Clinicopathological Analysis of Castleman Disease with TdT+
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Clinicopathological analysis features of castleman Castleman disease with TdT+
T-lymphoblastic proliferation: A case report.
Luting Zhou*, Jinfeng Zheng*, Yongcheng Cao, Guoli Yu, Xiaohong Liu, Ming Geng
Department of Pathology, General Hospital of Jinan Military Command, Jinan 250031, Shandong Province, China.
*Equal contributors.
Address correspondence to: Xiaohong liu, Department of Pathology, General Hospital of Jinan Military Command, Jinan 250031, P.R. China. E-mail: liuxh333@; Ming Geng, Department of Pathology, General Hospital of Jinan Military Command, Jinan 250031, P.R. China. E-mail: gm2227@.
Running title: :Castleman disease with TdT+ T-lymphoblastic proliferation
Acknowledgements
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Address correspondence to: Xiaohong Liu and Ming Geng, Department of Pathology, General Hospital of Jinan Military Command, Jinan 250031, China. E-mail: liuxh333@ (XHL); gm2227@ (MG)
Disclaration of conflict of interest
The authors declare no conflicts of interest.
Disclosure of conflict of interest
None.
Abstract:
To investigate the clinicopathological features, treatment, and prognosis of TdT+ T-lymphoblastic proliferation in Castleman disease. A detailed analysis of pathological features, immunohistochemistry, diagnosis, and differential diagnosis, was conducted on a case of Castleman disease with TdT+ T-lymphoblastic proliferation, and related literature was reviewed. An irregular soft tissue mass with paraneoplastic pemphigus features was seen in the posterior mediastinum of the patient. Microscopic images of the proliferated lymphoid mass showed widely distributed lymphoid follicles, follicular vascular proliferation, hyaline degeneration in the germinal center, densely packed lymphocytes surrounding the lymphoid follicles, vascular proliferation in the interfollicular region, vascular wall hyaline degeneration, and loss of lymphatic sinuses. Immunohistochemistry showed the following results: TdT (interfollicular region +), CD5 (interfollicular region +, follicles diffusely +), cytokeratin (CK, -), CD20 (follicles +, interfollicular region diffusely +), CD3 (interfollicular region +, follicles diffusely +), CD21 (follicular dendritic cells +), CD10 (interfollicular region +), CD4 (+), DC99 (+), CD1a (diffusely +), CD8 (diffusely +), and Ki-67 (germinal center 80% +, interfollicular region 30% +). The T-lymphocytes were negative for gene rearrangement studies. Castleman disease is a rare lymphoproliferative disorder. It is easy to misdiagnose Castleman disease as TdT+ T-lymphoblastic proliferation. Diagnosis requires differentiation of the disease from T-lymphoblastic lymphoma, angioimmunoblastic T-cell lymphoma, follicular lymphoma, accessory spleen, and other disorders. TdT+ T-lymphoblastic proliferation may be associated with poor patient prognosis. Close follow-up is recommended.
Key words: TdT,; castlemanCastleman,; lymphoblastic proliferation,; t-lymphoblastic lymphoma,; gene rearrangement
Introduction
Castleman disease was first described by Benjamin Castleman in 1956 [1]. The disease is also known as angiofollicular or giant lymph node hyperplasia. It is rarely identified, and its etiology is not yet understood. TdT stands for terminal deoxynucleotidyl transferase, which is mainly expressed in the cells of the thymic cortex and a small number of bone marrow lymphocytes. However, it is not expressed in the lymph nodes, spleen, and most mature lymphocytes. Although TdT is expressed at a higher rate in lymphoblastic lymphoma, many lymphoproliferative disorders show various levels of TdT lymphoblastic proliferation expression. There are also reports of TdT expression in uterine fibroids and hepatocellular carcinomas [2-4]. In 1999, Velankar et al. first proposed the concept of indolent T-lymphoblast proliferation [5]. In our clinical work, we found a case of Castleman disease with TdT+ T-lymphoblastic proliferation in the posterior mediastinum. In the context of relevant literature, we conducted a detailed analysis of its clinicopathological features, immunohistochemistry, diagnosis, and differential diagnosis.
Materials and methods
Clinical information
A 19-year old female patient was admitted to the hospital on June 2, 2016, because of ulceration of the mucus membranes of her eyes, mouth, and genitals for more than two months, as well as chest tightness for more than ten days. She was discharged from the hospital on August 26, 2016. Two months prior to admission, the patient did not have any factors that would predispose her to developing oral ulcers. Oral cephalosporin did not alleviate symptoms. After this, she developed a fever that lasted for three days, with a maximum body temperature of 38.3ºC. The ulcers worsened, affecting the oral mucosa, lips, vulva, anus, and canthus of the eyes, which all showed mucosal ulceration, desquamation, and blistering, with visible clear, pale yellow exudate. Her palms showed erythema and white desquamation. Chest CT showed an irregular posterior mediastinal soft tissue mass, approximately 5.9 × 4.8 cm in size, with heterogeneous enhancement. Blood tests were positive for CA125 IgG antibodies and weakly positive for antinuclear antibodies. On June 11, the patient suddenly developed chest tightness and dyspnea, which was thought to be caused by oral and pharyngeal ulceration leading to inflammatory laryngeal edema. Oxygen was administered, and her cardiac function was monitored. Her oxygen saturation decreased to 77%, with a heart rate of 120-–140 beats/min and blood pressure of 93-–104/59-–68 mmHg. She was given nebulized Pulmicort, but no significant improvement was observed. She was then emergently intubated and placed on a mechanical ventilator, which gradually stabilized her condition. The patient underwent a right thoracotomy with resection of the mediastinal mass on July 12, 2016, after her condition stabilized. The mass was located in the right posterior mediastinum, anterior to the esophagus, inferior to the azygos vein, and was approximately 6 × 5 × 5 cm in size, with an intact capsule and rich surface blood supply. The mass was completely surgically resected, and the patient showed good postoperative recovery. The preliminary clinical diagnosis was a mediastinal space-occupying mass and Behcet’s disease, not excluding paraneoplastic syndromes.
Methods
Surgical specimens were fixed in 10% neutral formalin, dehydrated, embedded in paraffin, and sectioned in the conventional manner. Sections were examined by light microscopy. Immunohistochemical staining was performed using the Envision 2-step method, DAB substrate, and hematoxylin counterstaining, with primary antibodies TdT, CD79a, CD20, CD8, CD3, CD43, CD5, CD4, CD99, CD10, CD1a, CD31, EMA (epithelial membrane antigen), bcl-6, cytokeratin (CK), MPO (myeloperoxidase), and Ki67, which were all purchased from Fuzhou Maixin Biotech. Co., Ltd. An in situ hybridization assay was used to detect Epstein-Barr virus (EBV)-encoded small RNA (EBER) in the tissue. EBV in situ hybridization kits were purchased from Wuhan Boster Biotech. Co., Ltd. Negative and positive controls were included in all tests. The operating procedures and interpretation of results, as outlined by the manufacturer, were strictly followed. The tissue was tested for T-lymphocyte gene rearrangement by Xiamen Amoy Diagnostics Co., Ltd.
Results
Gross examination
The mass was a dark red, irregular piece of tissue, 7 × 6 × 3 cm in size. Upon sectioning, the cut surface revealed a solid mass of 5 × 5 × 3.5 cm with an intact capsule that was sallow, grayish-red in color. (Figure 1).
Microscopic examination
The mass was a hyaline-vascular histologic variant. Lymphoid follicles were mostly distributed in the proliferated lymphoid mass. There was follicular angiogenesis, mantle cell hyperplasia forming concentric layers, and hyaline degeneration of germinal centers. Tightly packed lymphocytes and vascular proliferation were seen in the interfollicular area. There was also vascular wall hyaline degeneration, as well as the loss of lymphatic sinuses.(Figure 2).
Immune phenotype
Immunohistochemical staining showed TdT (interfollicular region +), CD5 (interfollicular region +, follicles diffusely +), CK (-), CD20 (follicles +, interfollicular region diffusely +), CD79a (follicles +, interfollicular region diffusely +), CD3 (interfollicular region +, follicles diffusely +), CD43 (interfollicular region +, follicles diffusely +), CD21 (follicular dendritic cells +), CD10 (interfollicular region +), CD4 (+), CD99 (+), CD1a (diffusely +), CD8 (diffusely +), EMA (-), CD31 (vessels +), MPO (-), Ki-67 (germinal centers 80% +, interfollicular region 30% +) (Figure 2). In situ hybridization showed that the tissue was EBER (-).(Figures 3, Figure4).
Pathology diagnosis (posterior mediastinum)
This case was diagnosed in our hospital, as Castleman disease, hyaline-vascular type, with atypical proliferation of precursor T-cells in the interfollicular region. A T-cell gene rearrangement study and clinical bone marrow biopsy were recommended to exclude hematopoietic and lymphoid malignancies. Two external hospital pathological diagnoses were obtained. The first consultation determined that this was a case of Castleman disease, hyaline-vascular type, with multiple foci of infiltrative TdT+ cells. The number of cells was > 200 /HPF, not excluding T-lymphoblastic lymphoma; a blood test and bone marrow biopsy were recommended. The second consultation diagnosed this as a case of accessory spleen.
T-lymphocyte gene rearrangement
TCRB (T-cell receptor beta-chain [gene]) A, TCRB B, TCRG (T-cell receptor gamma-chain [gene]) A, TCRG B clonal tests were all negative. T-cell receptor (TCR) gene arrangement testing showed no clonal proliferation (Figure 3).
Bone marrow biopsy
Results showed 2% atypical lymphocytes, which did not support the diagnosis of T-lymphoblastic leukemia/lymphoma infiltration of the bone marrow.
Discussion
Etiology
Castleman disease is an atypical lymphoproliferative disorder. It lies between benign and malignant. Clinically, it is divided into unicentric Castleman disease (UCD) and multicentric Castleman disease (MCD), and its etiology and pathogenesis is very complex and not yet understood. It may be associated with viral infections, vascular proliferation, and immune dysregulation [6]. Human herpes virus (HHV) is closely associated with the occurrence of Castleman disease. Specifically, there is a strong correlation between HHV-8 infection and the occurrence of Castleman disease in HIV-positive and other immunosuppressed populations, and the HHV-8 DNA positive rate has been reported higher in the peripheral blood and bone marrow of patients with MCD than in patients without the disease [7-10]. The patient in this case was positive for HSV-1 IgG antibodies and had severe oral, perioral, and perianal ulcers, suggesting that the development of Castleman disease in this patient might be related to HSV infection. The development of paraneoplastic syndrome may also be related to the production of autologous immune IgG antibodies in vivo by tumor tissue; the reaction between IgG and plakins leads to skin and mucosal lesions [11].
Clinical features
Localized Castleman disease does not present with obvious clinical symptoms. It often presents as a single enlarged lymph node that is found during a physical exam. Patients with MCD have more complex clinical symptoms; many have fever, anemia, and multi-organ involvement. Some MCD patients also have combined POEMS (polyneuropathy, organomegaly, endocrine abnormalities, M protein and blood and skin changes) syndrome [12-14]. The clinical symptoms in this case were very severe. The oral, perioral, and genital ulcers could not be alleviated. Endotracheal intubation and mechanical ventilation were provided after the development of severe chest tightness and dyspnea. After her condition was stabilized, supplemental nutrition, acid reduction, and antibiotics were administered. However, the oral ulcers and skin lesions did not show any obvious improvement, and the patient was unable to be weaned off the ventilator. Additionally, a bilateral upper extremity rash with pruritis emerged on her head, face, and chest. Paraneoplastic syndrome was considered, and anti-allergics, hormones, and immunity-enhancing treatments were provided. When the patient’s condition had stabilized, a right thoracotomy with mediastinal mass resection was carried out on July 12, 2016. On August 1, the patient appeared unable to open her eyes and had difficulty breathing and swallowing. Tests for anti-acetylcholine receptor antibodies and neostigmine were both positive, indicating that the patient had myasthenia gravis. The patient was breathing on her own and was discharged. The oral ulcers and blisters improved significantly since admission to the hospital, and the patient’s condition was relatively stable. She continued taking hormones and anti-ulcer and myasthenia gravis medications after discharge. However, she again developed severe pulmonary infection and experienced pulmonary failure, and was admitted to a local hospital to be treated for infection. Her current condition is stable.
Immune phenotype
The diagnosis of Castleman disease is based primarily on microscopy and immunohistochemical staining. The large number of interfollicular TdT+ lymphoblasts in the lymph node of the patient in this case could easily lead to a misdiagnosis of T-lymphoblastic lymphoma. Most TdT+ cells in cases of T-lymphoblastic lymphoma show obvious atypia. On the contrary, TdT+ cells in Castleman disease are small to medium in size, without obvious nuclear atypia.
There are a growing number of reports in the literature of Castleman disease associated with TdT lymphoblast proliferation expression [15]; most of these cells are CD3, CD4, and CD8 positive, as well as CD10, CD99, and CD1a [16] positive, similar to the immune phenotype of thymic cortex lymphocytes [17]. This expression of TdT is evidence of indolent TdT+ lymphoblast proliferation. In 2013, Ohgami et al. proposed diagnostic criteria for indolent TdT+ lymphoblast proliferation [18]: (1) TdT+ cells aggregated in the interfollicular region; (2) lymphoid tissue with a normal structure; (3) TdT+ T-cells small-to-medium in size, without atypia; (4) no abnormal antigen expression; (5) no T-cell clonal proliferation; (6) no thymic epithelium expression; and (7) indolent clinical manifestations and no invasive metastasis during more than six months of follow-up.
Although there was no clonal proliferation of T-cells in this patient, and TdT+ cells were mainly aggregated in the interfollicular region, TdT+ lymphoblast proliferation in this patient has not yet been confirmed indolent, because her clinical symptoms were relatively severe and associated with paraneoplastic syndomesyndrome. The prognosis is poor, which may be associated with TdT+ lymphoblast proliferation. Therefore, long-term follow-up and timely evaluation of this patient are essential.
Differential diagnosis
(1) Reactive lymphoid hyperplasia: Normal structures of the lymph nodes are observed. Follicles are unequal in size. Germinal centers are divided into light and dark areas. There are no capillaries with hyaline degeneration within the follicles. In contrast, follicular germinal centers show hyaline degeneration and angiogenesis in Castleman disease.
(2) Accessory spleen: These nodules are mostly located at the splenic hilum and the pancreatic tail and are generally less than 4 cm. Grosslygrossly and microscopically, they are similar to the spleen. The splenic parenchyma is divided into three areas: the white pulp, red pulp, and marginal zone. The white pulp is lymphatic tissue, and the red pulp is splenic cords and sinuses. Microscopically, our case showed a large amount of vascular hyaline degeneration, which appeared very similar to splenic sinuses and could easily be misdiagnosed. However, these vessels were CD8 negative, indicating that they were not splenic sinus cells, ruling out accessory spleen. In addition, immunohistochemical staining in this case showed a large number of TdT+ cells, which does not support the diagnosis of accessory spleen.
(3) T-lymphoblastic lymphoma: This is a lymphoma derived from precursor T-lymphocytes that is highly invasive. Most cases occur in children and adolescents. TdT is its characteristic marker. Microscopically, lymph nodes show structural damage, diffusely distributed tumor cells, deeply stained nuclei, and easily visible mitosis. In this case, there was no evidence of clonal proliferation following T-lymphocyte gene rearrangement. Bone marrow biopsy showed only 2% atypical lymphocytes, which does not support a diagnosis of T-lymphoblastic leukemia/lymphoma.
(4) Angioimmunoblastic T-cell lymphoma: This is a type of systemic peripheral T-cell lymphoma. With this disease, the polymorphic cells within the lymph nodes are infiltrative and characterized by significant proliferation of endothelial venules and follicular dendritic cells. Most cases occur in middle-aged and elderly people. Patients often have full-body lymphadenopathy. Microscopically, lymph node structural damage, visible remnants of lymphoid follicles, and paracortical angiogenesis accompanied by proliferation of lymphocytes, plasma cells, and eosinophils are observed. Tumor T-cells express full T-cell markers, and most cases show clonal TCR gene rearrangement, which distinguish this disease from that of our case.
(5) Follicular lymphoma: This is a lymphoma where B-cells are found in the follicular center. Most cases of follicular lymphoma have an obvious follicular structure, lymph node structural damage, and indistinct neoplastic follicular borders, and cells in follicles are positive for Bcl2 and CD10 markers by immunohistochemical staining—-all of which distinguish this disease from that of our case.
(6) Thymoma: This is a tumor derived or differentiated from the thymic epithelium. It most commonly occurs in the anterior mediastinum. Tumor cells show different levels of CK expression, though all express CK. Our case was CK negative; therefore, thymoma can be ruled out.
Treatment and prognosis
Currently, there is no standard treatment for Castleman disease [19]. Cases of UCD have a better prognosis than MCD, and surgical resection results in a high cure rate with few recurrences [20]. MCD is often accompanied by systemic symptoms, including autoimmune reactive disease and organ damage, and it can easily progress to lymphoma. Adjuvant chemotherapy or radiotherapy often follows surgical resection. The prognosis with this disease is poor [21], and relapse can occur. The patient in this case had a good outcome following surgical resection. However, her systemic symptoms were severe. She developed myasthenia gravis postoperatively and required aggressive treatment. She also required timely treatment in response to changes in her condition.
Acknowledgements
Written informed consent was obtained from the patient for publication of this case report and accompanying images.
References
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[13] Ruwan, K.P., C. Parakramawansha C, I. Wijeweera I, Ratnatunga N, and Sumanasekara WG. A case of POEMS syndrome with mixed hyaline vascular and plasma cell type Castleman's disease. Ceylon Med J 2009; 54: 68-–9.
[14] Leite AC, Nascimento OJ, Lima MA, and Andrada-Serpa MJ. POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin lesions) syndrome: a South America's report. Arq Neuropsiquiatr 2007; 65: 516-–20.
[15] Ohgami RS, Zhao S, Ohgami JK, Leavitt MO, Zehnder JL, West RB, Arber DA, Natkunam Y, and Warnke RA. TdT+ T-lymphoblastic populations are increased in Castleman disease, in Castleman disease in association with follicular dendritic cell tumors, and in angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 2012; 36: 1619-–28.
[16] Qian YW, Weissmann D, Goodell L, August D, and Stair R. Indolent T-lymphoblastic proliferation in Castleman lymphadenopathy. Leuk Lymphoma 2009; 50: 306-–8.
[17] Kansal R, Nathwani BN, Yiakoumis X, Moschogiannis M, Sachanas S, Stefanaki K, and Pangalis GA. Exuberant cortical thymocyte proliferation mimicking T-lymphoblastic lymphoma within recurrent large inguinal lymph node masses of localized Castleman disease. Hum Pathol 2015; 46: 1057-–61.
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Figure legends
Figure 1. Gross examination. the cut surface revealed a solid mass of 5 × 5 × 3.5 cm with an intact capsule that was sallow, grayish-red in color.
Figure 2. Histological findings. A. Lymphoid follicles were mostly distributed in the proliferated lymphoid mass, (40x×). B. Lymphoid follicles were mostly distributed in the proliferated lymphoid mass, (100×X). C. Tightly packed lymphocytes and vascular proliferation were seen in the interfollicular area, (100×X). D. mantle cell hyperplasia forming concentric layers, and hyaline degeneration of germinal centers, (200×x). E. vascular wall hyaline degeneration, (400×x). F. the loss of lymphatic sinuses and follicular angiogenesis, (400×x).
Figure 3. immunochistochemical features (IHC, 100×x). A. CD3 (interfollicular region +, follicles diffusely +), B. CD43 (interfollicular region +, follicles diffusely +), C. CD20 (follicles +, interfollicular region diffusely +), D. CD79a (follicles +, interfollicular region diffusely +), E. CD21 (follicular dendritic cells +), F. CD8 (diffusely +).,
Figure 4. immunochistochemical features. A. TdT (interfollicular region +) (IHC, 40×X). B. TdT (interfollicular region +) (IHC, 100×X). C. TdT (interfollicular region +) (IHC, 200×X). D. CD1a (diffusely +). E. CD10 (interfollicular region +). F. CD99 (interfollicular region +, follicles diffusely +).
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