A rare case of Castleman disease presented with diffuse ground glass nodules in both lungs

doi:10.21203/rs.3.rs-3232026/v1

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A rare case of Castleman disease presented with diffuse ground glass nodules in both lungs

https://doi.org/10.21203/rs.3.rs-3232026/v1

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Castleman disease(CD), also known as giant lymphadenopathy or angiofollicular lymphadenopathy, was firstly reported by Castleman in 1954[1]. CD is a rare chronic lymphoproliferative disease, and its etiology and pathogenesis is still not completely clear. Clinically, according to the distribution of swollen lymph nodes, CD is divided into Unicentric CD (UCD) and multicentric CD (MCD). The main manifestations of UCD are single-site lymph node enlargement, lack of specific clinical manifestations and abnormal laboratory indicators. MCD mostly presents as diffuse lymphadenopathy, which is a rare polyclonal B lymphoproliferative disorder that straddles the intersections of hematology, oncology, rheumatology, and virology[2]. CD that presents with diffuse parenchymal lung disease is extremely rare. Here, we report a 48-year-old woman diagnosed with CD, which presents with diffuse nodules in both lungs.

A 48-ye-old female patient was investigated because of chest tightness after exercise. The patient had a 3-week history of cough, expectoration and reduced exercise tolerance. It was white foamy and sticky sputum that was not easy to cough out. There was no blood in the sputum or hemoptysis. There was no fever, chest pain, amaurosis or syncope. The patient had a history of anemia for several years, and was diagnosed as "iron deficiency anemia", irregular oral administration of iron sucrose. The mother of the patient died of blood system disease one year ago (details are not specified), and her father, one sister and two brothers are healthy.

Physical examination findings: vital signs demonstrated temperature of 36.5 ℃, with a heart rate of 86 beats/min, a blood pressure measurement of 125/70 mmHg, and a respiratory rate of 22 breaths/min with oxygen saturation of 91% on room air. Anemia, no cyanosis. The breath sounds in both lungs were thickened, and the moist rales could be heard in both lungs. No enlargement was found in the neck or bilateral axillary lymph nodes. Both sides of the groin area can reach about 1 × 1cm enlarged lymph nodes, mobile, firm and painless. No obvious abnormalities were observed in the rest of the physical examinations.

Arterial blood gas analysis while breathing ambient air showed an arterial oxygen tension of 59 mm Hg, carbon dioxide arterial tension of 46 mmHg, pH of 7.39 and arterial oxygen saturation of 93%. Blood tests noted decreased hemoglobin (89 g/L, normal 120–160), increased0 C-reactive protein (CRP, 72.9mg/L, normal < 6mg/L), increased erythrocyte sedimentation rate (ESR, 120mm/H, normal < 20mm/H), increased serum total protein (TP, 93g/L, normal 60-80g/L), increased serum globulin (GLB, 69.3g/L, normal 20-30g/L), decreased serum albumin (ALB, 23g/L, normal 35-50g/L), increased serum cholinesterase (CHE, 2860U/L, normal 130-310U/L). Index of liver and renal function test were all within normal ranges. Studies of coagulability were all within normal ranges. Rheumatism immunity combination test showed decreased IgA (4.69g/L, normal 7.0-16.0g/L), increased IgG (48.4g/L, normal 0.7-4.0g/L), suspicuous positive ENA-AbSSA, weakly positive ENA-AbRo, positive HEP2-ANA,(1:100). PANCA, CANCA, dsDNA and ACA-IgG were normal. Immunofixation electrophoresis test was normal. Light chain combination test showed increased serum light chain of LAM (6.22g/L, normal 0.90-2.10g/L), increased serum light chain of KAP (10.70g/L, normal 1.70-3.70g/L), increased urine light chain of LAM (13.5g/L, normal 0.00-3.90g/L), increased urine light chain of KAP (57.1g/L, normal 0.00-7.10g/L). Indicators all increased. Serum tumor marker: NSE, CEA, Cytokeratin 19 fragment and CA125 normal were all in normal ranges. Moreover, the antibody tests revealed negative for tuberculosis antibodies (IgM and IgG), negative for T-SPOT.TB, negative for human immunodeficiency virus, negative for EBV-CA IgG, negative for EBV-CA IgM, and negative for EBV-EA IgA, and that increased serum IgG4 (7.700 g/L, normal 0.020-2.000g/L).

Pulmonary function tests revealed a mild restrictive defect with a reduced diffusing capacity. Color doppler ultrasound of the abdomen indicated enlargement of the liver and spleen. Chest enhanced CT scan showed diffuse nodules of different sizes and densities in the bilateral lung fields, multiple enlarged lymph nodes in the mediastinum and bilateral axillas and no definite fusion changes among the lymph nodes (Fig. 1A-D). Abdominal enhanced CT scan showed enlargement of the liver and spleen, enlargement of abdominal aortic and inguinal lymph nodes (Fig. 1E).

Bronchoscopy revealed no endobronchial involvement. Subsequent biopsies by means of EBUS-TBNA (4R and 7th lymph nodes): lymphocytes and lymphoid tissues were observed. Furthermore, the enlarged inguinal lymph node was biopsied, and showed reactive lymph node hyperplasia and large amount of plasma cell infiltration.

Therefore, the patient was initially considered a plasma cell infiltration disease, especially lymphomas, and the hematological examination was further performed. Bone marrow biopsy showed hyperplasia was active in the granulocytes of the three lines and abnormal plasma cells account for 9% in all cells(Fig. 2).

Subsequently, the patient underwent inguinal lymph node biopsy to obtain a more precise diagnosis. The enlarged right inguinal lymph node was resected, and haematoxylin and eosin (H&E) staining of the biopsy samples showed lymphoid follicular hyperplasia, large amount of plasmacytoid cell infiltration seen in the follicle, combined with immunohistochemical examination results, consistent with reactive lymph node hyperplasia and large amount of plasma cell infiltration. Immunohistochemical showed CD3 (T lymphocytes+), CD20( B lymphocytes ++), Ki67 (lymphoid follicle germinal center +), Ckpan (-), Bcl − 2 (lymphoid follicle germinal center -), EBER (-), CD38 ( plasma cells +), CD138 (plasma cells +), LAM light chain (+), KAP light chain (+), CD10 (-), the Bcl − 6 (lymphoid follicle germinal center +)(Fig. 3).

After consultation with another multidisciplinary team including pathologists, an oncologist, and a haematologist, the diagnosis was made that these findings were consistent with multicentric CD, which mainly involved lymphatic system and presented with diffuse ground glass nodules in both lungs. Considering that the patient is Castleman's disease, 50mg/ day of prednisone acetate was given to the patient, and the symptoms of chest tightness, shortness of breath, cough and expectoration were significantly alleviated. Chest CT after 1 month of hormone therapy showed no significant changes than before. It suggests that hormone therapy alone is ineffective to CD. The patient is being received systemic chemotherapy.

This middle-aged female patient, presented with diffuse ground glass nodules in both lungs. After excluding common diseases such as sarcoidosis, tuberculosis and metastatic tumor, Castleman Disease (CD) was finally diagnosed according to the pathology of inguinal lymph nodes and other clinical data. At present, the pathogenesis of CD is not completely clear, but interleukin (il-6), human herpes virus (HHV) and HIV infection have been reported to play an important role in the pathogenesis of CD [3, 4, 5]. Unicentric CD (UCD) is commonly seen in patients aged 30 to 40 with an average diagnostic age of 34 years (range, 2 to 84 years). The UCD has a slight female advantage (1:1.4). Most cases of UCD are histologically classified as the hyaline-vascular variant, which is characterized by increased numbers of small, hyalinized blood vessels within and between follicles with obliteration of the medullary sinuses. Lymphoid follicles are increased in number and exhibit features of “regression,” a term referring to a predominance of dendritic cells within germinal centers with a relative paucity of lymphocytes and a consequent broadening of mantle zones. The small lymphocytes of the mantle zones are frequently arranged in concentric rings around the germinal center (“onion-skinning”), and follicles may be radially penetrated by a blood vessel [6]. Plasma cells may be found in the interfollicular regs ion, but they are typically few and present in small clusters. Cases with abundant plasma cells likely reflect examples of UCD with “mixed” or “transitional” features between the hyaline-vascular and plasma cell histological variants [5]. The main manifestations of UCD are single-site lymph node enlargement, lack of specific clinical manifestations and abnormal laboratory indicators, most of which are found in physical examination.

MCD is a systemic disease, usually occurring in the 60s, with a slight male advantage. About 1/3 of MCD patients develop malignant tumors, such as Kaposi's sarcoma and malignant lymphoma [7, 8]. MCD is a more aggressive disease with 65% average 5-year survival [9]. According to the characteristics of histopathology, CD can be divided into clear blood vessel type (HV-CD), plasma cell type (PC-CD), mixed type and plasma mother cell type [10]. HV-CD accounted for 90% of all cases. the performance of polycentric type, often involved in the body multiple organs. MCD mostly presents as diffuse lymphadenopathy, which can be accompanied by splenomegaly, type B symptoms (fever, night sweats, weight loss), POMES syndrome (multiple peripheral neuropathy, immunoglobulosis, organ enlargement, endocrine lesions, skin damage). POMES syndrome exists in about 15%-25% of MCD patients [8, 11, 12]. In addition, there may be ascites and/or pleural effusion, anemia, elevated inflammatory indicators, high gamma globulinemia, hypoalbuminemia and abnormal immunological indicators. The international consensus treatment guidelines for idiopathic MCD (iMCD) pointed out [13], patients with severe iMCD must have at least 2 of the 5 criteria: ①Eastern Cooperative Oncology Group (ECOG) score ≥ 2;②Stage IV renal dysfunction (estimated glomerular filtration rate, eGFR < 30; Creatinine > 3.0); ③Anasarca and/or ascites and/or pleural/pericardial effusion (effects of hypercytokinemia/low albumin);④Hemoglobin ≤ 8.0g/dL;⑤Pulmonary involvement /interstitial pneumonitis /dyspnea. Patients should be classified as nonsevere iMCD if the above criteria are not met. Xuanye Zhang [14] et al showed that MCD patients with older age (40 years old), plasma cell or mixed histological type, type B symptoms, splenomegaly, ascites and/or pleural effusion, hypoalbuminemia and hyperglobulinemia had poor prognosis. According to the diagnosis and treatment guidelines, this patient meets severe MCD, and the prognosis is poor.

The 2015 NCCN guidelines for the diagnosis and treatment of non-hodgkin's lymphoma emphasized [15], the diagnosis of CD disease should meet the following three aspects: 1. Carry out pathological examination on all sections (at least 1 paraffin block containing lymphatic proliferative disease tissue; 2. Single fine-needle biopsy(FNA) or hollow needle biopsy alone should not be used as the basis for CD initial diagnosis. However, in some cases, when lymph nodes are difficult to be removed or removed for biopsy, FNA or hollow needle biopsy combined with auxiliary examinations (IHC, FCM, PCR, ISH and other techniques) can provide sufficient information for diagnosis.3. Diagnosis must depend on adequate immune typing. The IHC antigens were: Kappa/ Lambda, CD20, CD3, CD5, CD138, human herpes virus 8 incubation-related nuclear antigen 1 (HHV-8LANA-1), etc. In this case, TBNA-EBUS was used at the early stage of diagnosis and treatment, but no obvious abnormal pathological changes were detected by pathology. Lymph node follicular hyperplasia was confirmed after inguinal lymph node biopsy, and a large number of plasma cells were infiltrated between lymph follicles. Therefore, lymph node resection or biopsy should be performed as far as possible for patients with suspected CD.

Although CD can occur at any site where lymphoid tissue is normally present, approximately 70% of CD occurred in the thorax [16, 17], the mediastinum and hilum were more common, followed by the anterior mediastinum and the posterior mediastinum. CT scan is of great value in the diagnosis and differential diagnosis of the disease. Mainly manifested as [18]: ①A single large soft tissue mass with well-defined margins; ②The tumor foci of enhanced scan showed obvious uniform enhancement.The degree of enhancement can be the same as the artery in the same layer.It rarely invades the surrounding tissue; ③ In 5 to 10 percent of cases, there is cluster-like branching calcification in the center of the tumor, which is characteristic of dendritic calcification; ④ Liquefaction and necrosis rarely occur in the lesion. CD diffuse parenchymal lung disease is rare, with only a few reports, most of which are found in MCD [19, 20]. Several cases of interstitial pneumonitis with infiltration by lymphocytes and plasma cells have been described. In MCD, pulmonary parenchymal involvement and timely CT scanning were mainly manifested as ground glass lesion (GGO), small nodules with blurred edges and lobular centripetal distribution, bronchovascular bundle thickening, lobular septal thickening, air cavity consolidation, and thin-walled pulmonary air sacs [21]. The histopathological change of intrapulmonary invasion in MCD was lymphocytic interstitial pneumonia (LIP), which was mainly infiltrated by a large number of lymphocytes and plasma cells in the lung parenchyma. The patient in this case had bilateral lung parenchymal involvement, and high resolution chest CT mainly showed multiple ground glass nodules with different sizes, uneven density and irregular distribution, and was accompanied by multiple mediastinal lymph node enlargement. It was indeed a rare case of MCD.

In terms of the differential diagnosis of this patient, both inguinal lymph node biopsy and bone marrow biopsy pathology indicated a large amount of plasma cell infiltration, and immunohistochemistry of inguinal lymph node tissue indicated that IgG4 (+) /IgG (+) was 30%. Therefore, the differentiation with IgG4-related disease (IgG4-RD) was very important, and he treatment methods of the two diseases were completely different. IgG4-RD has its own characteristics, such as increased serum IgG4 and IgE level, increased peripheral blood eosinophil count, slightly increased or noamal IL-6 and CRP level. The pathological features of IgG4-RD include the following three aspects: ①large amount of lymphocyte infiltration; Immunohistochemical staining of organs and tissues with IgG4-RD related disease lesions can reveal infiltration of IgG4(+) lymph cells. If more than 30% IgG4(+) plasma cells are visible in each high-power field, the proportion of IgG4 (+) /IgG(+) cells > 40% has a highly suggestive effect on diagnosis, and the sensitivity and specificity of diagnosis are significantly higher than the increase of serum IgG4 level; ②fibrosis, characterized by mat striation; ③ occlusive phlebitis [22, 23]. Pulmonary imaging finding of some IgG4-RD patients was organized pneumonia or NSIP (nonspecific interstitial pneumonia). In this case, IL-6, ESR and CRP were significantly increased, and there was no increase in eosinophils in serum and alveolar lavage fluid. Besides, no striated fibrosis and occlusive phlebitis were found in lymph nodes and lung tissues, so the evidence supporting IgG4-RD was insufficient. IgG4-RD is a kind of immune mediated inflammatory fibrosis disease, common clinical symptoms including sclerosing salivary gland inflammation, pulmonary inflammatory pseudotumor and interstitial pneumonia, autoimmune pancreatitis, fibrous mediastinum infection, retroperitoneal fibrosis, sclerosing cholangitis and cholecystitis, etc. The patients had no clinical symptoms above. In addition, glucocorticoid therapy is usually effective for IgG4-RD [24]. However, on this patient, after 1 month of treatment with prednisone acetate tablets, the patient's condition was not remission after comprehensive evaluation, and the progression of pulmonary nodules and interstitial fibrosis was observed in both lungs, so the diagnosis of IgG4-RD for the patient was not supported further.

In conclusion, CD is a chronic lymphoproliferative disease with complex and nonspecific pathogenesis, clinical and imaging manifestations. CD is often considered in clinical differential diagnosis when patients present with a single large soft tissue mass in the lung and mediastinal lymph node enlargement. However, it is still necessary to be alert to the possibility of MCD in case of pulmonary parenchymal involvement, which requires us clinicians to break through solid thinking and cooperate with multiple disciplines to achieve early diagnosis and treatment. MCD is a diagnosis of exclusion and requires systemic treatment.

CD:Castleman disease;UCD:Unicentric CD;MCD:multicentric CD.

Acknowledgement

None.

Authors’ contributions

X. Guo had the conception and design of the study, acquisition of data,drafting the article.F. Zhang had the acquisition of data and literature. C. Zhu, J. Chen, and K. Zhang had amended the manuscript, revising the article critically for important intellectual content. All authors read and approved the final manuscript.

Funding

This work was supported by the Key R&D program of Ningxia Hui Autonomous Region in China (Grant Number 2021BEG02027).

Availability of data and materials

The datasets used and analysed during the current study available from the corresponding author on reasonable request.

Ethics approval and consent to participate

Appropriate written informed consent was obtained for the publication of this case report and accompanying images. It was approved by the Clinical Research Ethics Committee of Ningxia Medical University and was implemented (Ethics Number 2022-79)

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Competing interests

The authors have no conflicts of interest to declare.

Conflict of interest: The authors have no conflict of interest to declare.

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No competing interests reported.

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A rare case of Castleman disease presented with diffuse ground glass nodules in both lungs

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