely affects prognosis.^{1, 4, 36, 39} 

It is fair to say that there have been no controlled clinical trials to determine optimal therapeutic approaches.⁴  Treatment for localized tumors is usually surgical, while single agent or multi-agent chemotherapy has been when there is more diffuse or bilateral involvement or when there is concomitant extra-pulmonary disease.

Pathologic Features: As noted above, MALT lymphomas are the most frequent type of primary pulmonary lymphoma, accounting for 72-90% of lymphomas originating in lung.^{8, 36, 55}  Pulmonary MALTomas constitute approximately 14% of MALTomas from all sites of the body.⁶⁰ 

The tumors usually present grossly as masses or nodules.³⁵  They only rarely show necrosis. Microscopically, they consist of small lymphocytes, centrocyte-like lymphocytes, plasmacytoid lymphocytes (often showing typical Dutcher bodies) and occasional immunoblasts.^{24, 28, 31, 36, 39, 44}  The plasma cells tend to cluster beneath epithelium (so-called compartmentalization). Up to 90% of the tumors invade respiratory epithelium to produce distinctive lymphoepithelial lesions.

These lymphomas form dense lymphoid masses in their centers and show a marked lymphangitic pattern of spread around and into airways, vessels, and pleura at their periphery .^{7, 9, 10, 16, 33, 36, 55}  Sometimes, the principal growth pattern is lymphangitic with a minor interstitial component, resembling lymphocytic interstitial pneumonia (LIP). Lymphoepithelial lesions, formed by invasion of the bronchial or bronchiolar epithelium, are common (90-100%), and can be highlighted by keratin stains.^{4, 16, 36}  Peripheral tumors can penetrate the visceral pleural elastica over broad areas (at least a low-power microscopic field) in over 50% of cases.^{16, 35}  The involvement may be so extensive that it produces polypoid protrusions into the pleural cavity. Invasion of the parietal pleura or perichondrium is definitive for lymphoma, as opposed to reactive lymphoid lesions.³⁵ 

Multinucleated giant cells or sarcoid-like granulomas are seen in 20-50% of cases; even granulomatous vasculitis can occur, but less frequently.^{16, 35, 36}  This granulomatous inflammation is non-specific, since it can be seen as well in lymphoid hyperplasia. Its origin is unclear but it may be related to cell breakdown (see below).

Approximately 20% of low-grade lymphomas of MALT type show giant lamellar bodies, laminated eosinophilic whorled structures measuring approximately 25 microns in diameter, and composed, at least in part, of surfactant apoprotein A.⁴⁸  The bodies often appear in conjunction with foam cells and cholesterol clefts, suggesting origin from cell breakdown or failure to clear surfactant and other cell breakdown products. In one study, these bodies were not found in patients with either large cell lymphomas or reactive lymphoid lesions, suggesting that they might be a marker for low-grade MALToma.⁴⁸ 

Reactive germinal centers are also commonly found (20-85% of cases) in low-grade marginal zone B-cell lymphomas of lung.^{1, 33, 35, 36, 39}  They may be scattered throughout the tumor, or they may be largely peribronchial or at the neoplasm's periphery.²²  Most of these follicles stain polytypically for immunoglobulin light chains, although as many as 25% may be monotypic.³⁹  Colonization of reactive follicles by the neoplastic cells probably accounts for monotypic staining of the follicles.²⁵ 

Amyloid can be present in 5-10% of cases.^{4, 36} 

The immunohistochemical profile of low-grade B-cell lymphomas of MALT is shown in detail Table 2. In essence, they are B cells with the immunoprofile CD20(+)/CD43(+/-) /bcl2(+) and CD5(-)/CD10(-). T cells can be found at the margin of peribronchial lymphoid nodules and in the alveolar interstitium.

Most (70-80%) low-grade B-cell lymphomas of lung are, as expected, monotypic for immunoglobulin light chain in paraffin sections; the remaining tumors either show few stained cells or do not stain at all.³⁹  If flow cytometry or frozen sections are used, the frequency of light chain restriction can be over 90%.³⁶ 

When light chain restriction is not present by immunohistochemical stains, molecular studies may be useful. Specifically, about 60-70% of the tumors show clonal rearrangement of the joining region (JH) of the immunoglobulin heavy chain gene.^{4, 62}  This feature may be of use as well in transbronchial biopsies, where the amount of tissue is small. In 60% of cases, cytogenetic studies show trisomy 3, and a t (11;18)(q21;q21) translocation is present in 25-50% of cases.²⁸  A novel gene, MALT1, located at18q21, was found in 4 of 5 patients with MALT lymphoma.² 

As noted above, low-grade MALT lymphomas may be associated with large B-cell lymphomas. In one series, approximately 20% of the patients showed concomitant diffuse large B-cell lymphoma with the same light chain restriction as seen in the low-grade tumor.³⁶  The assumption is that low-grade tumors evolve into large cell lymphomas in this setting, but there is also some dispute about this since the cytogenetic marker of low-grade MALtomas, the t(11:18) translocation, has not been convincngly found in these large cell lymphomas.⁸ 

Etiology/Pathogenesis:
Low-grade MALTomas are believed to arise from chronic inflammation, which in turn can arise from auto-immune disorders or chronic infection. In the gut, they are most often found in the stomach in association with chronic antigenic stimulation due to H. pylori infection, and treatment of the infection may lead to regression of the lymphoma. It is known that lymphoid inflammation, known as bronchus-associated lymphoid tissue, is usually not present in lung except in disease states or, in a more general way, after chronic antigenic stimulation. Also, a small number of patients with pulmonary MALToma have a background of auto-immune diseases, such as Sjogren syndrome and rheumatoid arthritis, which could induce lymphoid hyperplasia (Table 2). Specifically, follicular bronchitis/bronchiolitis, in which lymphoid aggregates are present around airways, and LIP, a generalized reactive interstitial lymphoid proliferation, may result in MALToma, but the frequency is small.⁷  Also, nodular lymphoid hyperpasia is a localized lesion that might potentially be a precursor to lymphoma. With the possibility of an underlying chronic inflammatory process in mind, the high incidence of follicle centers in pulmonary MALTomas is of particular interest. Could this be morphologic evidence of pre-existing chronic inflammation from which MALTomas arise, or is a reaction to the presence of lymphoma? Unfortunately, at this point, in most cases of MALToma, a specific inciting or triggering agent or condition is unknown.⁸ 

Differential Diagnosis:
Perhaps the most important differential diagnosis is reactive lymphoid processes in lung. In general terms, a low-grade, dense and monomorphic lymphoid proliferation in lung that presents as a mass, effacing much of the underlying lung architecture, will almost always be a MALToma. The case for MALToma, as opposed to reactive lymphoid process, is strengthened by finding lymphangitic spread of the tumor within the lung, plaque-like invasion of the pleura, or destruction of bronchial cartilage. Immunohistochemical stains showing co-expression of CD20 and CD43 strongly point towards malignancy.⁴  Lymphoepithelial lesions (LELs), although ubiquitous in MALTomas of lung, can also be seen in reactive lymphoid lesions (up to 60% of cases in one study.⁴  Still, when the cells of LELs are CD20+/CD43+, they suggest lymphoma, for the LELs of reactive processes are either CD3+/CD43+ or CD20+/CD43-.⁴ 

Finally, small tissue samples, such as bronchial biopsies, produce a problematic situation. The presence of a dense monomorphic B-cell lymphoid infiltrate that invades the bronchial wall is suggestive of lymphoma, but definitive diagnosis is often best supported by molecular methods.⁶² 

OTHER NON-HODGKIN'S LYMPHOMAS
Non-Hodgkins lymphomas other than MALTomas can occur in lung, but they are infrequent. Follicular lymphomas are neoplasms of B cells derived from the follicle center that show at least a follicle center pattern. Normally, these tumors involve the lymph nodes, spleen or bone marrow. Extra-nodal involvement usually occurs in the setting of disseminated disease.⁴⁵  These tumors represent about 5% of lymphomas presenting in lung.³⁹  Most cases have an extensive follicular pattern by light microscopy and are composed of either small to medium centrocytes with twisted or cleaved nuclei, inconspicuous nucleoli and scant clear cytoplasm. There may be variable numbers of centroblasts with round or oval nuclei. The tumor cells are CD20+, CD10+, Bcl 2+, and Bcl 6+. There are also CD21+ and CD23+ cells present. They are usually CD43- and CD5-.

High-grade lymphomas, such as large cell lymphomas of B-cell type and Burkitts-type lymphomas can also present in lung, but they are very rare. Again, they usually affect lung in the setting of disseminated disease. They usually grow as masses or ill defined infiltrates in the lung, demonstrating massive necrosis. The neoplastic cells are mitotically active, fill alveoli with admixed fibrin ("tumoral pneumonia") and invade vascular walls, including arterial walls.^{35, 39}  The tumor cells may be large cleaved, non-cleaved or immunoblastic lymphomas. In general, germinal centers are not a feature of these MALTomas. Low-grade B-cell lymphomas can occur in conjuction, suggesting that high-grade lymphomas can result from transformation of a previous low-grade lymphoma. Large cell lymphomas involve regional nodes in up to 50% of cases.

T-cell lymphomas are a component of these large cell lymphomas that are often distinctive. They are rare, constituting only about 3% of pulmonary lymphomas. Many of these tumors are angiocentric lymphomas and resemble grade 3 lymphomatoid granulomatosis or malignant lymphomas. Anaplastic large cell (or Ki-1) lymphomas are a particular form of T-cell lymphoma that can also occur in lung. In fact, the lung is affected in 11% of cases of this disease; skin, bone and soft tissues are also often involved.⁶  In general, the malignant lymphoid cells are pleomorphic and have abundant cytoplasm and eccentric kidney-shaped or horse-shoe-shaped nuclei; some resemble Reed-Sternberg cells. They stain with CD30 (Ki-1) and can express anaplastic large cell lymphoma kinase.¹² 

Overall 5-year survival of patients with high-grade lymphoma is only 44-60%. Treatment is surgical resection with adjuvant chemotherapy and/or radiation.

The differential diagnosis includes large cell carcinoma and metastatic melanoma. Immunohistochemical stains with a panel of epithelial (keratin and EMA), melanoma (HMB45, S-100 protein) and lymphoid (CD45) markers are best way to distinguish these neoplasms.

LYMPHOMATOID GRANULOMATOSIS (LYG)

Definition:
Lymphomatoid granulomatosis is an extranodal angiocentric and angiodestructive lymphoproliferative disorder. Most cases are composed of a polymorphous infiltrate of atypical-appearing Epstein-Barr virus-infected B cells and numerically more abundant admixed reactive T cells.⁴  Some histologically similar cases have been described in which both the atypical cells and the background small lymphocytes are T-cells. Lymphomatoid granulomatosis shows a histologic spectrum, from low-grade lymphoid lesions to high grade lymphomas that are equivalent to malignant lymphoma of immunoblastic type.

Historical annotation and Synonym:
These lesions were first described nearly 25 years ago by Averill Liebow, who simply could not decide whether they were a variant of Wegener's granulomatosis or a malignant lymphoma - hence, the unusual name "lymphomatoid granulomatosis".¹¹  There is an equally complicated and equally descriptive name, "angiocentric immunoproliferative lesion" (AIL), indicating that the disease is a lymphoproliferative disorder with the capability of evolving into lymphoma Jaffe.⁶ 

Clinical Features:
LYG is rare. It typically presents in middle-aged adults (although both younger and older patients have been reported).^{2, 8, 9, 11, 16}  The disease can occur as an apparently idiopathic lesion, but it can also occur in patients who have been immunosuppressed. Examples include patients who have AIDS or Wiskott-Aldrich syndrome, those who have had organ transplants or who have been treated for acute lymphoblastic lymphoma or follicular lymphoma and those who have agnogenic myeloid metaplasia.¹⁵  Masses or nodules can involve a variety of organs, most often lung, skin (in the form of ulcerated or nonulcerated subcutaneous nodules, erythematous dermal papules or plaques),¹  or central nervous system, with a correspondingly complex array of symptoms. The upper respiratory tract can be involved by ulcero-destructive lesions and the kidney may contain multiple nodules, but lymphadenopathy is infrequent.

Up to 70% of patients show bilateral, usually peripheral, lung nodules that measure up to 9 cm. in diameter by chest X-ray.^{8, 9, 16}  Cavitation may or may not be present. Other radiographic patterns include diffuse reticulonodular or alveolar infiltrates, localized infiltrates or a solitary mass.

Pathologic Features:
The lungs usually show yellow-white well demarcated masses that can have a solid or granular, cheesy appearance. They often have a "cannon ball" appearance. They may be cavitated. Similar masses can be found in other organs, such as the kidney or brain.

LYG consists of small round lymphocytes, lymphocytes with elongated, twisted nuclei and variable numbers of atypical large mononuclear lymphoid cells in a background of macrophages and occasional plasma cells.^{8, 9, 11}  Some of the atypical cells may show double nuclei, suggesting Reed-Sternberg cells, but classic Reed-Sternberg cells are not seen. Despite the name "granulomatosis," epithelioid granulomas and giant cells are almost always absent.

The lymphoid infiltrate often surrounds muscular pulmonary arteries and veins early in the course of the disease, and typically invades the walls of these vessels. Necrosis is a frequent, although not universal, feature of the disease, and it can range from extensive in larger masses or high-grade lesions to minimal in low- grade lesions.

Sample size is important to make the diagnosis: Less than 30% of transbronchial biopsies are diagnostic, whereas almost all open lung biopsies are potentially diagnostic.¹⁶ 

There is a histologic grading system for LYG that is based on the degree of atypical (or EBV-infected) cells, extent of necrosis and retention of a polymorphous cellular infiltrate.¹²  Grade 1 lesions show little or no EBV-infected cells (less than 5 per high-power field), usually lack necrosis, and are polymorphous. Grade 2 lesions have scattered EBV-infected cells (5-20 per high-power field) and foci of necrosis (extensive at times), but they remain polymorphous; this is the classic and most frequently encountered type of case. Grade 3 lesions show sheets of EBV-infected cells, necrosis, and cellular monomorphism. They correspond to angiocentric lymphomas.⁶ 

Most cases of LYG consist of a T-cell-rich, B-cell lymphoproliferative process, as shown by a number of studies, both in lung and in other sites, such as skin.^{1, 4, 5, 13, 15, 17}  The immunoprofile of these classic cases of LYG is shown in Table 3.

Genetics and Pathogenesis:
In grade 2 and 3 lesions, the B-cells are either clonal or oligoclonal by methods such as VJ-PCR and Southern blot and appear to be proliferating, at least by proliferation indices.^{3, 6}  The EBV sequences also are typically clonal. Finally, the proliferation index of the B cells in grade 3 LYG is equivalent to that of lymphomas. By contrast, the T cells that are so abundant in LYG are polyclonal by molecular methods and proliferation indices suggest that they are recruited, not proliferating.³ 

These results suggested that LYG is a T-cell-rich B-cell lymphoma. Still, there is an alternate view of LYG, which is that LYG is a lymphoproliferative disorder that can evolve to malignant lymphoma, analogous to the post-transplant lymphoproliferative disorders.^{3, 6}  This concept is supported by a number of factors. The post-transplant lymphoproliferative disorders are EBV-driven B cell proliferations that can show a spectrum of morphology, ranging from polyclonal mixed inflammatory infiltrates to monoclonal B cell proliferations. Similarly, some cases of grade 1 LYG are polyclonal; further, the higher the histologic grade of LYG, the more likely the B cells are to be monoclonal. Also, different monoclonal B-cell clones can occur in different sites in the same patient in LYG.^{1, 19}  This finding is similar to that seen in EBV-associated B-cell lymphoproliferative disorders that occur in immunosuppressed individuals, such as the PTLDs, in which multiclonal and oligoclonal expansions of EBV-infected B cells frequently occur.

What is the significance of the finding of EBV in LYG? It may be that, despite the rich T-cell background, patients with LYG have reduced levels of circulating CD8-positive cells and defects in cytotoxic T-cell function.⁷  This explains the occurrence of the disease in immunosuppressed patients, such as those with AIDS, Wiskott-Aldrich syndrome and in post-transplantation states. If this is the case, the diseae may benefit from antiviral strategies, such as interferon alpha, rather than further immunosuppression with chemotherapeutic agents. Second, EBV in a partially immunocompetent host may explain the vascular damage that is a hallmark of the disease. Chemokines, such as IP-10 and Mig, elaborated as a result of the EBV infection may be responsible for vascular damage by promoting T-cell adhesion to endothelial cells.¹⁸ 

There appear to be cases histologically similar to LYG that do not show atypical EBV-infected B cells, but rather show atypical cells that are CD3+ T cells.^{13, 14}  One suggestion is that these T-cell lesions are peripheral T-cell lymphomas, that, because they are angiocentric and polymorphous, are histologically similar to LYG.¹³  Cases of enteropathy-associated T-cell lymphoma and of acute T-cell lymphoblastic leukemia have been confused as cases of LYG in some series.¹⁵  T-cell lymphomas of other types, such as angiocentric CD56+ NK/T-cell lymphomas are also known to mimic LYG histologically. Finally, some cases of LYG may lack EBV-positive B cells because the number of these cells varies with histologic grade of LYG and organ system involved. Cases of low-grade (grade 1) LYG ordinarily show few EBV-infected B cells, and in small tissue samples may show no B cells at all. Skin lesions also often have very few EBV-infected B cells and are subject to sampling problems.¹ 

Prognosis, Predictive Factors and Treatment:
Outcome is variable: Patients may show waxing and waning of their disease, but the most common result is death, with median survival of 2 years.⁶  The number of atypical cells, or grade of the lesion, seems to have an affect on outcome.^{8, 12}  Only one-third of patients with grade 1 lesions progress to malignant lymphoma, whereas two-thirds of patients with grade 2 lesions develop lymphoma (all patients with grade 3 lesions have lymphoma by definition).¹²  Interestingly, long-term survival may occur even in untreated patients with grade 1 and 2 lesions, particularly those whose disease is restricted to lung.^{8, 9} 

Combination chemotherapy has been advocated for patients with grades 2 or 3 lesions.¹⁰  Interferon has also been used successfully in treatment.¹⁹  It is less clear whether stage of disease does: One study reported a worse prognosis in patients with neurologic lesions, while another did not.^{8, 9}  Treatment of grade 2-3 disease is usually with combination chemotherapy such as CHOP, EPOCH or C-MOPP. A small number of patients with grade 1 or 2 disease have been treated with interferon alpha, which has anti-viral, anti-proliferative and immunomodulating effects, with good results.^{1, 19} 

HODGKIN DISEASE PRESENTING IN THE LUNG
Primary Hodgkin disease of lung without extra-pulmonary tumor is rare. Pulmonary involvement in Hodgkin's disease usually occurs by direct extension from the mediastinum or occurs secondarily in the setting of disseminated (stage 4) disease. The largest series of isolated Hodgkin's disease had only 15 patients and 61 cases were encompassed in one review.^{52, 64}  These patients are older than those who present with only lymph node disease, men averaging 33 years of age and women 51 years. Women outnumber men by 2 to 1. Symptoms are cough, fever, dyspnea and weight loss. The tumor usually presents itself as multiple bilateral masses, but solitary nodules, infiltrates and cavitated nodules can be seen. The prognosis depends on the patient' age and extent of pulmonary disease.

Microscopically, the cellular infiltrate usually shows a lymphangitic pattern of involvement around vessels, airways and pleura. Necrosis is common. There is the expected polymorphous cellular infiltrate, with classic Reed-Sternberg cells or their variants, but at times Reed-Sternberg cells may be difficult to find or even absent. Nodular sclerosis and mixed cellularity are the most common subtypes seen. A dramatic granulomatous component may occasionally be seen, causing confusion with sarcoidosis or infection.¹¹  Large lesions may give the appearance of a tumoral pneumonia, with malignant cells filling alveolar spaces. Endobronchial Hodgkin disease is a natural extension of lymphangitic involvement of the airways.²¹  Immunohistochemical stains for CD15 and CD30 decorate the large cells, supporting the diagnosis. An important tumor to consider in differential diagnosis is giant cell carcinoma, which can sometimes show a tumor pneumonia pattern. Keratin stains should easily distinguish the two tumor types.

INTRAVASCULAR LARGE B-CELL LYMPHOMA
Intravascular large B-cell lymphoma (intravascular lymphomatosis) is a systemic lymphoma that is a rare form of diffuse large B-cell lymphoma, characterized by aggregates of lymphoma cells within small vessels, particularly capillaries.^{17, 54}  The disease is rare, occurring in adults. Its initial presentation is most often in the brain, but it is often extensively disseminated at autopsy. It affects the lung in up to 60% of cases at autopsy.

Clinical Features:
Symptoms arise from aggregates of tumor cells within vessels, producing microthrombi. In the lung, these symptoms include dyspnea, fever, and cough, which may or may not be associated with reticular or reticulonodular infiltrates by chest X-ray.⁵⁶  Pulmonary hypertension with enlargement of the pulmonary artery can occur. Pulmonary function tests usually show a restrictive pattern. The tumor is highly aggressive, untreated patients die within 2 years, and even treated patients fare poorly.¹³ 

Pathologic Features:
Microscopically, there is patchy pulmonary congestion and hemorrhage. The low-power view mimics interstitial pneumonitis, in that there are increased numbers of cells within alveolar septa. However, at higher magnification, the pulmonary capillaries, venules and small muscular arteries are engorged by tumor cells.^{54, 56, 63}  At high magnification, the neoplastic cells show large, vesicular, indented nuclei, one or a few eosinophilic nucleoli and moderate cytoplasm. Pulmonary arteries show muscular hypertrophy, intraluminal thrombi and eccentric or concentric subintimal fibrous scars.

The typical immunohistochemical profile is that of a B-cell lymphoma, with staining for CD20, CD22, CD19, and CD79a.¹⁷  Rarely, a T-cell immunophenotype may be seen.⁵³  The majority of cases have clonal rearrangement of the immunoglobulin gene.^{14, 47} 

Intravascular localization is believed to be due to an abnormality in homing receptors on the surface of the neoplastic cells, such that egress from vessels is impeded. Two putative receptors that have been found to be missing in the small numbers of cases so far tested include CD29 and CD54 (ICAM-1).^{17, 50} 

Table 1. Some Auto-immune and Other Disorders Reported in Pulmonary MALT tumors ^{4, 36} 

Sjogren syndrome	Hashimoto thyroiditis
Systemic lupus erythematosus	Rheumatoid arthritis
Atrophic gastritis	Pernicious anemia
Primary biliary cirrhosis	Multiple sclerosis
Addison disease	Polymyalgia rheumatica
Hepatitis C virus hepatitis	H. pylori gastritis
Pulmonary adenocarcinoma	Cerebellar ataxia
Peripheral neuropathy	Transverse myelitis

Table 2. Immunohistochemical Profile of MALTomas ^{4, 28} 

Positive	Negative
CD20+	cyclin D1
bcl2	CD21
CD79a+	CD5
CD43+/-	CD10
CD21 (follicles)	bcl6
CD35 (follicles)

Table 3. Immunoprofile of Lymphomatoid Granulomatosis
(Jaffe & Wilson, 1997; **Morice et al, 2002; Haque et al, 1998).

B cells (immunoblasts)

CD20+, CD79a+, CD30+ (EBV-induced), CD43+/- CD15- EBV+ (by in situ hybridization for EBER 1/2 RNA or by immunohistochemistry for LMP)

T cells

CD3+, CD4+ > CD8+ (10-20% of cells) Cytolytic markers: TIA-1(30-90%, mean 55%), granzyme B (0-70%, mean 20%)

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18. Guinee DG, Perkins SL, Travis WD, et al. Proliferation and cellular phenotype in lymphomatoid granulomatosis. implications of a higher proliferation index in B cells. Am J Surg Pathol 1998;22:1093-100.
19. Guinee DJ, Jaffe E, Kingma DF, N. , et al. Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol 1994;18:753-64.
20. Haque AK, Meyers JL, Hudnall SD, et al. Pulmonary lymphomatoid granulomatosis in acquired immunodeficiency syndrome: lesions with Epstein-Barr virus infection. Mod Pathol 1998;11:347-56.
21. Harper P, Fischer C, McLennan K, et al. Presentation of Hodgkin's disease as an endobronchial lesion. Cancer 1984;53:147-50.
22. Harris NL. Extranodal lymphoid infiltrates and mucosa-associated lymphoid tissue (MALT). A unifying concept. Am J Surg Pathol 1991;15:879-84.
23. Isaacson P, Chan J, Tang C, et al. Low grade B cell lymphoma of mucosa associated lymphoid tissue arising in the thymus. A thymic lymphoma mimicking myoepithelial sialadenitis. Am J Surg Pathol 1990;14:342-51.
24. Isaacson P, Spencer J. Malignant lymphoma of mucosa-associated lymphoid tissue. Histopathology 1987;11:445-62.
25. Isaacson P, Wotherspoon A, Pan L. Follicular colonization in B-cell lymphoma of mucosa-associated lymphoid tissue. Am J Surg Pathol 1991;15:819-28.
26. Isaacson P, Wright D. Malignant lymphoma of mucosa-associated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer 1983;52:1410-6.
27. Isaacson PG. Gastric MALT lymphoma: from concept to cure. Ann Oncol 1999;10:637-45.
28. Isaacson PG, Muller-Hermelink HK, Piris MA, et al. Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In: Jaffe ES, Harris NL, Stein H, et al., eds. Pathology & Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2001:157-60.
29. Jaffe ES, Wilson WH. Lymphomatoid granulomatosis. In: Jaffe ES, Harris NL, Stein H, et al., eds. Pathology & Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2001:185-7.
30. Jaffe ES, Wilson WH. Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications. Cancer Surv 1997;30:233-48.
31. Kaplan MA, Pettit CL, Zukerberg LR, et al. Primary lymphoma of the trachea with morphologic and immunophenotypic characteristics of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue. Am J Surg Pathol 1992;16:71-5.
32. Katzenstein A-L, Carrington C, Liebow A. Lymphomatoid granulomatosis - a clinico-pathologic study of 152 cases. Cancer 1979;43:360-73.
33. Kennedy J, Nathwani B, Burke J, et al. Pulmonary lymphomas and lymphoid lesions. Cancer 1985;56:539-52.
34. Koss M, Hochholzer L, Langloss J, et al. Lymphomatoid granulomatosis: A clinicopathologic study of 42 patients. Pathology 1986;18:283-8.
35. Koss M, Hochholzer L, Nichols P, et al. Primary non-Hodgkin's lymphoma and pseudolymphoma of lung: A study of 161 patients. Hum Pathol 1983;14:1024-38.
36. Kurtin PJ, Myers JL, Adlakha H, et al. Pathology and clinical features of primary pulmonary extranodal marginal zone B-cell lymphoma of MALT type. Am J Surg Pathol 2001;25:997-1008.
37. L'Hoste R, Filippa D, Lieberman P, et al. Primary pulmonary lymphomas. A clinicopathologic analysis of 36 cases. Cancer 1984;54:1397-406.
38. Letendre L. Treatment of lymphomatoid granulomatosis: Old and new perspectives. Semin Respir Med 1989;10:178-81.
39. Li G, Hansmann M-L, Zwingers T, et al. Primary lymphoma of the lung: morphological, immunohistochemical and clinical features. Histopathology 1990;16:519-31.
40. Liebow A, Carrington C, Friedman P. Lymphomatoid granulomatosis. Hum Pathol 1972;3:457-558.
41. Lipford E, Margolick J, Longo D, et al. Angiocentric immunoproliferative lesions: A clinicopathologic spectrum of post-thymic T-cell proliferations. Blood 1988;72:1674-81.
42. Morice WG, Kurtin PJ, Myers JL. Expression of cytolytic lymphocyte-associated antigens in pulmonary lymphomatoid granulomatosis. Am J Clin Pathol 2002;118:391-8.
43. Myers JL, Kurtin PJ, Katzenstein A-L, et al. Lymphomatoid granulomatosis: Evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol 1995;19:1300-12.
44. Nathwani B, Hernandez A-M, Deol I, et al. Marginal B-cell lymphomas: an appraisal. Hum Pathol 1997;28:42-6.
45. Nathwani BN, Harris NL, Weisenberger D, et al. Follicular lymphoma. In: Jaffe ES, Harris NL, Stein H, et al., eds. Pathology & Genetics. Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2001.
46. Nicholson AG, Wotherspoon AC, Diss TC, et al. Lymphomatoid granulomatosis: evidence that some cases represent Epstein-Barr virus-associated B-cell lymphoma. Histopathology 1996;29:317-24.
47. Ostrakji C, Voigt W, Amador A, et al. Malignant angioendotheliomatosis - A true lymphoma: A case of intravascular malignant lymphomatosis studied by Southern blot hybridiztion analysis. Hum Pathol 1988;19:475-8.
48. Perry L, Florio R, Dewar A, et al. Giant lamellar bodies as a feature of pulmonary low-grade MALT lymphomas. Histopathology 2000;36:240-4.
49. Pisani R, DeRemee R. Clinical implications of the histopathologic diagnosis of pulmonary lymphomatoid granulomatosis. Mayo Clin Proc 1990;65:151-63.
50. Ponzoni M, Arrigoni G, Gould VE, et al. Lack of CD29 (beta1 integrin) and CD54 (ICAM-1) adhesion molecules in intravascular lymphomatosis. Hum Pathol 2000;31:220-6.
51. Raderer M, Vorbeck F, Formanek M, et al. Importance of extensive staging in patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma. Br J Cancer 2000;83:454-7.
52. Radin AI. Primary pulmonary Hodgkin's disease. Cancer 1990;65:550-63.
53. Sheibani K, Battifora H, Winberg C, et al. Further evidence that "malignant angioendotheliosis" is an angiotropic large cell lymphoma. N Engl J Med 1986;314:943-8.
54. Snyder L, Harmon K, Estensen R. Intravascular lymphomatosis (malignant angioendotheliosis) presenting as pulmonary hypertension. Chest 1989;96:1199-200.
55. Tamura A, Komatsu H, Yania N, 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. Jap J Clin Oncol 1995;25:140-52.
56. Tan T, Spaande P, Blaisse M, et al. Angiotropic large cell lymphoma presenting as interstitial lung disease. Thorax 1988;43:578-9.
57. Taniere P, Thivolet-Bejui F, D. V, et al. Lymphomatoid granulomatosis - a report on four cases: evidence for B phenotype of the tumoral cells. Eur Respir J 1998;12:102-6.
58. Teruya-Feldstein J, Jaffe ES, Burd PR, et al. The role of Mig, the monokine induced by interferon-gamma, and IP-10, the interferon-gamma-inducible protein-10, in tissue necrosis and vascular damage associated with Epstein-Barr virus-positive lymphoproliferative disease. Blood 1997;90:4099-105.
59. Teruya-Feldstein J, Temeck BK, Sloas MM, et al. Pulmonary malignant lymphoma of mucosa-associated lymphoid tissue (MALT) arising in a pediatric HIV-positive patient. Am J Surg Pathol 1995;19:357-63.
60. Thieblemont C, Bastion Y, Berger F, et al. Mucosa-associated lymphoid tissue gastrointestinal and non-gastrointestinal lymphoma behavior: analysis of 108 patients. J Clin Oncol 1997;15:1624-30.
61. Wilson WH, Kingma DW, Raffeld M, et al. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood 1996;87:4531-7.
62. Wotherspoon A, Pan L, Diss T, et al. A genotypic study of low grade B-cell lymphomas, including lymphomas of mucosa associated lymphoid tissue (MALT). J Pathol 1990;162:135-40.
63. Yousem S, Colby T. Intravascular lymphomatosis presenting in the lung. Cancer 1990;65:349-.
64. Yousem, SA, Weiss LM, Colby TV. Primary pulmonary Hodgkin's disease: a clinicopathologic study of 15 cases. Cancer 1986; 57: 1217-24.

LYMPHOMATOID GRANULOMATOSIS - References

1. Beaty MW, Toro J, Sorbaro L, Stern JB, Pittaluga S, Raffeld M, Wilson WH, Jaffe ES. Cutaneous lymphomatoid granulomatosis. Correlation of clinical and biologic features. Am J Surg Pathol 25: 1111-1120, 2001.
2. Fauci A, Haynes B, Costa J, Katz P, Sheldon M. Lymphomatoid granulomatosis - prospective clinical and therapeutic experience over 10 years. N Engl J Med 306: 68-74, 1982.
3. Guinee DG, Perkins SL, Travis WD, Holden JA, Tripp SR, Koss MN. Proliferation and cellular phenotype in lymphomatoid granulomatosis. implications of a higher proliferation index in B cells. Am J Surg Pathol 22: 1093-1100, 1998.
4. Guinee DJ, Jaffe E, Kingma DF, Wallberg K, Krishnan J, Frizzera G, Travis W, Koss M. Pulmonary lymphomatoid granulomatosis. Evidence for a proliferation of Epstein-Barr virus infected B-lymphocytes with a prominent T-cell component and vasculitis. Am J Surg Pathol 18: 753-764, 1994.
5. Haque AK, Meyers JL, Hudnall SD, Gelman BB, Lloyd RV, Payne D, Borucki M. Pulmonary lymphomatoid granulomatosis in acquired immunodeficiency syndrome: lesions with Epstein-Barr virus infection. Mod Pathol 11: 347-356, 1998.
6. Jaffe ES,Wilson WH. Lymphomatoid granulomatosis. In: Pathology & Genetics. Tumours of Haematopoietic and Lymphoid Tissues, edited by Jaffe ES, Harris NL, Stein H and Vardiman JW. Lyon: IARC Press, 2001, p. 185-187.
7. Jaffe ES, Wilson WH. Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications. Cancer Surv 30: 233-248, 1997.
8. Katzenstein A-L, Carrington C, Liebow A. Lymphomatoid granulomatosis - a clinico-pathologic study of 152 cases. Cancer 43: 360-373, 1979.
9. Koss M, Hochholzer L, Langloss J, et al. Lymphomatoid granulomatosis: A clinicopathologic study of 42 patients. Pathology 18: 283-288, 1986.
10. Letendre L. Treatment of lymphomatoid granulomatosis: Old and new perspectives. Semin Respir Med 10: 178-181, 1989.
11. Liebow A, Carrington C, Friedman P. Lymphomatoid granulomatosis. Hum Pathol 3: 457-558, 1972.
12. Lipford E, Margolick J, Longo D, Fauci A, Jaffe E. Angiocentric immunoproliferative lesions: A clinicopathologic spectrum of post-thymic T-cell proliferations. Blood 72: 1674-1681, 1988.
13. Morice WG, Kurtin PJ, Myers JL. Expression of cytolytic lymphocyte-associated antigens in pulmonary lymphomatoid granulomatosis. Am J Clin Pathol 118: 391-398, 2002.
14. Myers JL, Kurtin PJ, Katzenstein A-L, Tazelaar HD, Colby TV, Strickler JG, Lloyd RV, Isaacson PG. Lymphomatoid granulomatosis: Evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection. Am J Surg Pathol 19: 1300-1312, 1995.
15. Nicholson AG, Wotherspoon AC, Diss TC, et al. Lymphomatoid granulomatosis: evidence that some cases represent Epstein-Barr virus-associated B-cell lymphoma. Histopathology 29: 317-324, 1996.
16. Pisani R, DeRemee R. Clinical implications of the histopathologic diagnosis of pulmonary lymphomatoid granulomatosis. Mayo Clin Proc 65: 151-163, 1990.
17. Taniere P, Thivolet-Bejui F, Viteym D, Isaac S, Loire S, Cordier JF, Berger F. Lymphomatoid granulomatosis - a report on four cases: evidence for B phenotype of the tumoral cells. Eur Respir J 12: 102-106, 1998.
18. Teruya-Feldstein J, Jaffe ES, Burd PR, Kanegane H, Kingma D, Wilson WH, Longo DL, Tosato G. The role of Mig, the monokine induced by interferon-gamma, and IP-10, the interferon-gamma-inducible protein-10, in tissue necrosis and vascular damage associated with Epstein-Barr virus-positive lymphoproliferative disease. Blood 90: 4099-4105, 1997.
19. Wilson WH, Kingma DW, Raffeld M, Wittes RE, Jaffe ES. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood 87: 4531-4537, 1996.

REACTIVE LYMPHOID LESIONS
LYMPHOCYTIC INTERSTITIAL PNEUMONIA (LIP)

Definition:
Lymphocytic interstitial pneumonia is a disease characterized by a diffuse, prominent interstitial lymphoid infiltrate.⁵⁵  The infiltrate most often diffusely invades alveolar septa; it consists of lymphocytes and variable numbers of plasma cells.³⁴  LIP is best viewed as a descriptive clinicopathologic term rather than a distinct disease entity. Other synonymous terms are lymphoid interstitial pneumonia, lymphoid interstitial pneumonitis, diffuse hyperplasia of bronchus-associated lymphoid tissue (BALT), lymphocytic interstitial pneumonitis, lymphoplasmacytic pneumonia and plasmacytic interstitial pneumonia. The separation between LIP and follicular bronchitis/bronchiolitis (pulmonary lymphoid hyperplasia), in which the lymphoid cells are largely confined to peribronchial and lobular septal areas, is arbitrary because cases with overlapping appearance can occur.⁴² 

Clinical Features:
LIP is most often seen in children with AIDS.^{24, 41, 51}  One autopsy series suggested an incidence of 6%.³⁹  The association has been known since 1983 .^{43, 49}  Indeed, the presence of LIP in a child under the age of 13 years (assuming that the test for HIV is positive) is now part of the case definition of AIDS, even when no opportunistic infection is present. Surprisingly, adults who are infected with HIV usually have either minimal or mild interstitial lymphoid infiltrates (so-called non-specific interstitial pneumonitis), not LIP;^{19, 46, 51}  still, occasional adults with AIDS do develop LIP. The affected patients are usually black and have AIDS-related complex (ARC) and polyclonal hypergammaglobulinemia.^{37, 41, 46, 47} 

LIP can also occur in both children and adult patients who do not have HIV infection. Affected children usually have congenital immune deficiencies. The adults have a variety of underlying diseases, but most commonly they suffer from Sjogren syndrome. It has been estimated that 0.9% of patients with Sjogren syndrome have LIP and up to 25% of adults with LIP have Sjogren syndrome.^{16, 47, 50}  In one study of 20 patients with Sjogren syndrome, nine had radiographic evidence of interstitial infiltrates, and LIP was one of a number of findings, ranging from follicular bronchiolitis to fibrosis with honeycombing.¹²  A large number of other disorders, primarily autoimmune diseases but also viral infections, have also been reported with LIP (Table 2). These systemic lupus erythematosus,⁴  autoerythrocyte sensitization,¹¹  Hashimoto's thyroiditis,³⁴  pernicious anemia,³³  myasthenia gravis,³⁸  chronic active hepatitis ²⁰ and primary biliary cirrhosis.²⁸ 

Most adult patients with LIP are women in the fifth through seventh decades of life.^{28, 34, 52}  Symptoms are the usual ones seen in diffuse interstitial lung disease: Most (50-80%) have cough, dyspnea or a combination of the two.⁵⁷  However, there can also be symptoms and signs related to associated immunologic diseases, such as Sjogren syndrome or myasthenia gravis.⁵³ 

The most remarkable laboratory abnormality is the presence of dysproteinemia, occurring in at least 60% of adults. Most frequently, there is hypergammaglobulinemia.⁵⁴  In about 10 percent of cases, there is hypogammaglobulinemia.^{28, 53}  Reduced lung volumes and diffusing capacities appear to be consistent and sensitive indicators of disease in LIP
19).

Chest radiographic findings in patients with LIP are typically non-specific. They include bilateral reticular and nodular opacities as well as ground glass opacity and parenchymal consolidation.¹⁷  These abnormalities usually exhibit a lower lung zone predominance. Nodular patterns are also described, particularly in patients with AIDS.

Computed tomography (CT) of the chest may demonstrate ground glass attenuation and poorly defined centrilobular nodules. Thickening of the bronchovascular interstitium and interlobular septa, cystic spaces and lymph node enlargement are also described in studies using thin section and high resolution CT techniques.²²  Lymphadenopathy may be more common in patients who also have AIDS. In rare cases, fibrosis and honeycomb lung may be demonstrated. Pleural effusion is rare.²¹ 

LIP in adults is usually treated with corticosteroids, but response is variable. Further, the improvement in symptoms related by some patients after treatment is difficult to assess, since spontaneous remission has been reported.⁵⁷ 

Overall, the clinical course of adults with LIP is also variable.^{34, 52}  In our experience, equal numbers of patients died, improved and remained stable.²⁸  In general, about one-third to one-half of adults with LIP die within five years.⁴¹  Death is most frequently due to infectious complications of treatment with immunosuppressive drugs, but occasionally patients die from respiratory insufficiency or malignant lymphoma.

B-cell lymphomas can develop in patients with LIP, particularly when they have associated Sjogren's syndrome. About 5 per cent of patients with LIP develop disseminated malignant lymphoma,^{2, 28}  in particular B-immunoblastic sarcoma.³¹  Well-differentiated lymphomas associated with prolonged survival have also been reported in patients with LIP.⁵⁰  As noted above, a minor population of monoclonal lymphoid cells can be present in LIP-like lesions, supporting the idea that evolution of LIP to lymphoma can occur.

Children who have LIP and who are HIV-positive have a variable prognosis. The disease may respond to corticosteroid treatment with significant clinical improvement;⁴¹  still, it may evolve into lymphoma on occasion.

Pathologic Features:
Typically, the lung shows pink-tan or tan-gray diffuse consolidation. In late stages of disease, the lung may be contracted and the pleural surface may show a cobblestone pleural surface and subpleural cysts with surrounding gray, firm tissue, due to honeycombing fibrosis.

LIP is part of a spectrum of pulmonary lymphoid proliferations, ranging from follicular bronchitis/bronchiolitis to low-grade malignant lymphoma. These patterns may be difficult to distinguish from each other. When lymphoid nodules are centered about and largely restricted to airways, vessels and interlobular septa (ie, the pathways of the lymphatics in lung), the disease is termed follicular bronchitis/bronchiolitis (or pulmonary lymphoid hyperplasia in the pediatric AIDS literature).²³  As the disease becomes more florid, the lymphoid infiltrate penetrates into the pulmonary interstitium, which is extensively involved. This is the classical form of LIP initially described by Liebow and Carrington.³⁴ 

This diffuse interstitial infiltrate is usually composed of small lymphocytes with variable numbers of admixed plasma cells. HIV-infected patients, in particular, may have few plasma cells, while occasional cases of LIP are so rich in plasma cells that they have been termed lymphoplasmacytic pneumonia ¹⁸ or plasma cell interstitial pneumonitis.^{40, 57} 

Germinal centers can occur in up to one-half of cases of LIP.^{28, 34, 52}  Scattered, multinucleated giant cells or ill-formed granulomas are also found in the lymphoid infiltrate in up to 50 per cent of cases.²⁸  Why giant cells occur is unclear, but they are also seen in malignant lymphomas of the lung.²⁹  Possibly, they are a reaction to lipid released by cellular breakdown; indeed, the giant cells may contain cholesterol clefts. In late stages, LIP can produce advanced interstitial fibrosis with honeycombing.

LIP usually shows a mixture of B cells and T cells. The B cells often appear in nodules corresponding to lymphoid follicles, while T cells are present in the pulmonary interstitium. The B cells show polyclonal staining for immunoglobulin light chains.^{2, 28, 30}  The lymphoid infiltrates of a few cases of LIP associated with hypogammaglobulinemia have been studied using frozen tissues, and appear to consist largely of T-cells ²⁷ and more particularly of T-helper cells.⁸  The predominant phenotype of the lymphocytes of AIDS patients with LIP may be either T-cells or B-cells.^{41, 14} 

Etiology:
LIP appears to be associated with several disorders of immunologic type; it may therefore have more than one etiology and pathogenesis.²⁸  Cellular-induced autoimmunity and viral infection with secondary disorders of the immune response are potential causes.^{30, 52, 57} 

One recent study favored autoimmunity as the pathogenetic mechanism.³²  This was based on the finding of minor clones of lymphoid cells with a high homology to autoreactive lymphocytes (rheumatoid factor, anti-DNA antibody, and G6-positive lymphocytes). This, in turn, suggests that immature B cells stimulated by auto-antigens might play some role in the pathogenesis of true LIP.³² 

Perhaps the most promising etiological agent is a viral one. An LIP-like lesion can be induced in sheep by a member of the lenti-retrovirus group, the maedi/visna virus.⁴⁷  Interstitial lymphoid infiltrates can also be induced in cats by feline leukemia virus.⁵  These animal models suggest that LIP-like reactions may be a common feature of lentivirus infection.

In humans, there appears to be an association between LIP and several different viral infections. The potential culprits include Epstein-Barr virus (EBV), human immunodeficiency virus-1 (HIV), and human herpes virus 8 (HHV-8). It is well known that chronic Epstein-Barr virus infection can induce a prominent chronic interstitial pneumonitis with abundant lymphocytes. Further, Epstein-Barr virus DNA has been found in lung tissues from 8 of 10 children with LIP and acquired immune deficiency syndrome (AIDS) using Southern blot hybridization.¹  It has also been found in lung tissue sections from adults with LIP in greater frequency than in control lung tissues.^{3, 25, 35}  Of interest, EBV latent membrane protein-1 appears to be most prevalent in bronchiolar epithelial cells, not in lymphoid cells.²⁵  The mechanism of EBV action to produce LIP is unclear. Also, in no series of LIP cases is EBV present in all patients, suggesting that other viruses can play a role.^{25, 35} 

HIV has been found in broncho-alveolar lavage fluids and lung tissues of some patients with the acquired immune deficiency syndrome.^{7, 46, 59}  Since disorders in T-cell regulation induced by retroviruses such as HIV can produce polyclonal B-cell activation and hyperplasia, the relation of viral infection to LIP is of great interest. There is also a case report of a patient who had LIP and simultaneous HHV-8 infection, without demonstrable Kaposi sarcoma.⁵⁶  That HHV-8 might have played a pathogenic role was suggested by the absence of HIV infection, but other potential viral infections were not excluded.

Children who are infected with HIV may have CD8-lymphocytosis in lung tissue, bronchoalveolar lavage fluid, peripheral blood, and salivary gland. These children often show the human leukocyte antigen (HLA)-DR5 haplotype. In one case, epithelial cells lining the air spaces expressed HLA-DR, while lymphocytes and macrophages in the alveolar spaces strongly expressed transforming growth factor (TGF)-ß. This suggests that abnormal expression of HLA-DR in non-immune cells and exaggerated production of TGF-ß played important roles in the pathogenesis of LIP in this patient.²⁶ 

Differential Diagnosis:
The differential diagnosis of LIP is low-grade marginal zone B-cell lymphoma of MALT (MALTOMA) and benign lymphoid processes in lung (Table 1). Low-grade marginal zone B-cell lymphoma (MALToma) can occasionally assume a widespread interstitial pattern on radiographs and in histologic sections. As well, reactive lymphoid follicles or their remnants can be present in MALTOMAS. Further, sometimes nodules of low-grade lymphoma can be surrounded by areas of interstitial reactive lymphoid cells, producing a resemblance to LIP.¹³  In fact, it is probable that some cases classified as LIP on purely morphologic grounds are malignant lymphomas.¹⁵  We suspect that this may be particularly true in the setting of Sjogren syndrome. Radiologic features suggestive of lymphoma include: pleural effusion, consolidation and large nodular opacities or masses.²²  Microscopically, malignant lymphoma is strongly favored if the lymphoid infiltrate shows a distinctly lymphangitic pattern, monomorphism, and/or invasion of parietal pleura or regional lymph nodes .⁹  Invasion of bronchial cartilage or of visceral pleura by the cellular infiltrate also favors malignant lymphoma but does not exclude a reactive process. In general, we recommend that the pathologist perform immunohistochemical stains on all cases of LIP to ensure that there is no evidence of a monoclonal lymphoid cell population. Further, in doubtful cases, we recommend that the polymerase chain reaction (PCR) be done for immunoglobulin gene rearrangement (Table 1).^{13, 32}  Sometimes, however, these studies produce a result that complicates decision-making. For example, a recent clonality study of five cases morphologically believed to be LIP showed minor monoclonal populations, which were interpreted as neoplastic clones hidden in normally reactive lymphocyte clones.³²  In these cases, in which the morphology shows an apparently benign lymphoid process and clonality studies show focal clonal cell populations, perhaps the best diagnosis is a descriptive one, rather than one of unequivocal lymphoma. If, however, the lymphoid cell population is markedly distorted so that it is uncertain whether it is benign or malignant morphologically, then PCR clonality studies may play an important role in diagnosis of malignant lymphoma.⁴² 

Nodular lymphoid hyperplasia (or pseudolymphoma) is microscopically similar to LIP, but it occurs in the lung as one or several localized lesions, rather than as a diffuse bilateral interstitial infiltrate.

Angioimmunoblastic lymphadenopathy (AIBL) can involve the lung in the form of diffuse interstitial infiltrates. Typically, there is little difficulty in distinguishing AIBL from LIP, since AIBL has a distinctive set of clinical features including generalized lymphadenopathy, hepatosplenomegaly, Coombs-positive hemolytic anemia and skin rash. Microscopically, AIBL is polymorphous but shows numerous atypical immunoblasts as well as lymphocytes and plasma cells. The cellular infiltrate also predominantly involves lymphatic routes (around airways and vessels), rather than the interstitial compartment that is affected in LIP.⁹ 

LIP and hypersensitivity pneumonitis (extrinsic allergic alveolitis) may be difficult to distinguish from each other. Computed tomography of both conditions may demonstrate bilateral ground glass opacities. Microscopically, hypersensitivity pneumonitis may resemble LIP in showing diffuse interstitial lymphoplasmacytic infiltrates containing ill-formed granulomas, but the lymphoid infiltrate is more dense in LIP, and bronchiolitis obliterans, a hallmark of hypersensitivity pneumonitis, is not present.

Finally, prominent peribronchial lymphoid aggregates can be present in interstitial pneumonitides associated with connective tissue diseases, such as systemic lupus erythematosus and rheumatoid arthritis. The lymphoid infiltrate is typically denser and more diffuse in LIP.

FOLLICULAR BRONCHITIS/BRONCHIOLITIS
This pattern of injury, also termed follicular hyperplasia of BALT or pulmonary lymphoid hyperplasia (PLH), refers to the presence of lymphoid nodules, with or without reactive follicles, next to and confined to the walls of the airways, associated peribronchial tissue, and septal areas.¹¹  This pattern of injury may be seen in a variety of diseases. These include acquired immune deficiency syndrome, where it is called pulmonary lymphoid hyperplasia,⁶  congenital immune deficiency syndromes such as Wiskott-Aldrich syndrome, collagen vascular diseases such as rheumatoid arthritis, and infectious and obstructive pneumonias including localized infections.^{1-3, 7, 10, 11} 

Grossly, there are numerous minute (1-2 mm.) nodules located adjacent to airways.⁵  Microscopically, there are peribronchiolar and/or peribronchial nodular aggregates of lymphoid cells, sometimes containing reactive germinal centers.¹¹ 

Radiologic findings in patients with follicular bronchitis/bronchiolitis are similar to those seen in LIP. Chest radiographs demonstrate diffuse reticular and nodular opacities. Thin section CT may demonstrate multifocal bilateral small (less than 3 mm) nodules or larger (3-12mm) nodules in centrilobular and peribronchial distributions.⁴  Centilobular branching structures bronchial wall thickening, bronchiectasis, bronchiolectasis, branching opacities and areas of low attenuation have also been described on HRCT.^{5, 9} 

The absence of a solitary mass helps distinguish follicular hyperplasia from nodular lymphoid hyperplasia (Table 1). The separation between follicular bronchitis/bronchiolitis, in which the lymphoid cells are largely confined to peribronchial and lobular septal areas and lymphoid interstitial pneumonitis, in which the lymphoid infiltrate penetrates more diffusely into the alveolar septae, is arbitrary because cases with overlapping appearance can occur.⁸ 

NODULAR LYMPHOID HYPERPLASIA OF LUNG
Definition: Nodular lymphoid hyperplasia is a term that refers to one or a few nodules or localized lung infiltrates consisting of reactive lymphoid cells.⁷ 

Historical Annotation and Synonym:
A less favored synonym is pseudolymphoma. The concept of masses of reactive lymphoid tissue in lung is controversial because most microscopically low-grade lymphoid proliferations in lung, including those with abundant germinal centers, are now known to be extra-nodal marginal zone B-cell lymphomas of MALT type.^{2, 5, 10}  This has led to suggestions, particularly from European authors, that the term "pseudolymphoma" be disregarded as redundant or inaccurate.^{2, 3, 12}  However, a recent immunohistochemical and molecular pathologic study has confirmed the existence of pulmonary nodular lymphoid hyperplasia.¹ 

Clinical Features:
Nodular lymphoid hyperplasia is infrequent. In the largest published series, only 14 verifiable cases were found.¹  Men slightly outnumber women (ratio, 1.3:1). The patients range from 19 to 80 years old (mean, 60 years; median 65 years). Most cases (70%) are detected as incidental lesions on radiologic studies obtained for other reasons. Symptoms, when present, include shortness of breath, cough and/or pleuritic chest pain. Serological studies have not been systematically performed.

The most common radiological manifestation of nodular lymphoid hyperplasia of the lung is a solitary pulmonary nodule or mass or a focal area of parenchymal consolidation. The lesions have variable sizes: They range from 2 to 5 cm, although masses measuring up to 10 cm. have been described. In the vast majority of cases, air bronchograms are present within these lesions. Lymphadenopathy can occur, but pleural effusions are rare and their presence should suggest the diagnosis of lymphoma. Multifocal lesions have also been descibed.⁴ 

Pathologic Features:
The lesions are usually gray, white or tan nodules or masses with a firm, rubbery or fleshy consistency.^{1, 8}  Most of them are solitary, but occasionally two, three or even "multiple" lesions can occur, the last emphasizing the potential for overlap with lymphocytic interstitial pneumonia. The pulmonary nodules measure from 0.6 cm to 6 cm in greatest dimension; most are 2-4 cm.¹  There is no predilection for any lobe.

The lymphoid lesion is usually subpleural, but it can be peribronchial. Of interest, even when the lesion is subpleural, there is usually no evidence of the plaque-like invasion of the overlying pleura seen so commonly in MALTomas.

As opposed to lymphocytic interstitial pneumonia, nodular lymphoid hyperplasia is histologically localized. The most striking features are the numerous reactive germinal centers with well-preserved mantle zones and the interfollicular sheets of mature plasma cells. As well, there is usually interfollicular fibrosis of varying degrees that at least focally obliterates the underlying lung parenchyma. The plasma cells may show Russell or Mott bodies, but they don't contain Dutcher bodies. Giant cells can be present in the lymphoid infiltrate, but this is a non-specific feature since they can be seen in low-grade B-cell lymphomas. Limited lymphangitic spread of the lymphoid and plasma cell infiltrate can be present. Still, lymphoepithelial lesions and invasion of the visceral pleura or invasion or bronchial cartilage, features frequently seen in pulmonary low-grade marginal zone B-cell lymphomas are not found.

Regional lymph nodes show benign reactive follicular hyperplasia.

Immunohistochemical stains demonstrate a reactive pattern of B cells and T cells. In particular, the germinal centers stain for the B-cell marker CD20, while interfollicular lymphocytes are immunoreactive for CD3, CD43 and CD5.¹  Antibodies to CD45RA stain the mantle zone lymphocytes, but stains for bcl-1 and bcl-2 do not decorate the follicles. The CD20-positive lymphocytes do not co-express either CD43 or CD5. Staining for immunoglobulin light chains shows a polyclonal pattern among the plasma cells.

Genotype and Pathogenesis:
Molecular genetic analysis has shown no rearrangement of the immunoglobulin heavy chain gene.¹  Assays for the chromosomal rearrangement t(14;18) have been negative.

The pathogenesis of nodular lymphoid hyperplasia is unclear. It shows a microscopic resemblance to lymphocytic interstitial pneumonia, and when there are several lesions of nodular lymphoid hyperplasia, the distinction can be difficult and even arbitrary. Still, nodular lymphoid hyperplasia, unlike lymphocytic interstitial pneumonia, has is no known association with HIV infection, connective tissue diseases, or Sjogren syndrome.^{6, 11}  Of interest, there are two reported cases that showed either a small microscopic focus of acute inflammation or a small foreign body aspiration granuloma, suggesting that inflammatory stimuli may give rise to these prominent follicular lymphoid masses.¹ 

Treatment and Prognosis:
Surgical excision of the nodule(s) appears to be adequate therapy. The abundance of reactive follicles in extra-nodal low-grade marginal B-cell lymphomas of lung ^{5, 7, 9, 10} naturally gives rise to the concern that some of them might have arisen in lesions such as nodular lymphoid hyperplasia, but in seven cases followed for 8-72 months (mean, 30 months) there has not been recurrence of the pulmonary lesion or development of malignant lymphoma.¹ 

Differential Diagnosis:
The differential diagnosis of nodular lymphoid hyperplasia and other reactive and low-grade malignant lymphomas is presented in Table

Table 1. Differential Diagnosis of Nodular Lymphoid Hyperplasia (NLH),
Lymphocytic Interstitial Pneumonia (LIP), Follicular Bronchitis/Bronchiolilitis (FB),
and Extra-nodal Marginal Zone Lymphoma (Maltoma).

Feature	NLH	LIP	FB	Maltoma
Chest Radiograph
Mass	+	-	-	+
Diffuse	-	+	+	+
Histologic
Localized	+	-	-	+
Diffuse interstitial	-	+	-	+ (lymphangitic)
Peribronchial only	-	-	+	-
Infiltrate	poly	poly	poly	mono or poly
Germinal centers	+	+/-	+/-	+/-
Plasma cells	+	+/-	+/-	+/-
Dutcher bodies	-	-	-	+
Monoclonality	-	-	-	+
Monocytoid B-cells	-	-	-	+

+ = present
- = absent
+/- = may be present or absent
poly = polymorphous
mono = monomorphic

Table 2. Diseases Associated with Lymphocytic Interstitial Pneumonia Patterns in Lung*

Autoimmune diseases   Sjogren syndrome 42, 50, 53    Primary biliary cirrhosis 28    Myasthenia gravis 38    Hashimoto's thyroiditis 34    Systemic lupus erythematosus 4    Autoerythrocyte sensitization 11    Pernicious anemia 33      Immunodeficiency   Acquired immune deficiency syndrome 24, 39, 48    Common variable immunodeficiency 45    Unexpalined childhood immunodeficiency 58    Chronic active hepatitis 20, 28      Virus-Associated (excluding HIV infection)   Epstein-Barr infection 35    Human herpesvirus-8 56    Chronic active hepatitis 20      Drug-induced   Dilantin 6      Miscellaneous   Crohn disease 10    Tuberculosis 36    Graft versus host disease 44

*excluding animal hosts

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