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Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, PolandDepartment of Pathology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
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.
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.
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.
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.
What is the diagnosis?
Diagnosis: Benign tumor of the thymus: lipofibroadenoma accompanied by renal limited ANCA-associated vasculitis
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.
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.
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.
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.
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.
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
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.
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.
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.