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Figure 1: Right thyroid ultrasonography. The tests were performed two months apart. (upper: first ultrasonography). Note the tumor measures.

The tissue showed a diffuse infiltrate of lymphoid large cells with lobulated nuclei, marked nucleoli, frequent mitosis and apoptosis. With broad-spectrum cytokeratins (CK AE1-AE3), nests of dispersed thyroid epithelium were identified. After immunohistochemical evaluation, the lymphoid nature of the neoplasm (CD45 +) was confirmed. It showed germinal center lymphocyte B-cell differentiation (CD20 +, CD10 +, BCL-2 +, MUM1 +, BCL-6 - and c-MYC -) and it had accompanying T lymphocytes (CD3 +). The proliferation index with Ki67 was greater than 80% (Figure 2A-F) and the immunoglobulin chain rearrangement analysis showed IgH clonality. Staining for PD-L1 (clone 22C3) showed low expression in atypical lymphoid cells (1-2%). As there was no adenopathy or alterations on the imaging tests (including PET/CT), the diagnosis of primary thyroid diffuse large B-cell lymphoma, germinal center B-cell subtype (WHO, 2017) was made.

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Figure 2: Primary thyroid diffuse large B-cell lymphoma. A) Lymphoid large cells with lobulated nuclei, marked nucleoli, frequent mitosis and apoptosis are present (H&E; x 600). B) Nests of thyroid epithelium are identified (CKAE1/AE3; x100). C) Cells show positivity for CD20 (IHC; x200). D) Cells show positivity for CD10 (IHC; x200). E) High proliferation (Ki67; x100). F) There is accompanying T-lymphocytes (CD3; x200).

At the time of staging, two months after the first FNA, a clinical decrease of tumor dimensions was observed so a new ultrasound was performed. It showed a nodule with the same characteristics as the previous one that now measured 2.5 cm (Figure 1B). A new biopsy was taken showing thyroid follicles, fibrous tracts and non-atypical small lymphocytes. There was also plasma cells and macrophages with no apparent neoplastic population. The absence of tumor cells was confirmed immunohistochemically (CD20 -, CYCLIN D1 -, CD5 - and CD10 -) with Ki67 less than 1% and a marked increase in the T-cell population (Figure 3A-D). Residual lymphocytes showed no morphological or immunohistochemical characteristics suggestive of any other type of lymphoma.

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Figure 3: A) Thyroid with small lymphocytes infiltration (H&E; x100). B) Cells are CD20 negative (IHC; x100). C) Cells are CD3 positive (IHC; x100). D) Ki67 is less than 1% (IHC; x100).

Finally, a hemithyroidectomy was carried out five months after the first FNA. The right hemithyroid had regular weight and dimensions and whitish fibrous bands without defined solid nodules. After microscopic examination, we showed thyroid follicles of variable sizes with lymphoid clusters and germinal centers as well as a fibrotic area with lymphocytes like scar tissue (Figure 4A-C). No neoplastic population was demonstrated in any slide and the genetic rearrangement did not indicate clonality.

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Figure 4: A-B) Thyroid showing features of thyroiditis with follicles of variable sizes and lymphoid clusters forming germinal centers (H&E; x20, H&E; x200). C) In some areas, fibrotic bands with lymphocytes are present (H&E; x100).

The patient passed away twenty-six months after the diagnosis due to endocarditis and there was no clinical or radiological relapse. In addition, she had undergone a PET/CT scan prior to her death which only showed the infectious cardiac focus without uptake elsewhere. No new treatments were added at any time.

Meanwhile, STR is a striking entity described by TC Everson and WH Cole in the second half of the 20th century. In their work the definition of STR was proposed for the first time as well as a review of cases published until then ⁸. Most hypotheses trying to explain it have been in agreement afterwards. Most advocate a massive release of heteroantigens after aggression on the tumor that would enhance the immune response against it. In this way, local or systemic infections, vaccination, contusion, biopsy and even exposure to X-radiation could be triggers. Therefore, the most accepted theory to explain STR attributes is that the immune system plays the main role ^9,10. In the current case, we believe that FNA started the T-lymphocyte response that we found on needle biopsy and the surgical specimen and resulted in complete STR.

With reference to non-Hodgkin’s lymphomas, some studies estimate 10-20% of STR in low-grade types but it is anecdotal in high-grade lymphomas. Immunoregulation has been considered important because regression of the lymphoma appears to a greater or lesser degree if T-mediated response is promoted on animal or in vitro models (after virus infection, addition of anti-idiotypic antibodies, cytokines, etc.) ¹¹. There is also an association between the immunity status and the presence of some lymphoproliferative disorders as in AIDS patients, posttransplant lymphoproliferative disorders, and Epstein-Barr virus-associated lymphomas ^11,12.

Furthermore, it is known that thyroid lymphomas often show IgH clonality, especially in those from lymphocytic thyroiditis ^1, although its prognostic role is unknown nowadays. We found only one published case of thyroid lymphoma regression in which immunoglobulin chain restriction was studied. This patient had IgH clonality and recurrence was earlier ¹³ as opposed to our case.

Finally, regarding PD-L1, its expression in lymphomas seems to inhibit T-cell activity against the tumor ¹⁴. In the present case, the low expression of PD-L1 could be a favorable point for the immune response against the neoplastic population.

CONFLICT of INTEREST
The authors declare no conflict of interest.

FUNDING
The authors have not received funding from any organization.

1) Chan JKC, Burke JS, Ferry JA, Wotherspoon A. Primary thyroid lymphoma. In: Lloyd RV, Osamura RY, Klöppel G, Rosai J, editors. WHO Classification of Tumours of Endocrine Organs. Lyon: WHO PRESS; 2017. 137-8.

2) Ghatalia P, Morgan CJ, Sonpavde G. Meta-analysis of regression of advanced solid tumors in patients receiving placebo or no anticancer therapy in prospective trials. Crit Rev Oncol Hematol. 2016;98:122-36.

3) Potts DA, Fromm JR, Gopal AK, Cassaday RD. Spontaneous remission of an untreated, MYC and BCL-2 coexpressing, highgrade B-cell lymphoma: A case report and literature review. Case Rep Hematol. 2017;2017:2676254.

4) Caturegli P, De Remigis A, Chuang K, Dembele M, Iwama A, Iwama S. Hashimoto’s thyroiditis: Celebrating the centennial through the lens of the Johns Hopkins Hospital surgical pathology records. Thyroid. 2013;23: 142-50.

5) Rosai J, Tallini G. Thyroid gland. In: Juan Rosai, editor. Rosai and Ackerman’s surgical pathology. 10th ed. Edinburgh: Elsevier. 2011. 492-5.

6) Chai YJ, Hong JH, Koo DH, Yu HW, Lee JH, Kwon H, Kim SJ, Choi JY, Lee KE. Clinicopathological characteristics and treatment outcomes of 38 cases of primary thyroid lymphoma: A multicenter study. Ann Surg Treat Res. 2015;89: 295-9.

7) Lai X, Xia Y, Zhang B, Li J, Jiang Y. A meta-analysis of Hashimoto’s thyroiditis and papillary thyroid carcinoma risk. Oncotarget. 2017;8: 62414-24.

8) Cole WH, Everson TC. Spontaneous regression of cancer: Preliminary report. Ann Surg. 1956;144: 366-83.

9) Jessy T. Immunity over inability: The spontaneous regression of cancer. J Nat Sci Biol Med. 2011;2: 43-9.

10) Sasaki J, Kurihara H, Nakano Y, Kotani K, Tame E, Sasaki A. Apparent spontaneous regression of malignant neoplasms after radiography: Report of four cases. Int J Surg Case Rep. 2016;25: 40-3.

11) Drobyski WR, Qazi R. Spontaneous regression in non-Hodgkin’s lymphoma: Clinical and pathogenetic considerations. Am J Hematol. 1989;31:138-41.

12) Lim DH, Rhee JY, Park KW. Stage IV advanced diffuse large B-cell lymphoma in human immunodeficiency virus infection with achieving cure by using highly active antiretroviral therapy alone: A case report. Int J STD AIDS. 2017;28: 932-6.

13) Uohashi A, Imoto S, Matsui T, Murayama T, Okimura Y, Chihara K, Ohbayashi C, Itoh H. Spontaneous regression of diffuse largecell lymphoma associated with Hashimoto’s thyroiditis. Am J Hematol. 1996;53: 201-2.

14) Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM. Programmed death ligand 1 is expressed by non-Hodgkin lymphomas and inhibits the activity of tumorassociated T cells. Clin Cancer Res. 2011;17: 4232-44.