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Giant Intrathoracic Mass in a Young Woman With Acute Kidney Injury

      Case Presentation

      A 35-year-old woman without past medical history sought treatment for fatigue and dry cough of 3 weeks’ duration. Basic laboratory tests revealed severe anemia. She had no history of bleeding, hemoptysis, dyspnea, or fever. The patient was admitted for RBC transfusion and more extensive diagnostics.
      On presentation, a notable discrepancy was found between her slim body silhouette with 168 cm of height and unexpectedly high body weight (69 kg). BP was 154/96 mm Hg, heart rate was 91 beats/min, and respiratory rate was 21 breaths/min with the use of additional respiratory muscles. Oxygen saturation was 96% on room air. Respiratory system examination revealed diminished breath sounds by auscultation and a dull note on percussion in both lower lung fields, which, together with inflated body weight, suggested the presence of an intrathoracic mass.
      Apart from anemia (hemoglobin, 7.0 g/dL), laboratory tests showed significantly elevated serum creatinine (4.5 mg/dL), proteinuria of 3.4 g/24 h, and microscopic hematuria suggesting rapidly progressive glomerulonephritis. Renal biopsy confirmed active pauci-immune glomerulonephritis indicative for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and showed an advanced chronic injury. Subsequent immunologic tests detected a high titer of anti-myeloperoxidase (anti-MPO) ANCAs (> 134 International Units/mL; reference, < 2 International Units/mL) and showed negative results for anti-proteinase 3 ANCAs and antinuclear antibodies. Laboratory tests, neurologic examination, and imaging-based screening excluded vasculitis involvement of other organs.
      According to clinical presumption, chest radiography showed a giant mediastinal mass (Fig 1A). Subsequent CT scan confirmed the presence of a mediastinal tumor filling more than half of the chest (26 × 23 × 19 cm), compressing and shifting adjacent structures without their infiltration or destruction. The tumor contained mainly fat with scattered linear soft tissue attenuation, raising suspicion for well-differentiated liposarcoma (WD-LPS) (Fig 1B-D). Plethysmography showed a significant reduction in total lung capacity (2.21 L; 0.02 percentile), whereas echocardiography revealed left ventricle hyperkinesis and pulmonary hypertension secondary to external compression of the heart, great vessels, and lungs.
      Figure thumbnail gr1
      Figure 1Initial imaging. A, Posteroanterior chest radiograph showing a large, lobulated mass with a well-defined upper margin, most probably located in the mediastinum, causing opacification of the lower portion of the lungs with areas of atelectasis. Central catheter inserted via right subclavian vein (vascular access to therapeutic plasma exchange procedures) is visible. B-D, Non-contrast-enhanced CT scans, coronal (B) and axial (C-D) orientation, obtained through the mediastinal window showing a giant lesion exhibiting an extensive amount of fat tissue, with scattered areas of soft tissue component consistent with fibrotic septa, filling the anterior mediastinum and spreading into the thoracic region bilaterally, to a greater extent on the left side, filling about two thirds of the chest volume on this side and about half of the chest volume on the right side, reaching the diaphragm on both sides. The tumor shifts the mediastinal organs posteriorly, surrounds the nonenlarged heart, and presses on both lungs, causing segmental atelectasis. No invasive infiltration of organs or chest walls and no enlarged lymph nodes are detected.
      CT scan-guided tru-cut biopsy of the tumor was performed. Conventional microscopy showed only mature adipose tissue, which could be a part of WD-LPS. Nevertheless, fluorescence in situ hybridization revealed a lack of MDM2 gene amplification and of RB1 gene loss, excluding WD-LPS and minimizing the risk of atypical spindle-cell lipomatous tumor, respectively (Fig 2A, 2B ). The definite diagnosis could not be established without tumor resection. However, surgical intervention was possible only after remission of life- and organ-threatening symptoms of AAV.
      Figure thumbnail gr2
      Figure 2Photomicrographs showing molecular test results at ×1000 magnification. A, Fluorescence in situ hybridization (FISH) analysis indicating no MDM2 (mouse double minute 2 homolog proto-oncogene) gene amplification: two orange and two green probe signals (arrow) are visible. In a cell with amplification of the MDM2 gene locus, multiple copies of the orange signal or orange signal clusters would be observed. B, FISH test results excluding deletions affecting the RB1 (retinoblastoma transcriptional corepressor 1) gene locus: two orange and two green signals as expected in a normal interphase nucleus (arrow).
      Initially, for induction remission of AAV, therapeutic plasma exchange procedures and glucocorticoids were introduced. This immunosuppressive regimen was the safest option for AAV therapy in a patient with concomitant potentially malignant tumor. When the most probable malignancy, WD-LPS, was excluded, the treatment of choice with IV cycles of cyclophosphamide for 6 months was implemented. It resulted in resolution of anemia and improvement of renal function (e-Fig 1A-C).
      After completion of the induction therapy, two consecutive both-sided lateral thoracotomies were planned. A one-step complete removal was impossible because of the tumor size and bilateral location, as well as the lack of definite diagnosis implying the extent of resection. The first surgery debulked the left hemithorax from about 8 kg of mass (Fig 3A). After 6 months of adaptation to the new hemodynamic conditions, the residual mass of about 5 kg was removed completely from the right side of the chest cavity.
      Figure thumbnail gr3
      Figure 3Photographs demonstrating tumor morphologic features. A, First thoracotomy: debulked tumor with total dimensions of 36 × 30 × 11 cm. B-C, Second thoracotomy: pedunculated tumor with total dimensions of 20 × 19 × 11 cm, surrounded by a pseudocapsule. Arrows indicate the wide fibroadipose core attaching the tumor to the superior mediastinum.
      The tumor was encapsulated partially and attached to the superior mediastinum (Fig 3B, 3C). Microscopically, it consisted predominantly of adipose tissue with areas resembling fibroadenoma of the breast. Fibrous stroma contained strands of CK7 and p40-positive epithelial cells intermingled with few lymphoid cells, mainly immature T lymphocytes (thymocytes) (Fig 4A-D). Their presence indicated the thymic origin of the tumor.
      Figure thumbnail gr4
      Figure 4A, B, Photomicrographs showing histologic results on hematoxylin and eosin stain slides at ×100 magnification. A, Lipoma-like areas correspond to lobules of adipose tissue separated by fibrous bands, occasionally filled with two or more layered epithelial cells with few intermingled lymphocytes. B, Solid areas represent fibrotic and hyaline stroma with entrapped single or clustered adipose cells, separated by interanastomosing strands of bland-looking epithelial cells with lymphocytic infiltrate, mostly without follicle formation. Focally, residual thymic tissue also is present. C, D, Photomicrographs showing histologic results on immunohistochemical stain slides at ×100 magnification. C, Epithelial cells showing positive results for p40. Staining results also are positive for CKAE1/3, CK19, CK7, and p63. The cells show no atypia or mitotic activity (Ki-67 < 1%). D, Thymocytes showing positive results for terminal deoxynucleotidyl transferase. Staining results also are positive for CD3 and CD5. Scattered CD20-positive B cells also are seen.
      What is the diagnosis?
      Diagnosis: Benign tumor of the thymus: lipofibroadenoma accompanied by renal limited ANCA-associated vasculitis

      Discussion

       Clinical Discussion

      Thymic tumors are known to be accompanied by secondary autoimmune diseases with an estimated incidence of 30%. Multiple autoimmunity occurs in up to half of these cases. The plausible pathway involves impaired T-cell maturation favoring survival of self-reactive clones that induce an autoimmune response and tissue damage.
      Lipofibroadenoma is a very rare type of benign thymic tumor, reported so far in eight patients (six in the English literature) (e-Table 1), mainly young adults. In all of these patients, lipofibroadenoma tumors were well circumscribed, allowing complete surgical removal. No recurrences were noted. However, in 50% of patients, coexistence of malignant thymoma (type B1) was observed. An autoimmune condition was reported in one patient.
      • Travis W.D.
      • Brambilla E.
      • Burke A.P.
      • Marx A.
      • Nicholson A.G.
      WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.
      • Kuo T.
      • Shih L.Y.
      Histologic types of thymoma associated with pure red cell aplasia: a study of five cases including a composite tumor of organoid thymoma associated with an unusual lipofibroadenoma.
      • Aydin Y.
      • Sipal S.
      • Celik M.
      • et al.
      A rare thymoma type presenting as a giant intrathoracic tumor: lipofibroadenoma.
      • Qu G.
      • Yu G.
      • Zhang Q.
      • Ma J.
      • Wang X.
      Lipofibroadenoma of the thymus: a case report.
      • Makdisi G.
      • Roden A.C.
      • Shen K.R.
      Successful resection of giant mediastinal lipofibroadenoma of the thymus by video-assisted thoracoscopic surgery.
      • Hui M.
      • Paul T.R.
      • Uppin S.G.
      • Jyothi N.
      Lipofibroadenoma with B1 thymoma: a case report of a rare thymic tumor.
      The present patient is the first report of pure lipofibroadenoma accompanied by AAV. Although the direct link could not be confirmed, accidental co-occurrence of these two ultra rare diseases seems to be even less possible. We suppose that depleted lymphocyte count in lipofibroadenoma might have contributed to its lower autoimmunity potential compared with other thymic tumors. Therefore, the onset of AAV must have been delayed in this patient for many years of uninterrupted tumor growth. This hypothesis is supported by the absence of any respiratory distress despite the giant tumor size and total lung capacity comparable with that seen in a 6-year-old child, presumably resulting from long-term adaptation.
      The most common autoimmune disease associated with thymic tumors is myasthenia gravis. Systemic lupus erythematosus and pure red cell aplasia also have been reported, among others.
      • Shelly S.
      • Agmon-Levin N.
      • Altman A.
      • Shoenfeld Y.
      Thymoma and autoimmunity.
      To the best of our knowledge, evidence of small vessel vasculitis (either ANCA positive or negative) secondary to thymic tumors encompasses only 11 published case reports, including ours (e-Table 2). Similarly to other autoimmune entities, AAV was recognized either before, at the time of, or after tumor detection. Anti-MPO antibodies predominated over antiproteinase 3 antibodies. A clinical course was limited to kidney or skin involvement, or both.
      The patient also demonstrated isolated renal vasculitis without concomitant autoimmune diseases. Comprehensive immunosuppression along with tumor removal resulted in an improvement of her clinical condition and a substantial decrease in MPO ANCA level (to 25 International Units/mL) (e-Fig 1D). No AAV flares were observed. However, at the 2-year follow-up, the patient’s renal insufficiency reached the end stage, reflecting rather irreversible damage at baseline than persistent AAV activity. Until that date, the patient remains peritoneally dialyzed while waiting for a kidney transplantation. No lipofibroadenoma recurrence was noted within the postoperative period of 12 months. As a result of tumor removal and organ decompression, total lung capacity and pulmonary BP returned to normal.

       Radiologic Discussion

      Lung disease is one of the most common and life-threatening symptoms of AAV. Therefore, routine screening with CT imaging, particularly high-resolution CT scanning, should be performed. Pulmonary abnormalities in anti-MPO AAV include: interstitial pneumonia, chronic fibrosis, and alveolar hemorrhage, rather than nodules, masses, ground-glass opacity, or endobronchial inflammatory infiltration, which are typical for antiproteinase 3 AAV. Pleural effusion or lymphadenopathy are seen rarely.
      • Thickett D.R.
      • Richter A.G.
      • Nathani N.
      • Perkins G.D.
      • Harper L.
      Pulmonary manifestations of anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis.
      Mediastinal tumor was an unexpected finding.
      For intrathoracic mass, the first method of choice is chest radiography, although, multislice CT scanning and MRI are best for further characterization and narrowing the differential diagnosis. CT imaging can detect the presence of adipose tissue accurately within a lesion with a typical fat attenuation of –20 to –150 Hounsfield Units. Additionally, MRI with the use of fat-saturation techniques and chemical shift imaging can show the presence of microscopic intralesional fat. Fat-containing lesions of the mediastinum could be divided into location specific—such as thymic hyperplasia, thymolipoma, teratoma, and lipomatosis—and location nonspecific, including mainly lipoma and liposarcoma.
      In this patient, the extensive fatty nature, heterogenicity, and size of the mass favored the suspicion of WD-LPS over thymic lesion, despite the uncommon location and patient age (median age of occurrence for WD-LPS is 50-65 years). However, the final diagnosis could not be established by imaging.

       Pathologic Discussion

      For lipomatous intrathoracic tumors, histologic differential diagnosis encompasses malignancies—WD-LPS (including its variant thymoliposarcoma), atypical spindle-cell tumor, and myxoid pleomorphic liposarcoma—as well as benign tumors, such as thymolipoma and lipoma (Table 1). Although diagnosing fatty tumors could be difficult because of the limited value of a sample obtained during needle biopsy, even peripheral mature adipose tissue is usually sufficient for fluorescence in situ hybridization analysis of MDM2 gene amplification, which is observed in more than 90% of WD-LPS patients.
      Table 1Pathological Differential Diagnosis of a Lipomatous Intrathoracic Mass
      CharacteristicsType of Lipomatous Tumor
      LipofibroadenomaThymolipoma (Including Thymofibrolipoma)LPS, Well-Differentiated (Including Thymoliposarcoma)Atypical Spindle Cell / Pleomorphic Lipomatous TumorMyxoid Pleomorphic LiposarcomaLipoma (Including Elastofibrolipoma)
      Intrathoracic locationYesYesYesRarelyYesYes
      One case of elastofibrolipoma described in mediastinum.
      Patient age, y20-6020-6050+30+10-3050+
      Tumor components under microscopy:
       Epithelial+ (interconnecting cords)++– (lipoma-like and inflammatory LPS)

      + (thymoliposarcoma)
       Lymphocytic+
      Including thymocytes – cells positive for terminal deoxynucleotidyl transferase.
      +++
      Including thymocytes – cells positive for terminal deoxynucleotidyl transferase.
      (reminiscent of unremarkable thymic tissue)
      – (lipoma-like LPS)

      +
      Including thymocytes – cells positive for terminal deoxynucleotidyl transferase.
      (thymoliposarcoma)

      +++ (inflammatory LPS)
       Fibrous+ / ++ / +++ (variably reported)+ (thymolipoma)++ (fibrous strands and areas of fibrosis)++ / +++– (myxoid matrix)– +++ (elastofibrolipoma: elastic fibers present)
      +++ (thymofibrolipoma)
       Adipose+ / ++ / +++ (variably reported)++++++ (atypical lipoblasts present)+++– (no mature fat, atypical lipoblasts present)+++
      Molecular studies
      One case reported with HMGA2 rearrangement.
      MDM2 amplificationRB loss (60%)RB lossHMGA2 rearrangement (70%)
      LPS = liposarcoma; - = absent; + = present in a low amount; ++ = present in a moderate amount; +++ = present in a large amount.
      a One case of elastofibrolipoma described in mediastinum.
      b Including thymocytes – cells positive for terminal deoxynucleotidyl transferase.
      c One case reported with HMGA2 rearrangement.
      In this patient, the diagnosis was based on a histologic picture reminiscent of fibroadenoma of the breast, a hallmark of lipofibroadenoma. Additional extensive sectioning excluded the coexistence of malignant thymoma. Because no genetic abnormalities have been identified in lipofibroadenoma, we searched for fusion transcripts by targeted next generation sequencing with the Archer FusionPlex Sarcoma Kit sequenced on Mini Seq (Illlumina). It included, among others, HMGA2 gene translocation, present in up to two-thirds of lipomas and one thymolipoma.
      • Hudacko R.
      • Aviv H.
      • Langenfeld J.
      • Fyfe B.
      Thymolipoma: clues to pathogenesis revealed by cytogenetics.
      No translocation was detected.
      Some authors consider lipofibroadenoma as a variant of thymolipoma, or recognize it as thymofibrolipoma.
      • Makdisi G.
      • Roden A.C.
      • Shen K.R.
      Successful resection of giant mediastinal lipofibroadenoma of the thymus by video-assisted thoracoscopic surgery.
      ,
      • Suster S.
      Atlas of Mediastinal Pathology.
      These tumors contain similar histologic elements, albeit in different proportions. Despite unrecognized pathogenicity, both lipofibroadenoma and thymolipoma likely represent one family of closely related tumors, postulated to be either lipomas arising in the thymus, neoplasms of both thymic fat and epithelium, hyperplastic processes, or thymoma variants.
      • Travis W.D.
      • Brambilla E.
      • Burke A.P.
      • Marx A.
      • Nicholson A.G.
      WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart.
      ,
      • Hudacko R.
      • Aviv H.
      • Langenfeld J.
      • Fyfe B.
      Thymolipoma: clues to pathogenesis revealed by cytogenetics.
      ,
      • Suster S.
      Atlas of Mediastinal Pathology.

      Conclusions

      This patient highlights the crucial role of physical examination, which indicated an intrathoracic mass. In addition, clinicians should be aware that various autoimmune diseases, as well as malignant thymoma, may coexist with benign thymic tumors such as lipofibroadenoma. Clinical examination supported by laboratory tests and pathologic examination are necessary to their exclusion. Although vasculitis secondary to thymic tumor remains a casuistic entity, it should be considered in cases of abnormal urinalysis or impaired renal function, because it mainly affects kidneys and is associated with poor renal outcome. In conclusion, clinical vigilance and multidisciplinary collaboration are fundamental.

      Acknowledgments

      Financial/nonfinancial disclosures: None declared.
      Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.
      Additional information: The e-Figure and e-Tables can be found in the Supplemental Materials section of the online article.

      Supplementary Data

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