Importance of early detection in multiple endocrine neoplasia type 1: Clinical insights and future directions

Abstract

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-inherited syndrome involving multiple endocrine tumors. It is characterized by multiple mutations in the tumor suppressor gene MEN1, which is located on chromosome 11q13. As main etiology of MEN1 is genetic mutations, clinical symptoms may vary. In this editorial, we comment on the article by Yuan et al. This article describes a case of (MEN1) characterized by low incidence and diagnostic complexity. MEN1 commonly presents as parathyroid, pancreatic, and pituitary tumors. Diagnosis requires a combination of serologic tests, magnetic resonance imaging, computed tomography, endoscopic ultrasonography, immunologic and pathology. The diagnosis is unique depending on the site of disease. Surgical resection is the treatment of choice for MEN1. The prognosis depends on the site of origin, but early detection and intervention is the most effective.

Key Words: Multiple endocrine neoplasia type 1; Diagnosis; Treatment; Primary hyperparathyroidism; Pancreatic neuroendocrine neoplasms

Core Tip: Multiple endocrine neoplasia is a rare syndrome in which tumors occur simultaneously or sequentially in multiple endocrine organs. It is important to identify potential patients early and conduct multiple examinations, including biochemical multitype and multisite imaging examinations, according to the disease spectrum of each type. This emphasizes the need for a multidisciplinary approach to help achieve an accurate diagnosis and effective treatment.

INTRODUCTION

Multiple endocrine neoplasia type 1 (MEN1) also known as Wermer’s syndrome, is an autosomal dominantly inherited syndrome that occurs due to inactivating mutations of the MEN1 gene locus, which codes for a tumor-suppressor protein, Menin[1]. MEN1 is characterized by the presence of functioning and non-functioning tumors or hyperplasia of the parathyroid, duodenum, pancreas, and anterior pituitary, as well as neuroendocrine carcinoid tumors[2-5]. In addition, nonendocrine mesenchymal tumors, such as lipomas, collagenomas, angiofibroma, and leiomyomas have also been reported[6,7]. Studies have also reported that females with MEN1 were at increased risk of breast cancer[8-10]. This syndrome is infrequent, occurring in approximately two to three individuals per 100000 population, with a gender distribution that is balanced between males and females[11,12]. Because of the rarity of this disorder, MEN1 is easily missed in clinical practice. A recent case report on MEN1 presented also indicates that is a significantly complicated disorder[13].

In 1953, studies identified eight patients with a syndrome characterized by pituitary, pancreatic islet, and parathyroid adenomas[14,15]. In 1968, studies coined the term "multiple endocrine neoplasia" (MEN) to describe disorders involving multiple endocrine tumors, classifying Wermer syndrome as MEN1 and Sipple syndrome as MEN2[14,16]. MEN1 is considered a refractory condition due to its clinical variability, which results from the complexity of the various hormones involved. Early detection of these tumors leads to significant improvements in prognosis, particularly in asymptomatic individuals[3]. As such, careful diagnosis and personalized treatment are essential for optimizing patient outcomes.

CASE PRESENTATION

This case involved a middle-aged male presenting with recurrent abdominal pain and diarrhea. Initial blood tests revealed hypercalcemia and hypophosphatemia, which prompted further investigations. Parathyroid emission tomography identified a hyperactive parathyroid lesion, and ultrasound endoscopy revealed a hypoechoic lesion in the duodenal bulb. Elevated serum gastrin levels and subsequent pathological analysis confirmed the diagnosis of a parathyroid adenoma and a neuroendocrine tumor (NET). The patient was diagnosed with MEN1 within a year of symptom onset, highlighting the importance of an early and accurate diagnosis.

DIAGNOSTIC CHALLENGES AND STATEGIES

Diagnosis of MEN1 often involves a combination of clinical, familial, and genetic criteria[17]. Given the rarity of this syndrome and the nonspecific nature of its symptoms, MEN1 can easily be overlooked as a differential diagnoses. In many cases, diagnosis is postponed, and patients often present with advanced complications associated with these tumors, resulting in a worsened prognosis and higher morbidity and mortality rates[3]. MEN1 commonly presents as parathyroid, pancreatic, and pituitary tumors. In this discussion, we have detailed the diagnostic characteristics of these individual tumors.

Parathyroid neoplasms

In the context of MEN1, parathyroid tumors manifest primarily as primary hyperparathyroidism (PHPT), observed in approximately 95% of patients, often as the initial presentation of the disease[18]. This condition highlights the high penetrance of MEN1, with nearly all patients exhibiting clinical or biochemical evidence of tumor development by the age of 50 years[2]. Compared to non-MEN1 PHPT, MEN1-related PHPT has an earlier onset and often involves synchronous or asymmetric involvement of all four parathyroid glands[19].

Clinical characteristics: Although PHPT in patients with MEN1 frequently remains asymptomatic, symptomatic patients may experience complications from hypercalcemia, such as polyuria, constipation, and discomfort, as well as kidney stones and osteitis fibrosa cystica. Studies on MEN1 patients have indicated that females aged 20 to 35 years with the condition experience a significantly higher incidence of osteopenia and osteoporosis compared to age-matched individuals in the general population[20]. It has been reported that MEN1-related PHPT is associated with a more significant decrease in bone mineral density compared to non-MEN1 PHPT, making osteoporosis and osteopenia common in patients with MEN1[21-23]. The reduction in bone mineral density and bone demineralization is particularly noticeable in the lumbar spine, femoral neck, and distal radius of patients with MEN1 compared to those with sporadic PHPT[23]. Diagnosis of PHPT is confirmed by the presence of elevated calcium levels and inappropriately high parathyroid hormone (PTH) levels. The observed hypercalcemia is typically mild, with severe cases or parathyroid carcinoma being rare.

Pathological characteristics: The World Health Organization’s (WHO) classification of parathyroid tumors encompasses several entities including multiglandular parathyroid disease, adenoma, atypical parathyroid tumor, and carcinoma[24]. An adenoma is characterized as a benign tumor that is typically well-circumscribed. In approximately 50% of cases, adjacent normal or atrophic glandular tissue can still be observed and contrasts with the tumor tissue. These tumors consist of chief, oncocytic, transitional, or water-clear cells amongst others. The histological diagnosis of parathyroid carcinoma is confined to parathyroid tumors that concurrently present with any of the following features: (1) Angioinvasion, characterized by the tumor invading through a vessel wall and associated thrombus or intravascular tumor cells admixed with thrombus; (2) Lymphatic invasion; (3) Perineural (intraneural) invasion; (4) Local malignant invasion into adjacent anatomic structures; and (5) Histologically or cytologically documented metastatic disease.

From an immunohistochemical perspective, parathyroid adenomas exhibit diffuse positivity for PTH, transcription factor GATA3, and chromogranin A (CgA). Synaptophysin (Syn) may also be positive. Thyroid follicular cell markers such as thyroid transcription factor 1, thyroglobulin, and monoclonal paired box gene 8 test negative.

Treatment: Surgical excision of the hyperfunctioning parathyroid glands is the treatment of choice for PHPT associated with MEN1. The extent to which the parathyroid gland tissue should be removed is subject to ongoing investigations. Given the fact that all parathyroid glands are affected due to the underlying genetic predisposition, a subtotal parathyroidectomy, which entails the removal of at least three and a half glands, or total parathyroidectomy with autotransplantation of parathyroid tissue is advised[2,25]. The number of cases that need reoperations for persistent or recurrent PHPT range from 2.5% to 9.4%[26-28]. Predisposing factors for reoperations include a patients aged ≥ 70 years, obesity, facility inexperience with PHPT surgical procedures (50 or fewer cases per year), surgeons inexperience, and unclear localization on mass during preoperative scintigraphic examination[27]. Reoperations in patients with MEN1 syndrome have been reported to ranging from 9% to 50%[29]. Selective parathyroid resection of the enlarged glands has recently been discussed as an alternative approach, as asymmetric parathyroid hyperplasia is common[30,31]. With this focused surgical technique, the risk of postoperative permanent hypoparathyroidism is almost completely eliminated. Hence, it is conductive to prevent long-term effects of hypocalcemia, such as cardiac arrhythmias and extrapyramidal abnormalities as well as lifelong calcium and vitamin D supplementation[32,33]. However, the high risk of recurrence associated with this selective procedure is accepted, as patients often only develop a recurrence after several years which then again can be treated using a limited approach[30]. The necessity of reoperation in patients with MEN1 syndrome is primarily dependent on recognizing the presence of this syndrome preoperatively. Genetic tests can thus be used to recognize MEN1 syndrome before surgery and to determine the appropriate surgical approach.

Pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms (PNETs) represent the second most common type of tumor in MEN1 and a significant cause of mortality[34]. These tumors may be functional, producing excess hormones that lead to distinctive clinical syndromes, or non-functional with no significant hormone production.

Clinical characteristics: Functional PNETs often present with specific hormone-related syndromes due to the excessive production of hormones. For instance, insulinomas typically produce hypoglycemia, while gastrinomas can lead to Zollinger-Ellison syndrome, among other manifestations. In contrast, non-functional PNETs usually do not produce active hormones and are often diagnosed at a larger size due to their asymptomatic nature in early stages. These tumors may manifest with symptoms related to space occupation of the mass, which affects surrounding tissues, caused conditions such as gastric outlet obstruction, obstructive jaundice, fatigue, or other nonspecific signs. Additionally, patients might experience symptoms related to metastatic spread, including nausea, intra-abdominal hemorrhage, abdominal discomfort, or a palpable mass[35]. To ensure early diagnosis of PNETs, MEN1 clinical guidelines recommend annual pancreatic imaging using techniques like magnetic endoscopic ultrasonography (EUS), computed tomography, or resonance imaging (MRI)[2]. Diagnostic approaches for non-functional PNETs typically involve a combination of imaging techniques and biochemical tests designed to detect hormone levels that do not cause overt clinical syndromes. A diagnostic approach using both MRI and EUS for non-functional PNETs has been proposed, though there remains some uncertainty regarding the most effective modality[36]. For sporadic non-functioning PNETs, the European NET Society Guidelines suggest EUS guided biopsies, but no specific recommendations are proposed for patients with MEN1[37].

Pathological characteristics: The WHO classifies PNETs based on proliferative markers such as Ki-67 and mitotic count, distinguishing between well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). Well-differentiated NETs are further categorized into grades G1, G2, and G3, with G1 and G2 typically presenting low proliferative activity, and G3 showing higher activity, which is comparable to NECs[38].

Well-differentiated NETs often exhibit distinct morphological features, being circumscribed and possibly presenting as nodular or infiltrative. These tumors are generally organized in trabecular, solid, or glandular patterns, characterized by uniform cells with minimal mitotic figures. In contrast, NECs include small cell NECs (SCNEC) and large cell NEC (LCNEC). SCNEC typically displays fusiform nuclei, finely granular chromatin, scant cytoplasm, and obvious nuclear moulding. In contrast, LCNEC is characterized by rounder nuclei, sometimes with prominent nucleoli, and moderate amounts of cytoplasm. Both forms of NECs are considered high-grade neoplasms due to their aggressive behavior and poor differentiation.

The immunohistochemical profile of PNETs commonly includes markers such as CgA, Syn and CD56, and may also express proteins such as insulinoma-associated protein 1 and somatostatin receptor type 2A. These markers assist in confirming the neuroendocrine origin and specific subtypes of neoplasms.

Genetic mutations associated with well-differentiated NETs frequently involve mutations in MEN1, ATRX, and DAXX genes[39]. Such mutations are predominantly absent in poorly differentiated NECs, indicating a distinct genetic background that contributes to the differing behaviors and treatment responses of these tumors. This distinction underscores the importance of accurate histopathological and molecular profiling in guiding therapeutic decisions for patients with PNETs.

Treatment: The approach to treating PNETs in patients with MEN1 varies based on functionality and stage. Surgical resection is the standard treatment protocol, with medical management or adjuvant therapy for inoperable cases[40-43]. These guidelines also recommend surveillance for small, asymptomatic PNETs < 2 cm in size, and surgical resection (enucleation, pancreatectomy) for localized PNETs. EUS radiofrequency ablation may be considered for patients with mass < 2 cm of localized insulinomas who are deemed unfit for surgery. Location of the tumor will determine whether the patient needs a total pancreatectomy, distal pancreatectomy, pancreaticoduodenectomy, or the Thompson procedure. Patients with advanced disease require a multi-modal approach involving supportive, surgical, interventional, hormonal, and anti-proliferative therapies.

Pituitary NETs

Although less common, pituitary NETs (PitNETs) in MEN1 can profoundly affect patient health through excessive hormone production or mass effects[44]. PitNETs appear a larger size, with a more aggressive behavior, and in some cases, are more resistant to treatment[2,45,46].

Clinical characteristics: Around 40% of MEN1 patients have a pituitary adenoma, with 10% of cases being the initial manifestation of the syndrome. These adenomas are typically diagnosed early, around the age of 35, and occur more frequently in women[47]. Symptoms may include headaches, visual disturbances such as bitemporal hemianopsia, cranial nerve impairment, or seizures resulting from the tumor's mass effect. These tumors may also present with symptoms related to the overproduction of growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), and other pituitary hormones, leading to conditions such as acromegaly, prolactinoma, and Cushing's disease. The most common subtype to present in patients with MEN1 is a prolactinoma. Prolactin levels greater than 200 ng/mL confirm the diagnosis[48]. Diagnosis is often incidental during imaging for unrelated reasons or based on the presentation of endocrinological symptoms.

Pathological characteristics: PitNETs are characterized by a composition of neurohormonal cells arranged in an adenomatous pattern with minimal cellular atypia, surrounded by a dense capillary network.

The classification of pituitary tumors has evolved over recent years due to their complexity and heterogeneity. The WHO classification published in 2004 initially categorized these adenohypophyseal tumors into seven subtypes, based on their pathological immunoreactivity to anterior pituitary hormones: Thyroid stimulating hormone, luteinising hormone, GH, PRL, ACTH[49]. The present WHO classification of PitNETs is based on the identification of pituitary cell lineages, determined by the immunohistochemical expression of anterior pituitary hormones and pituitary-specific transcription factors (Pituitary transcription factor 1, T-box family member TBX19, Steroidogenic factor 1) in the tumor cells[50].

Treatment: Treatment includes pharmacotherapy, especially dopamine agonists for prolactinomas, and surgery for tumors causing significant symptoms or hormone overproduction[51]. For acromegalic patients whose surgery has failed, or whose tumors are unresectable, the first-generation somatostatin analogues octreotide and lanreotide represent the first-line treatment, followed by the second-generation somatostatin analogues pasireotide. The other treatment options include the dopamine agonist cabergoline, the GH receptor antagonist pegvisomant, and in special cases, radiotherapy[52,53].

THERAPEUTIC IMPLICATIONS

The early detection and timely surgical intervention in this case resulted in the successful management of the patient's condition. The patient underwent parathyroidectomy and duodenal bulbectomy, with significant symptomatic improvement postoperatively. This case highlights the importance of a multidisciplinary approach involving endocrinologists, gastroenterologists, surgeons, and pathologists to achieve optimal outcomes in MEN1 management.

FUTURE DIRECTIONS

Future research should focus on refining the diagnostic criteria for MEN1, exploring its underlying genetic and molecular mechanisms, and developing targeted therapies for MEN1-associated tumors. The integration of advanced imaging techniques, molecular diagnostics, and personalized medicine holds promise for enhancing the management of MEN1 and improving patient outcomes.

CONCLUSION

The case report by Yuan et al[13] serves as a compelling reminder of the critical role of early detection and comprehensive diagnostic evaluation in managing complex hereditary syndromes like MEN1. By sharing their clinical insights and diagnostic approaches, the authors provide a valuable resource for clinicians and researchers. Continued efforts in education, research, and clinical practice are essential to improve the diagnosis and treatment of MEN1, ultimately enhancing patient care and outcomes.