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Open access

Tu Vinh Luong, Zaibun Nisa, Jennifer Watkins and Aimee R Hayes

Summary

Colorectal poorly differentiated neuroendocrine carcinomas (NECs) are typically associated with poor outcomes. The mechanisms of their aggressiveness are still being investigated. Microsatellite instability (MSI) has recently been found in colorectal NECs showing aberrant methylation of the MLH1 gene and is associated with improved prognosis. We present a 76-year-old lady with an ascending colon tumour showing features of a pT3 N0 R0, large cell NEC (LCNEC) following right hemicolectomy. The adjacent mucosa showed a sessile serrated lesion (SSL) with low-grade dysplasia. Immunohistochemistry showed loss of expression for MLH1 and PMS2 in both the LCNEC and dysplastic SSL. Molecular analysis indicated the sporadic nature of the MLH1 mismatch repair (MMR) protein-deficient status. Our patient did not receive adjuvant therapy and she is alive and disease-free after 34 months follow-up. This finding, similar to early-stage MMR-deficient colorectal adenocarcinoma, is likely practice-changing and will be critical in guiding the appropriate treatment pathway for these patients. We propose that testing of MMR status become routine for early-stage colorectal NECs.

Learning points:

  • Colorectal poorly differentiated neuroendocrine carcinomas (NECs) are known to be aggressive and typically associated with poor outcomes.
  • A subset of colorectal NECs can display microsatellite instability (MSI) with mismatch repair (MMR) protein-deficient status.
  • MMR-deficient colorectal NECs have been found to have a better prognosis compared with MMR-proficient NECs.
  • MMR status can be detected using immunohistochemistry.
  • Immunohistochemistry for MMR status is routinely performed for colorectal adenocarcinomas.
  • Immunohistochemical expression of MMR protein and MSI analysis should be performed routinely for early-stage colorectal NECs in order to identify a subgroup of MMR-deficient NECs which are associated with a significantly more favourable prognosis.
Open access

Silvia M Becerra-Bayona, Víctor Alfonso Solarte-David, Claudia L Sossa, Ligia C Mateus, Martha Villamil, Jorge Pereira and Martha L Arango-Rodríguez

Summary

Diabetic foot ulcer morbidity and mortality are dramatically increasing worldwide, reinforcing the urgency to propose more effective interventions to treat such a devastating condition. Previously, using a diabetic mouse model, we demonstrated that administration of bone marrow mesenchymal stem cells derivatives is more effective than the use of bone marrow mesenchymal stem cells alone. Here, we used the aforementioned treatments on three patients with grade 2 diabetic foot ulcers and assessed their beneficial effects, relative to the conventional approach. In the present study, two doses of cell derivatives, one dose of mesenchymal stem cells or one dose of vehicle (saline solution with 5% of human albumin), were intradermally injected around wounds. Wound healing process and changes on re-epithelialization were macroscopically evaluated until complete closure of the ulcers. All ulcers were simultaneously treated with conventional treatment (PolyMen® dressing). Patients treated with either cell derivatives or mesenchymal stem cells achieved higher percentages of wound closure in shorter times, relative to the patient treated with the conventional treatment. The cell derivative and mesenchymal stem cells approaches resulted in complete wound closure and enhanced skin regeneration at some point between days 35 and 42, although no differences between these two treatments were observed. Moreover, wounds treated with the conventional treatment healed after 161 days. Intradermal administration of cell derivatives improved wound healing to a similar extent as mesenchymal stem cells. Thus, our results suggest that mesenchymal stem cell derivatives may serve as a novel and potential therapeutic approach to treat diabetic foot ulcers.

Learning points:

  • In diabetic mouse models, the administration of mesenchymal stem cells derivatives have been demonstrated to be more effective than the use of marrow mesenchymal stem cells alone.
  • Mesenchymal stem cells have been explored as an attractive therapeutic option to treat non-healing ulcers.
  • Mesenchymal stem cells derivatives accelerate the re-epithelialization on diabetic foot ulcers.
Open access

Anna Luiza Galeazzi Rech, Yvon Stüve, Andreas Toepfer and Katrin E Schimke

Summary

Acute Charcot neuropathic osteoarthropathy (CN) is a clinical entity which can easily go unrecognized in its acute early stages due to lack of awareness and unspecific presentation. However, missing early diagnosis can lead to severe complications. We present the case of a 72-year-old male patient who went through the natural course of the disease unnoticed before the very eyes of his physicians leading to a tragic end. We aim to raise awareness for this rare diabetic complication, emphasizing the necessity of early diagnosis and adequate, interdisciplinary treatment.

Learning points:

  • Clinical signs and symptoms of acute Charcot neuropathic osteoarthropathy (CN).
  • Red flags.
  • Importance of early diagnosis and correct treatment.
  • Diagnostic challenges of acute CN.
  • Awareness of high morbidity and mortality.
Open access

Daniela Gallo, Sara Rosetti, Ilaria Marcon, Elisabetta Armiraglio, Antonina Parafioriti, Graziella Pinotti, Giuseppe Perrucchini, Bohdan Patera, Linda Gentile, Maria Laura Tanda, Luigi Bartalena and Eliana Piantanida

Summary

Brown tumors are osteoclastic, benign lesions characterized by fibrotic stroma, intense vascularization and multinucleated giant cells. They are the terminal expression of the bone remodelling process occurring in advanced hyperparathyroidism. Nowadays, due to earlier diagnosis, primary hyperparathyroidism keeps few of the classical manifestations and brown tumors are definitely unexpected. Thus, it may happen that they are misdiagnosed as primary or metastatic bone cancer. Besides bone imaging, endocrine evaluation including measurement of serum parathyroid hormone and calcium (Ca) levels supports the pathologist to address the diagnosis. Herein, a case of multiple large brown tumors misdiagnosed as a non-treatable osteosarcoma is described, with special regards to diagnostic work-up. After selective parathyroidectomy, treatment with denosumab was initiated and a regular follow-up was established. The central role of multidisciplinary approach involving pathologist, endocrinologist and oncologist in the diagnostic and therapeutic work-up is reported. In our opinion, the discussion of this case would be functional especially for clinicians and pathologists not used to the differential diagnosis in uncommon bone disorders.

Learning points:

  • Brown tumors develop during the remodelling process of bone in advanced and long-lasting primary or secondary hyperparathyroidism.
  • Although rare, they should be considered during the challenging diagnostic work-up of giant cell lesions.
  • Coexistence of high parathyroid hormone levels and hypercalcemia in primary hyperparathyroidism is crucial for the diagnosis.
  • A detailed imaging study includes bone X-ray, bone scintiscan and total body CT; to rule out bone malignancy, evaluation of bone lesion biopsy should include immunostaining for neoplastic markers as H3G34W and Ki67 index.
  • If primary hyperparathyroidism is confirmed, selective parathyroidectomy is the first-line treatment.
  • In advanced bone disease, treatment with denosumab should be considered, ensuring a strict control of Ca levels.
Open access

Kazuhisa Kusuki, Saya Suzuki and Yuzo Mizuno

Summary

A 72-year-old man with no history of diabetes was referred to our department due to hyperglycemia during pembrolizumab treatment for non-small-cell lung carcinoma. His blood glucose level was 209 mg/dL, but he was not in a state of ketosis or ketoacidosis. Serum C-peptide levels persisted at first, but gradually decreased, and 18 days later, he was admitted to our hospital with diabetic ketoacidosis (DKA). The patient was diagnosed with fulminant type 1 diabetes (FT1D) induced by pembrolizumab. According to the literature, the insulin secretion capacity of a patient with type 1 diabetes (T1D) induced by anti-programmed cell death-1 (anti-PD-1) antibody is depleted in approximately 2 to 3 weeks, which is longer than that of typical FT1D. Patients with hyperglycemia and C-peptide persistence should be considered for hospitalization or frequent outpatient visits with insulin treatment because these could indicate the onset of life-threatening FT1D induced by anti-PD-1 antibodies. Based on the clinical course of this patient and the literature, we suggest monitoring anti-PD-1 antibody-related T1D.

Learning points:

  • Immune checkpoint inhibitors, such as anti-PD-1 antibodies, are increasingly used as anticancer drugs. Anti-PD-1 antibodies can cause immune-related adverse events, including T1D.
  • FT1D, a novel subtype of T1D, is characterized by the abrupt onset of hyperglycemia with ketoacidosis, a relatively low glycated hemoglobin level and depletion of C-peptide level at onset.
  • In patients being treated with anti-PD-1 antibody, hyperglycemia with C-peptide level persistence should be monitored through regular blood tests. Because of C-peptide persistence and mild hyperglycemia, it is possible to miss a diagnosis of life-threatening FT1D induced by anti-PD-1 antibody.
  • In particular, in patients who have no history of diabetes, hyperglycemia without DKA is likely to be the very beginning of anti-PD-1 antibody-induced T1D. Therefore, such patients must be considered for either hospitalization or frequent outpatient visits with insulin injections and self-monitoring of blood glucose.
Open access

Kaja Grønning, Archana Sharma, Maria Adele Mastroianni, Bo Daniel Karlsson, Eystein S Husebye, Kristian Løvås and Ingrid Nermoen

Summary

Primary adrenal lymphoma (PAL) is a rare cause of adrenal insufficiency. More than 90% is of B-cell origin. The condition is bilateral in up to 75% of cases, with adrenal insufficiency in two of three patients. We report two cases of adrenal insufficiency presenting at the age of 70 and 79 years, respectively. Both patients had negative 21-hydroxylase antibodies with bilateral adrenal lesions on CT. Biopsy showed B-cell lymphoma. One of the patients experienced intermittent disease regression on replacement dosage of glucocorticoids.

Learning points:

  • Primary adrenal lymphoma (PAL) is a rare cause of adrenal insufficiency.
  • Bilateral adrenal masses of unknown origin or in individuals with suspected extra-adrenal malignancy should be biopsied quickly when pheochromocytoma is excluded biochemically.
  • Steroid treatment before biopsy may affect diagnosis.
  • Adrenal insufficiency with negative 21-hydroxylase antibodies should be evaluated radiologically.
Open access

C Greco, G Brigante, E Taliani, S Corrado, M Simoni and B Madeo

Summary

A 74-year-old man was referred to the Endocrinology Unit because of multinodular goiter. The dominant nodule (1.7 × 1.9 × 2.4 cm), at the medium-superior third of the left lobe, was inhomogeneously hypoechoic, with irregular margins, macrocalcifications and intranodular vascularization. Fine-needle aspiration biopsy (FNAB) was performed. The cytological diagnosis was TIR 2, benign, according to the 2013 Italian thyroid cytology classification system. Moderately high serum calcitonin (s-Ct) (61.5 pg/mL, n.r. 0–7.5) and normal CEA were detected. The Ct level in FNAB wash-out fluid (Ct-FNAB) was 1450 pg/mL. Based on s-Ct and Ct-FNAB levels, patient underwent total thyroidectomy. Macroscopically, a dominant circumscribed nodule of 2 ecm was described; the histological and immunohistochemical features identified medullary thyroid carcinoma (MTC) with paraganglioma (PG)-like pattern positive for Ct, CEA and chromogranin and negative for S-100 sustentacular cells (SC). Moreover, papillary carcinoma of 3 mm in the right lobe was also associated. No areas of hyperaccumulation of the tracer were documented at Ga68 PET/CT. No RET-proto-oncogene mutations were found. Post-surgery s-Ct levels were within normal range (4 pg/mL). Two years after thyroidectomy, the patient is still disease-free. We reported a case of sporadic and rare variant of MTC: this is the ninth described case of PG-like MTC. In this case, cytologically benign, the clinical suspicion arose from high Ct values at FNAB wash-out fluid. Even if clinical behavior of this variant seems indolent, additional studies are necessary to understand prognoses and predictive factors.

Learning points:

  • Several unusual histological variants of medullary thyroid carcinoma (MTC) have been described such as spindle cell, giant cell, clear cell, melanotic, squamous, angiosarcoma-like variants; even rarer is the paraganglioma (PG)-like pattern.
  • We here describe a case of medullary PG-like thyroid carcinoma in a 74-year-old man. This is a rare histological variant of MTC hardly diagnosed by cytology, since immunohistochemical investigations are necessary.
  • Measurement of calcitonin both in serum and in wash-out fluid from fine-needle aspiration could be an additional tool for an early and non-invasive identification of these variants.
Open access

Misaki Aoshima, Koji Nagayama, Kei Takeshita, Hiroshi Ajima, Sakurako Orikasa, Ayana Iwazaki, Hiroaki Takatori and Yutaka Oki

Summary

Patients treated with immunosuppressive drugs, especially methotrexate (MTX), rarely develop lymphoproliferative disorders (LPDs), known as MTX-related LPD (MTX–LPD). The primary site of MTX–LPD is often extranodal. This is the first reported case of MTX–LPD in the pituitary. A 65-year-old woman was admitted to our hospital with symptoms of oculomotor nerve palsy and multiple subcutaneous nodules. She had been treated with MTX for 11 years for rheumatoid arthritis. Computed tomography showed multiple masses in the orbit, sinuses, lung fields, anterior mediastinum, kidney, and subcutaneous tissue. Brain magnetic resonance imaging revealed a sellar mass. She was diagnosed with hypopituitarism and central diabetes insipidus based on endocrine examination. Although pituitary biopsy could not be performed, we concluded that the pituitary lesion was from MTX–LPD, similar to the lesions in the sinuses, anterior mediastinum, and subcutaneous tissue, which showed polymorphic LPD on biopsy. MTX was discontinued, and methylprednisolone was administered to improve the neurologic symptoms. After several weeks, there was marked improvement of all lesions, including the pituitary lesion, but the pituitary function did not improve. When pituitary lesions are caused by MTX–LPD, the possibility of anterior hypopituitarism and central diabetes insipidus needs to be considered. Further studies are needed to investigate the effectiveness of early diagnosis and treatment of MTX–LPD in restoring pituitary dysfunction.

Learning points

  • Pituitary lesions from MTX–LPD may cause hypopituitarism and central diabetes insipidus.
  • Pituitary metastasis of malignant lymphoma and primary pituitary lymphoma, which have the same tissue types with MTX–LPD, have poor prognosis, but the lesions of MTX–LPD can regress only after MTX discontinuation.
  • In cases of pituitary lesions alone, a diagnosis of MTX–LPD may be difficult, unless pituitary biopsy is performed. This possibility should be considered in patients treated with immunosuppressive drugs.
  • Pituitary hypofunction and diabetes insipidus may persist, even after regression of the lesions on imaging due to MTX discontinuation.
Open access

Mona Abouzaid, Ahmed Al-Sharefi, Satish Artham, Ibrahim Masri, Ajay Kotagiri and Ashwin Joshi

Summary

An 82-year-old male with a proven diagnosis of primary hyperparathyroidism (PHPT) was found to have bilateral changes in the fundi during a routine eye examination which were consistent with SC. In this report, we discuss the link between SC and PHPT and question the need for prospective observational studies to establish the true association between these conditions. Though screening PHPT patients for SC might not be justified/warranted given the benign course of the latter, patients with SC need to be assessed for PHPT, as the former may be the first clue to an underlying treatable systemic disease.

Learning points:

  • Sclerochoroidal calcifications (SCs), though rare and harmless, could be associated with an underlying systemic disease, such as primary hyperparathyroidism (PHPT).
  • Biochemical screening for hypercalcaemia is a simple, cheap and widely available tool that could facilitate an identification of undiagnosed PHPT in patients with SC.
  • A joint care by endocrinologists and ophthalmologists is warranted for those patients, as thorough investigations and long-term follow-up plans are crucial.
Open access

Zaina Adnan, David Nikomarov, Michal Weiler-Sagie and Noga Roguin Maor

Summary

Phosphaturic mesenchymal tumor (PMT) represents a rare cause of osteomalacia. The clinical signs and symptoms are vague and these lead to diagnosis delay. In the presence of hypophosphatemia and relatively high urine phosphate excretion, this entity should be taken into consideration in the deferential diagnosis of osteomalacia. In the present article, we report 81-year-old man presented to our clinic for evaluation due to osteopenia. His laboratory results disclosed hypophosphatemia, relatively increased urine phosphate excretion and increased level of intact fibroblast growth factor 23 (FGF23). A 68Gallium DOTATATE PET/CT revealed pathological uptake in the upper aspect of the left shoulder adjacent to the coracoid process. For suspected PMT a wide resection of the tumor was performed and pathological findings were consistent for PMT. Laboratory tests were normalized postoperatively. Reviewing the literature, we had identified 33 reported cases of PMTs among elderly patients age ≥70 years. Unlike previously reported data, where tumors predominantly localized in the lower extremities and pelvis, our search disclosed a high rate of tumor localization (10 cases – 33.3%) in the head with equal number of tumors (14 cases – 42.4%) localized in the head and upper extremity as well as in pelvis and lower extremity. The present case describes unique tumor localization in an elderly patient and our literature search demonstrated for the first time a high rate of tumor localization in the head among this group of patients.

Learning points:

  • PMTs represent a rare entity that should be considered in the differential diagnosis of elderly patients presented with persistent hypophosphatemia.
  • Unlike previously reported data, head and neck tumor localization is frequent among elderly patients.
  • 68Gallium-conjugated somatostatin peptide analogs, such as 68Ga-DOTATATE PET/CT demonstrated the greatest sensitivity and specificity for tumor localization in patients with phosphaturic mesenchymal tumors (PMTs).
  • Wide tumor resection using intraoperative ultrasound is of major importance in order to ensure long-term cure.