Immunohistochemical expression of perforin in adult systemic lupus erythematosus associated macrophage activation syndrome: Clinicohematological correlation and literature review.

OBJECTIVE: To study the bone marrow (BM) immunohistomorphological characteristics in adult systemic lupus erythematosus (SLE) associated macrophage activation syndrome (SLE-MAS). MATERIALS AND METHODS: Immunohistochemical (IHC) expression of CD3, CD8, perforin (PFN), and CD163 was studied on BM trephine biopsies from 30 cytopenic adult SLE cases (male: female = 1:5, age; 24 years, range; 19-32) and compared them with ten age matched controls. Clinicopathological parameters were compared among the cases likely (L) or unlikely (U) to have MAS using probability scoring criteria. The best cut off laboratory parameters to discriminate between the two were obtained through receiver operator curve (ROC) analysis. RESULTS: MAS occurred in 12/30 (40%) cases and was more commonly associated with prior immunosuppressive therapy (p = .07), ≥ 3 system involvement (p = .09), lower fibrinogen (p < .01), increased triglyceride (p = .002), increased BM hemophagocytosis (p = .002), and higher MAS score [185 (176-203) vs. 105 (77-119), p < .01] than MAS-U subgroup. Although PFN+CD8+ T lymphocytes significantly decreased among cases than controls (p < .05), it was comparable between MAS-L and MAS-U subgroups. Fibrinogen (< 2.4 g/L, AUC; 0.93, p < .01), hemophagocytosis score (> 1.5, AUC; 0.71, p = .03), and an MAS probability score of ≥ 164 (AUC; 1, p < .01) discriminated MAS from those without MAS. CONCLUSION: We noted a decrease in perforin mediated CD8 + T cell cytotoxicity in SLE. Immunohistochemical demonstration of the same along with histiocytic hemophagocytosis on BM biopsy may be useful adjunct in early diagnosis and management of MAS in SLE.

Primary Extragastrointestinal Stromal Tumours in the Hepatobiliary Tree and Telocytes.

The first decade of the twenty-first century witnessed the presence and light microscopic, immunophenotypic, and ultrastructural characterization of interstitial Cajal-like cells (coined as 'telocytes') in virtually every extragastrointestinal site of the human body by Laurentiu M. Popescu and his co-workers. Not surprisingly, stromal tumours, immunophenotypically similar to that of telocytes [CD117 (c-KIT) +/CD34 +], have also been sporadically reported outside the tubular gut (so-called extragastrointestinal stromal tumours, EGISTs), including the gall bladder, liver, and pancreas. A meticulous literature search from January 2000 to November 2015 have found 9 such case reports of EGISTs in the gall bladder, 16 in the liver, and 31 occurring in the pancreas. The site wise mean age at presentation for these tumours were reported to be 62.2 ± 16.6, 50.9 ± 20.1, and 55.3 ± 14.3 years, respectively. Six of nine EGISTs in the gall bladder were associated with gallstones. On pathological evaluation, these tumours exhibited prominent spindled cell morphology and consistent expression of CD117/c-KIT and CD34 on immunohistochemistry and variable expression of vimentin and α-smooth muscle actin. The biological behaviour of hepatic and pancreatic lesions was favourable compared to that in the gall bladder, following definitive surgery with or without imatinib therapy. While the exact pathophysiologic role played by telocytes in various organs is yet to be fully elucidated, there seems to be a direct link between these enigmatic stromal cells and pathogenesis of gallstones and origin of EGISTs, and a hope for targeted therapies. Furthermore, the possible role of telocytes in hepatic regeneration and liver fibrosis opens a new dimension for futuristic research.

Pancreatic extragastrointestinal stromal tumors, interstitial Cajal like cells, and telocytes.

CONTEXT: The discovery and subsequent ultrastructural characterization of the interstitial Cajal like cells (now called telocytes) in virtually every anatomic sites of the human body, by Laurentiu M Popescu and co-workers, have dramatically improved the understanding the function of these cells and pathogenesis of extragastrointestinal stromal tumors (EGIST). Pancreatic extragastrointestinal stromal tumors (pEGIST), phenotypically similar to pancreatic interstitial Cajal like cells, are extremely rare with an unpredictable biological behavior. OBJECTIVE: To review the clinicopathological, radiological, immunohistochemical, and therapeutic outcome data of all reported cases of pEGIST, and highlight the developments in the field of pancreatic interstitial Cajal like cells/telocytes. METHODS: A systematic review of English literature (January 2000 to July 2012) was done by using the search engine of PubMed, PubMed Central, Google Scholar, and the Directory of Open Access Journals. RESULTS: There have been 19 reported cases of pEGIST during the last decade, over an age range of 31 to 84 years (mean: 56 years) with equal gender predilection ((male:female ratio: 9:10). Preoperative radiological characteristics have been mostly nondiagnostic though these were used, in some, for tissue diagnosis. Majority of pEGIST were localized to pancreatic head (8/19, 42.1%), and 15 of 19 patients (78.9%) were symptomatic at first presentation. The mean size ranged from 2.5 to 35cm (mean: 14 cm). Histomorphological features were that of predominantly spindle cell tumor which consistently expressed c-KIT/CD117 and CD34 by immunohistochemistry, making these two as the most sensitive markers at this site. RESULTS: from studies involving discovery on gastrointestinal stromal tumor 1 (DOG-1), the most specific biomarker of GIST/EGIST, has been inconclusive and this was found to be positive in one case only. Neoadjuvant chemotherapy with imatinib mesylate and sunitinib were used in few cases, and genetic analysis of c-KIT proto-oncogene was done in two. By univariate analysis, none of the clinicopathological parameters, except surgical resection with microscopic free margin (R0 resection) (P<0.05), were found to be an important indicators of outcome. CONCLUSION: The biological behavior of pEGIST, at present, seems unpredictable which requires indefinite period of follow-up. Large number of such cases with genetic analysis supplemented with immunohistochemistry studies will hopefully throw more light in these tumors.

Pyrexia in a patient with megaloblastic anemia: a case report and literature review.

Deficiency of vitamin B12 and/or folic acid as a cause of pyrexia, though known, is rarely reported in literature. We aimed to report a case in a 51 year old woman, who presented with fever and pancytopenia and was diagnosed to have megaloblastic anemia secondary to vitamin B12 and folate deficiency. The pyrexia subsided following the intramuscular injection of vitamin B12 and oral folic acid administration. All the other infective, inflammatory/autoimmune, endocrine causes of pyrexia were excluded by appropriate investigations. Therefore, we suggest that all physicians be aware of megaloblastic anemia as a treatable cause of pyrexia in order to avoid unnecessary costly investigations and antibiotic usage.

Core-binding factor abnormalities involving chromosome 16 in acute myeloid leukaemia: prognostic and therapeutic implications.

Core-binding factor (CBF) abnormality-associated myeloid neoplasms incorporate acute myeloid leukaemia (AML) (CBF-AML) with translocation t(8;21)(q22;q22.1) (AML1/ETO fusion) and inv(16)(p13.1q22) or translocation t(16;16)(p13.1;q22) (CBFB/MYH11 fusion) abnormalities which confer a favourable prognosis following cytarabine-based induction chemotherapy. Accumulating evidence from the molecular studies have stratified CBF-AML into favourable and unfavourable subgroups based on the associated cooperating mutations that impact the outcome. We describe a case of acute myelomonocytic leukaemia with abnormal eosinophils (M4Eo) in a woman in her 20s who was found to have CBFß/MYH11 fusion along with mutated c-KIT (exon 17) and KRAS (exon 2) genes by next-generation sequencing. She had an aggressive clinical course following initiation of cytarabine-based induction chemotherapy. The underlying mutational landscape may significantly influence the biological behaviour of otherwise favourable risk of CBF-AML cases.

Coinfection of Melioidosis and Tuberculosis Causing Infective Lumbar Spondylodiscitis: A Rare Case Report.

CASE: A 63-year-old farmer who is a known diabetic and chronic alcoholic presented with lower back pain and neurological weakness of lower limbs present for the past 3 months. His acute phase reactants were very high, and magnetic resonance imaging displayed L4-L5 vertebral involvement with epidural, paravertebral, and bilateral psoas abscesses. Cultures of an ultrasound-guided aspiration from the psoas were positive for Burkholderia pseudomallei, and a nucleic acid amplification test also detected Mycobacterium tuberculosis. He underwent posterior decompression and fixation, and intraoperative biopsy confirmed a granulomatous reaction. He received appropriate antibiotics for both diseases. At 1 year, he showed healing on radiographic imaging, with independent ambulation status. CONCLUSION: The coexistence of melioidosis and tuberculosis is rare, and as far as we know, a case of infective spondylodiscitis has not been reported. In patients with infective spondylodiscitis, every attempt should be made to confirm the diagnosis before starting empirical antitubercular treatment (ATT).

Gingival hyperplasia: An initial oral manifestation of acute myeloid leukemia.

Various systemic diseases can manifest oral signs and symptoms early, which may be crucial for diagnosis and outlining the treatment plan. This case report highlights the presentation of acute leukemia (a malignancy of white blood cells) in a young female. An 11-year-old girl presented with gingival overgrowth and bleeding from the gingiva, weakness, and recent history of weight loss. A detailed workup consisting of complete blood count, bone marrow examination, flow cytometric immunophenotyping, cytogenetics, and molecular studies were carried out. The investigations confirmed the infiltration of blast cells of myelomonocytic origin, and a confirmatory diagnosis of acute myeloid leukemia (French-American-British classification M5) was made. The patient was put on induction chemotherapy and responded well. She developed febrile neutropenia following chemotherapy, which was managed conservatively. Gingival overgrowth subsided after the chemotherapy, and at the time of discharge, she was asymptomatic and hemodynamically stable. The oral health-care professionals must recognize that gingival overgrowth/enlargement may represent an initial manifestation of an underlying systematic disease.

Acute Myeloid Leukemia following Radioactive Iodine Therapy for Metastatic Follicular Carcinoma of the Thyroid.

Radioactive iodine (RAI) therapy is widely used and has an important role in the management of hyperthyroidism and thyroid malignancies. The development of acute or chronic leukemia is a very rare complication of RAI therapy. We report a case of metastatic Follicular thyroid cancer (FTC) who underwent total thyroidectomy followed by treatment with a cumulative dose of 1600 mCi of RAI (for 4 years) and by palliative radiotherapy for L4 spinal metastasis, later on, developed acute myeloid leukemia. Thus, all patients with thyroid carcinoma treated with RAI should undergo periodic hematological examinations irrespective of RAI dose.

Eosinophilic Granuloma as a Solitary Lytic Lesion of the Cervical Spine in a Child.

Introduction: Eosinophilic granuloma (EG) is a type of Langerhan cell histiocytosis (LCH) with unknown etiology. This benign tumorous lytic lesion affects mainly children or young adults, causing bone destruction. Although, the flat or the long bones are commonly affected, localized spinal involvement in pediatric age group is rare. A thorough workup is therefore necessary for this condition, which may mimic other severe conditions. Case Report: A 10-year-old girl presented with neck pain for 4 months without any history of trauma, fever, or neurological weakness. An X-ray revealed radiolucency and sclerosis of the fifth cervical vertebral body, which was hypointense on T1 and heterogeneous on T2-weighted image, with mild peripheral enhancement on fat-suppressed post-contrast T1-weighted image. Biopsy histomorphology revealed a lymphohistiocytic lesion with scatted histiocytes with grooved nuclei, immunopositive for Langerin; thus consistent with LCH (EG). She was managed conservatively with a completely pain free course with full range of movement at 1-year follow-up. Her follow-up X-ray showed complete remodeling and ongoing fusion. Conclusion: EG should be considered as a differential diagnosis in the evaluation of solitary lytic lesion involving spine in pediatric age group. This, although self-resolving, may occasionally need surgical intervention with or without adjuvant therapy.

Cyclooxygenase 2 (Cox 2) Expression in Newly Diagnosed Plasma Cell Myeloma: A Clinicopathological and Immunohistochemical Study on 73 Cases from a Single Tertiary Care Center.

To study the cyclooxygenase 2 (Cox 2) expression in newly diagnosed plasma cell myeloma cases by immunohistochemistry (IHC) and correlate with clinicohematological characteristics. Immunohistochemical expression of Cox 2 on bone marrow trephine biopsy was studied in seventy-three newly diagnosed myeloma cases [56 males, 17 females, median age; 58 years (36-75)] and fifteen controls using SP21 clone antibody. A median immuno-score (proportion x intensity) stratified the entire cohort into low and high expressors. Cox 2 immunoexpression was compared and correlated with clinicolaboratory characteristics and marrow histomorphology and survival. Twenty one of 73 (38.7%) cases had a plasmablastic morphology whereas remainder fifty-two (61.3%) had a differentiated morphology. The Cox 2 expression was noted in 71/73 (97.2%) cases (median score = 127.3) and 15/15 (100%) controls. Low expressors was associated with higher circulating plasma cells, increased marrow tumor burden, blastic morphology, and lower proliferation index (p < 0.05) with a peculiar 'dot-block' cytoplasmic positivity (p < 0.001); whereas high expressors had thinned out bony trabeculae with granular cytoplasmic positivity with or without membrane accentuation (p < 0.001). Cox 2 expression had a weak negative correlation with tumor burden (r; -0.32, p = 0.01) and positive correlation with proliferation index (r; 0.29, p = 0.03). There was no statistically significant difference in the survival between low (n = 20) and high (n = 23) expressors (log rank p = 0.11). A high proportion of myeloma cells in our cohort expressed Cox 2 using SP21 clone; and this may have a role in futuristic research and therapy.

Usefulness of Leucocyte Cell Population Data by Sysmex XN1000 Hematology Analyzer in Rapid Identification of Acute Leukemia.

Leukocyte cell population data (CPD) generated by hematology auto analyzers are reported to be useful in screening of sepsis patients. However, there is a paucity of literature highlighting the utility of CPD in screening of acute leukemias (AL). Leucocyte CPD obtained by Sysmex XN1000 hematology analyzer from 210 cases of ALs [22 acute promyelocytic leukemia (APL), 79 non-APL acute myeloid leukemia (non-APL-AML) and 109 acute lymphoblastic leukemia (ALL)] were compared with 100 healthy and 52 reactive controls. Receiver operator curves were drawn to determine the cut-off values of individual parameters. The regression equations combining the best parameters were then formulated to calculate a cut-off value for discrimination among AL subgroups and controls. Acute leukemias showed significant differences (p < 0.05) in various CPD parameters compared to control subjects. A combination of best CPD parameters discriminated ALs from healthy controls (cut off; 0.443, sensitivity of 94% and specificity of 91%), ALs from reactive controls (cut off; 0.576, sensitivity; 97%, specificity; 92%), APL from non-APL-AML (cut off; 0.174, sensitivity of 91% and specificity of 67%), and AML from ALL (cut off; 1.338, sensitivity; 86.1%, specificity; 75%). The CPD from Sysmex XN 1000 analyzer could be a useful tool in screening and lineage characterization of acute leukemias; particularly at centers where high-end technical expertise is still not available. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-021-01488-9.

Acquired Pure Red Cell Aplasia and Recombinant Erythropoietin.

Recombinant erythropoietin (rEPO)-associated immunologically driven acquired pure red cell aplasia (PRCA) is an underreported, potentially worsening clinical syndrome in the setting of treatment of anemia of chronic kidney disease. Most cases reported in world literature are related to different formulations of erythropoiesis-stimulating agents with an implication in diagnosis and management. This brief review highlights the clinical guidelines of rEPO usage in nephrology practice, the pathophysiologic mechanism of PRCA, clinical features, diagnosis, and suggested management protocols.

Clinicopathological and Immunohistochemical Profile of Mantle Cell Lymphoma: An Institutional Experience.

Introduction Mantle cell lymphoma (MCL) is a biologically aggressive B-cell non-Hodgkin lymphoma (NHL) with distinctive morphologic, immunophenotypic, and molecular characteristics. Differentiation from other chronic lymphoproliferative disorders is essential for prognostication. Aim This paper aims to study the clinicopathological features of MCL with emphasis on immunohistochemical features and disease correlation. Method To do so, clinicopathological characteristics from 21 cases of MCL (14 males, seven females, M:F=2:1) diagnosed in the last five years i.e. 2015 to 2020, were retrospectively reviewed and correlated with immunohistochemistry (IHC) data. Particularly those pertaining to cyclin D1, SRY-box transcription factor 11 (SOX11), cluster of differentiation (CD) 5, CD23, MIB E3 ubiquitin protein ligase 1 (MIB1), tumor protein 53 (TP53), c-myelocytomatosis oncogene product (c-MYC), multiple myeloma oncogene 1 (MUM1), mouse double minute 2 homolog (MDM2), and Epstein-Barr virus latent membrane protein 1 (EBV-LMP1) expression with its aberrations. Observations This study shows that MCL constituted 4.2% (21/500) of all NHLs with a mean age of 57.5 years (median 60 years, range 30 to 80 years). The disease was nodal in 19, and extranodal in the remaining two cases. 14 of 21 (67%) had generalized lymphadenopathy and 71% had bone marrow (BM) involvement. The nodal involvement was diffuse in 9/17 (53%), 8/21 (38%) had a blastoid morphology, and an in-situ MCL pattern was not seen in any of the cases selected for the study. Cyclin D1 immunoexpression correlated well with SOX11; CD5-negative in five cases; and CD23-positive in three cases. TP53 and c-MYC expression were noted in 17/19 (89.4%) and 8/17 (47%), respectively. MUM1 registered positive in six cases. None of the cases showed immunopositivity for MDM2 and EBV-LMP1. Conclusion In essence, this study indicates that morphological and immunophenotypic subclassification of mantle cell lymphoma with a wider panel of IHC markers is essential for understanding disease biology and better prognostication.

Ergotamine Induced Retroperitoneal Fibrosis.

Retroperitoneal fibrosis (RPF) is an uncommon disease characterised by the presence of fibroinflammatory reaction which starts around the infrarenal portion of the abdominal aorta in the retroperitoneum and frequently entrap the ureter causing obstructive uropathy. Approximately, two thirds of the cases are idiopathic, where aetiopathogenesis is not known. Ergotamine-induced RPF, although rare, is considered under secondary group. The fibrogenic process here is thought to be due to serotonergic activity. We report a case of RPF in a young female with obstructive uropathy who had history of long-term ergotamine intake for migraine. Histopathological evaluation revealed different evolving stages of necrotising vasculitis. In addition, the patient has responded to withdrawal of offending drug along with immunosuppressive therapy. We believe, apart from serotonergic activity, ergotamine can lead to RPF through a vasculitic process which has not been reported earlier.

Peripheral blood T lymphocytosis in thymoma: an insight into immunobiology.

PURPOSE: Peripheral blood T lymphocytosis (PBTL) is a rare, yet poorly understood manifestations of thymoma, which is postulated to be linked with autoimmune/paraneoplastic manifestations such as myasthenia gravis (MG), pure red cell aplasia (PRCA), etc.; more commonly encountered in this neoplasm. METHOD: We aim to describe the flowcytometric immunophenotypic data of PBTL in a 43-year-old male; 6 months after successful completion of chemoradiotherapy (CT/RT) for a large, invasive, and metastatic type B1 thymoma; and present a comprehensive review of all such cases reported over last 42 years (N = 21) (1977-2019). RESULT: A larger size of the tumors (≥ 10 cm), presence of local invasion and/or distant metastasis, and type B (cortical or lymphocyte rich) histology were more likely to be associated with PBTL. Tumors associated with MG/PRCA (N = 9/21) tend to have lower PBTL compared to those without such manifestations; and PBTL subsided following thymectomy with or without CT/RT. Immunophenotypic analysis of PB revealed a CD8 + > CD4 + mature (naïve) polyclonal T cells resembling late cortical thymocytes. CONCLUSION: Thymic intratumoral microenvironment might influence occurrence PBTL that may have a pathophysiologic link to development of autoimmune manifestations. Immunophenotypic characteristics of peripheral blood lymphoid cells should be the clue for accurate characterization and to avoid a misdiagnosis of a lymphoproliferative neoplasm.

Bone marrow trephine immunohistochemistry is useful in characterizing malignancy-associated myelonecrosis: A retrospective observational study.

OBJECTIVE: We aim to describe the utility of immunohistochemistry (IHC) in characterizing malignancy-associated myelonecrosis (MN) on bone marrow trephine biopsies (BMBx) as a part of initial workup. MATERIALS AND METHODS: Patten and intensity of antigenic immunoexpression in necrotic tumor cells on BMBx were evaluated in a series of cases using standardized avidin-biotin-complex immunoperoxidase technique after heat-induced epitope retrieval and compared the same with viable tumor cells wherever available. RESULTS: Fifteen out of 2494 (0.6%) cases (median age: 28 years; range: 4 to 66 years) had evidence of MN (extensive in eight, moderate in five, and focal in two) secondary to hematological (N = 9) and solid (N = 6) malignancies. Five (33.3%) had pancytopenia, and eight (53.3%) had difficult and/or hemodiluted aspirate. Antigenic expression for CD10, CD79a, CD3, CD7, and CD20 was retained by necrotic leukemic blasts or lymphoma cells; CD34, TdT, and PAX5 showed heterogeneous expression; and a weak Golgi zone (dot like) CD30 positivity was noted in Reed-Sternberg (RS) or RS-like giant cells. Necrotic epithelial metastases retained pancytokeratin in all and showed variable positivity for prostate-specific antigen, carcinoembryonic antigen, CK20, ER, PR, and GATA3. Necrotic neuroblastomas (N = 2) retained positivity for synaptophysin and chromogranin, whereas retained nuclear positivity for NKX2.2 in necrotic Ewing family of tumor (N = 1) aided in early diagnosis. CONCLUSION: Myelonecrosis may retain tumor antigenicity, and immunohistochemistry using selected panel of antibodies should be tried in such challenging cases for an early presumptive diagnosis and further decision making.

Primary gastrointestinal anaplastic large cell lymphoma: A critical reappraisal with a systematic review of the world literature.

Anaplastic large cell lymphoma (ALCL) is a distinct T-cell non-Hodgkin lymphoma involving both nodal and extra-nodal sites with a specific anaplastic lymphoma kinase 1 (ALK-1) gene rearrangement. The commonly involved extranodal sites include skin, bone, soft tissue, lungs, and liver. ALCL primarily involving gastrointestinal (GI) tract is rare. In this manuscript, we describe a case of primary esophageal ALK1 positive-ALCL (null phenotype) in a young female, who presented with fleshy mucosal lesion in the lower third of the esophagus and present a systematic review of 35 cases of GI-ALCL reported in the English literature over the past 28 years (1990-2018) with regard to the clinicopathological characteristics, therapy, and outcome.

Pulmonary anaplastic large-cell lymphoma: A case-based systematic review of world literature.

We describe a case of ALK1 negative (-) pulmonary anaplastic large-cell lymphoma (pALCL) in an adult female with an unfavorable outcome following combination chemotherapy and present a systematic review of 39 such sporadic cases reported over the past 28 years (1990-2018). pALCL occurred in 26 males and 13 females (median age, 43 years [5-81]) and 13/39 (33.33%) were ≤18 years. The lesions were endobronchial in 21 (53.85%) and parenchymal in 18 (46.15%) cases. Twenty-six cases were ALK1-; 13 were ALK1+ (positive); and 27/34 cases had a T cell phenotype (where tested). ALK- cases were characterized by higher age (P = 0.012) at presentation, more B symptoms (P = 0.002), and more parenchymal than endobronchial lesions (P = 0.039). The median survival (N = 29/39) was 60 months; pediatric group had a better survival than adult/elderly group (log-rank, P = 0.026). pALCL is rare and may have a distinct biological behavior.

Extragastrointestinal stromal tumor arising in the pancreas: a case report with a review of the literature.

CONTEXT: Extragastrointestinal stromal tumors arising in the pancreas are extremely rare. To date, only eight cases have been reported in the literature. CASE REPORT: A 42-year-old female patient presented with gradually increasing abdominal pain of 6-month duration. Computerized tomography scan of the abdomen demonstrated a solid cystic mass in the body and tail of the pancreas. En-block R0 resection of the mass with distal pancreatectomy, splenectomy and left hemicolectomy was carried out following a radiological diagnosis of a malignant cystic neoplasm of the pancreas. Histopathological and immunohistochemical findings of the lesion were consistent with a gastrointestinal stromal tumor. CONCLUSION: Extragastrointestinal stromal tumor of the pancreas, though rare, should be considered in the differential diagnosis of the more common cystic lesions at this site.

Thyroid paraganglioma: A case-based systematic review of literature.

Thyroid paragangliomas are distinctly rare primary thyroid neoplasms with nearly 75 cases reported worldwide. Due to their similar embryological origin and cytohistomorphology with other thyroid neoplasms, they may pose great diagnostic challenges for pathologists, radiologists, endocrinologists, as well as surgeons leading to unnecessary aggressive therapy. With recent advances in molecular genetics, the prognostic significance of such seemingly innocuous thyroid neoplasms has been better understood. In this manuscript, we describe such a case and present a systematic review of all reported cases till date giving an update on our current knowledge regarding their diagnostic pitfalls, pathology, and molecular genetics.