Nodular Lymphoid Hyperplasia

Nodular lymphoid hyperplasia, also known as “pseudo-­ lymphoma,” is a localized mass characterized by a lymphoid infltrate with the lack of evidence of clonality despite immunohistochemical and genetic studies. The most common clinicoradiological feature is a localized and asymptomatic mass, only rarely presenting fever and/or elevated erythrocyte sedimentation rate (ESR). The lesion is usually curable by surgical excision. Finally, it is needed to evaluate the possibility of nodular lymphoid hyperplasia (pseudolymphoma)

in the lung as a potential manifestation of immunoglobulin (Ig)G4-related disease [1].

Clinical Vignette

A 37-year-old Nigerian male was admitted to our hospital suffering with cough and fever with chills. The patient immigrated from Nigeria 1 year prior to presentation. He reported no exposure to tuberculosis (Figs. 39.1, 39.2 and 39.3).

Fig. 39.1  Lung window of the contrast-enhanced CT scan of the chest. Multiple centrilobular ground glass opacities are present in both upper lobes. A relative subpleural sparing and mild septal thickening are also present

Fig. 39.3  CT scan shows bilateral areas of ground glass attenuation, with a patchy distribution. Some cyst, variable in size are present in both lower lobes, mainly on the right side. Mild interlobular septal thickening is also present. Findings are consistent with LIP

Fig. 39.2  (a, b) Histological fnding of axillary nodes biopsy: (a) A burned out follicle with a prominent, hyalinized penetrating blood vessel (lollipop appearance); characteristic “onion skin” appearance due to

the lamination of the mantle cell layers. (b) Focal immunoreactivity for HHV8. Interfollicular expansion composed predominantly of plasma cells and some degree of atypia associated with follicular hyperplasia

Lymphocytic Interstitial Pneumonia (LIP)

The rare Lymphocytic interstitial pneumonia (LIP) pattern is characterized by the presence of widespread aggregates of B and T reactive lymphocytes within the lung interstitium [3]. LIP is associated with a large variety of conditions including serum protein abnormality (monoclonal gammopathy, polyclonal dysproteinemia, hypogammaglobulinemia), immunological and infectious diseases (Sjögren syndrome—25% of cases—primary biliary cirrhosis, myasthenia gravis, Hashimoto thyroiditis, pernicious anemia, agammaglobulinemia, autoimmune hemolytic anemia, systemic lupus erythematosus, celiac disease, HIV infection, EBV infection, chronic active hepatitis, Pneumocystis infection, tuberculosis), drug-related lung injury, graft versus host disease (GVHD) due to allogeneic bone marrow transplantation, and hypersensitivity pneumonitis (extrinsic allergic alveolitis). LIP occurs more commonly in women and the mean age is around 55 years. Presenting symptoms are progressive cough and dyspnea, weight loss, fever, and arthralgias. Common physical fndings are bibasilar crackles and fnger clubbing (reported in about 50% of cases). Pulmonary function tests show reduction of lung volume, reduction of DLCO, hypoxemia and, usually, hypocapnia. The chest radiograph characteristically shows bibasilar reticulonodular infltrates; a mixed alveolar-interstitial pattern can occur when infltrates coalesce and cause compression of the alveoli. Typical HRCT abnormalities consist of areas of ground glass attenuation and poorly defned centrilobular nodules and subpleural small nodules, mostly bilateral (>90%) and with a diffuse distribution (>60%). Other common fndings are thickening of bronchovascular bundles, interlobular septal thickening (82%), cystic lesions (68%) (Fig. 39.3) [4], and lymph node enlargement (68%). Less common fndings include nodules 1–2 cm in diameter (41%), airspace consolidation (41%), emphysema (23%), bronchiectasis (18%), and pleural thickening (18%). Honeycombing and pulmonary hypertension appears in advanced disease. Pleural effusion is infrequent, except in HIV related LIP. Usually the presence of pleurisy, large nodules, and mediastinal adenopathy is suggestive for pulmonary lymphoma. Histologically, LIP is characterized by a heavy interstitial lymphoid infltrate with minor peribronchiolar involvement. Granuloma formation is rare. Intra-alveolar

accumulation of small lymphocytes, scanty granulation tissue tufts, and proteinaceous material along with type II cell hyperplasia are ancillary fndings. Immunohistochemistry using CD20 shows that B cells are mainly represented in lymphoid follicles with germinal centers (CD10+, Bcl6+, Bcl2−), whereas interstitial, interalveolar, lymphocytes are prominently T cells. At molecular investigation, no rearrangements of immunoglobulin heavy chain genes and T cell receptor gene can be evidenced. Epstein–Barr virus (EBER test) can be identifed in lung biopsy specimens from both HIV infected and non-infected patients [5, 6].

Clinical Vignette

A 75-year-old man with a history of progressive impairment of his general condition, intermittent fever, and weight loss was admitted. The peripheral blood picture was unremarkable. Right-sided pneumonia and bilateral pleural effusions were apparent on chest radiographs. Chest CT showed areas of alveolar consolidation with air bronchograms, ground glass attenuation, the presence of the “halo sign” and peribronchovascular nodules (Fig. 39.4a–c). The clinical and radiological picture worsened over 40 days and despite antibiotic treatment with macrolides. Transbronchial lung biopsies via rigid bronchoscopy were performed but the pathologic examination was inconclusive. Therefore, transthoracic fne needle aspiration/biopsy samples were obtained under CT guidance. The pathologic examination revealed histologic pattern compatible with nonspecifc interstitial pneumonia (NSIP). However, this diagnosis was not felt to be compatible with the clinical and radiological presentation, which included a signifcant increase of the right pleural effusion and evidence of anemia (Hb— 6.5 g/dL). We suspected a lymphoproliferative process and medical thoracoscopic lung biopsy was performed which revealed primary pulmonary MALT lymphoma by immunohistochemical analysis of pleural tissue specimens (Fig. 39.5a–c). Bone marrow examination was negative.

Fig. 39.4  CT scan shows bilateral consolidations, (a) particularly in the middle lobe (b) and in the posterior segment of left lower lobe (b). Moderate ground glass attenuation with interlobular septal thickening is

present in the lingula and in the middle lobe. (c) Small bilateral pleural effusions are present

Fig. 39.5  Medical thoracoscopic lung biopsy; (a) In this low magnifcation view, the neoplastic cells extensively infltrate the parietal pleura; (b) High magnifcation view of the pleural neoplastic infltrate com-

posed of smallto medium-sized B lymphocytes with relatively abundant, pale cytoplasm; occasional plasma cells are present. (c) Monotypic expression of K light chains

Treatment with corticosteroid and immunosuppressive drugs may lead to resolution. Median survival is 11.5 years. The outcome is unpredictable and may vary from resolution to death (caused in most fatal cases by progression to fbrosis, cor pulmonale and respiratory failure, superimposed infection, or to development of a complicating lymphoma).

Clinical Vignette

A 61-year-old woman with a history of worsening dyspnea and low grade fever lasting for at least 4 months. Upon presentation to the hospital, physical examination and radiological chest X-ray were unremarkable.

Peripheral blood tests were normal except for a slight increase of LDH (340 U/L) (normal range 120– 240 U/L) and mild thrombocytopenia. Soon after admission, however, he developed acute respiratory failure. A contrast enhanced CT ruled out acute pulmonary thromboembolism but documented a mild bilateral pleural effusion (Fig. 39.6a, b). He required intubation and mechanical ventilation. Pancytopenia and laboratory features consisting with a diagnosis of hemophagocytic syndrome appeared. A few days later the patient died in spite of supportive treatment. At autopsy a diagnosis of intravascular large B cell lymphoma involving the lung was made (Fig. 39.7a, b).