An 82-year-old woman was referred to the Department of Respiratory Medicine, Izumi City General Hospital, because of a 1-month history of cough and suspected miliary tuberculosis on chest radiography. The patient has a 10-year history of type 2 diabetes. Two years ago, the patient underwent lower anterior resection of the rectum for rectal cancer stage I (pT1bN0M0). One year ago, she was treated for suspected metastatic liver tumors with chemotherapy using 15 cycles of modified FOLFOX6 plus bevacizumab (bevacizumab 5 mg/kg, followed by oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2 and bolus infusion of fluorouracil 400 mg/m2 on day 1 and continuous fluorouracil infusion 2400 mg/m2 on day 1 through day 2 of a two-week cycle). Because her carcinoembryonic antigen value was normal, ultrasound-guided liver biopsy was performed for histologic confirmation. Ultrasonography showed a partially exophytic hypoechoic lesion in the left medial and right posterior inferior segment of the liver. A diagnostic thick needle biopsy was performed from the lesion in the left medial segment. Pathologic examination showed diffuse proliferation of small lymphocytes with a boundary on the liver tissue (Fig. 1) and positive for CD20 and CD79a. Ultimately, the liver lesions were interpreted as malignant lymphoma.
At her current presentation, miliary deposits throughout the lung bilaterally were demonstrated on chest radiography. Computed tomography of the chest showed innumerable, tiny, well-defined miliary nodules of 1-3 mm diameter in a random distribution pattern, and some of which are distributed in the subpleural (Fig. 2). The "tree-in-bud" appearance was not evident, and no mediastinal lymphadenopathy was detected. Metastatic lung tumor and miliary tuberculosis were in the list of differential diagnoses.
The patient had no cardiac murmur on presentation. Her lungs were clear to auscultation, and abdominal examination was unremarkable with no hepatosplenomegaly. No skin lesions were appreciated; there was no superficial lymphadenopathy.
The patient's C-reactive protein was 0.3 mg/dL, and liver function test results were within the normal range. Tumor markers (carcinoembryonic antigen was 1.0 ng/mL; carbohydrate antigen 19-9 was 3.0 U/mL), Interferon-gamma release assay (T-SPOT.TB, Oxford Immunotec) and angiotensin-converting enzyme levels were within the normal range. The value of lactate dehydrogenase was not elevated at 164 IU/L. The soluble interleukin-2 receptor was slightly elevated at 854 U/mL. Sputum smear for acid-fast bacilli stained negative. Polymerase chain reaction and culture of sputum, urine, and bronchial secretion, in addition to peripheral blood, bone marrow aspiration, and gastric lavage, were all negative for Mycobacterium tuberculosis. Furthermore, bronchoalveolar lavage was performed using a total volume of 150 mL of sterile saline solution (56% recovery) from the right posterior bronchus. The bronchoalveolar lavage fluid analysis revealed marked neutrophilia (0.2%), and other cells included lymphocytes (71.2%), eosinophils (0.8%), and macrophages (27.8%), with the total cell count elevated to 1075/muL. The alveolar CD4/CD8 T-cell ratio was high (2.03). Polymerase chain reaction for Pneumocystis jiroveci was negative, and the bronchoalveolar lavage fluid yielded no microorganisms.
Transbronchial lung biopsy specimens from the right posterior segment revealed only lymphocytes with collapsed lung alveolar tissue. Therefore, a thoracoscopic lung biopsy of the middle lobe was performed to rule out metastatic adenocarcinoma from rectum and granulomatous inflammation. Histopathologic examination of biopsied peripheral lung tissue from the posterior segment showed multiple small nodular lesions in pleural area, which composed of lymphoid cells. It scattered the interlobular septum of the lung and pleural (Fig. 3A). In peribronchovascular area (Fig. 3B, hematoxylin-eosin stain and Elastica van Gieson stain), these lymphoid cells found with the bronchovascular bundle, involving submucosa of the bronchiolar trees.
Tumor cells are predominantly composed of monotonous well differentiated lymphocytic type cell, and form follicle structures Grade 1. Immunohistochemical staining of the lymphocytes showed positive results for CD20, CD79a, and CD10. Subsequently, bone marrow studies revealed that lymphoid cells positive for CD20 and CD79a made a cluster of dozens of cells. These pathologic findings completely matched those in the liver biopsy. Whole-body positron emission tomography (PET) revealed increased uptake of 18F-fluorodeoxyglucose (FDG) in the liver lesions located in the left medial segment (26 x 16 mm) and located in right posterior inferior segment (27 x 23 mm), with a maximum standardized uptake value (SUVmax) of 8.7 and 5.1. The SUVmax in lymph node regions of paraaortic left infra-clavicular and mesenteric were >3.3 (Fig. 4). Based on these observations, malignant lymphoma clinical stage IV was diagnosed according to the Cotswolds-modified Ann Arbor classification, involving multiple lung metastases, bone marrow infiltration, metastatic liver tumors, and several lymph nodes. The patient was started on R-CHOP therapy (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, liposomal doxorubicin 50 mg/m2, vincristine sulfate 1.4 mg/m2 on day 1 and prednisone 40 mg/m2 on day 1-5 of a three-week cycle). Complete remission was achieved following 8 cycles of rituximab plus 6 cycles of CHOP therapy, and her symptoms have since been improved. Follow-up is ongoing, and the abnormal radiographic findings have been diminished to date.
Computed tomography showing bilateral, diffuse, multiple micronodules in a random distribution pattern, consistent with a miliary pattern throughout both lungs.