E.A. Ashok Kumar, M. Ravi Teja Raidu. A rare case of invasive pituitary macroadenoma with hemorrhage in MEN 1 syndrome - A case report. IAIM, 2021; 8(4): 106-117.

Case Report

A rare case of invasive pituitary macroadenoma with hemorrhage in MEN 1 syndrome - A case report

E.A. Ashok Kumar1*, M. Ravi Teja Raidu2

1Professor, 2Assistant Professor Department of General Medicine, Malla Reddy Institute of Medical Sciences, Hyderabad, India *Corresponding author email: [email protected]

International Archives of Integrated Medicine, Vol. 8, Issue 4, April, 2021. Available online at http://iaimjournal.com/ ISSN: 2394-0026 (P) ISSN: 2394-0034 (O) Received on: 25-03-2021 Accepted on: 05-04-2021 Source of support: Nil Conflict of interest: None declared. How to cite this article: E.A. Ashok Kumar, M. Ravi Teja Raidu. A rare case of invasive pituitary macroadenoma with hemorrhage in MEN 1 syndrome - A case report. IAIM, 2021; 8(4): 106-117.

Abstract Multiple Endocrine Neoplasia (MEN) disorders are very rare. These are hereditary diseases which develop into a number of endocrine glands and result in tumor formation. The MENs are run in families because they are the exact consequence of genetic mutations and their symptoms are completely dissimilar dependent on the involving glands. Multiple endocrine neoplasia (MEN) is characterized by the occurrence of tumors involving two or more endocrine glands in a single patient. Four major forms of MEN, which are autosomal dominant disorders, are recognized and referred to as: MEN type 1 (MEN1), due to menin mutations; MEN2 (previously MEN2A) due to mutations of a tyrosine kinase receptor encoded by the rearranged during transfection (RET) protoncogene; MEN3 (previously MEN2B) due to RET mutations; and MEN4 due to cyclin-dependent kinase inhibitor (CDNK1B) mutations. Each MEN type is associated with the occurrence of specific tumors. MEN1 is characterized by the occurrence of parathyroid, pancreatic islet and anterior pituitary tumors. In this case report we present a patient who developed an Invasive Pituitary Macroadenoma with Hemorrhage in MEN 1 Syndrome.

Key words MEN 1 Syndrome, Pituatory macroadenoma, Hemorrhage.

Introduction single patient [1-4]. Four major forms of MEN, Multiple Endocrine Neoplasia (MEN) is which are autosomal dominant disorders, are characterized by the presence of tumors recognized and referred to as: involving two or more endocrine glands in a

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E.A. Ashok Kumar, M. Ravi Teja Raidu. A rare case of invasive pituitary macroadenoma with hemorrhage in MEN 1 syndrome - A case report. IAIM, 2021; 8(4): 106-117.

MEN type 1 (MEN1) due to menin mutations; penetrance such that clinical and biochemical MEN1 is characterized by the occurrence of manifestations of the disorder will have parathyroid, pancreatic islet and anterior pituitary developed in 80% and greater than 98% of tumors. MEN1 patients, respectively, by the fifth decade MEN2 (previously MEN2A) due to mutations [3, 6, 7]. of a tyrosine kinase receptor encoded by the rearranged during transfection (RET) Genetics protoncogene; MEN2 is characterized by the MEN1 is an autosomal dominant disorder that is occurrence of medullary thyroid carcinoma due to mutations in the tumor suppressor gene (MTC) in association with MEN1, which encodes a 610-amino acid protein, and parathyroid tumors. menin. In this way, the finding of MEN1 in a MEN3 (previously MEN2B) due to RET patient has important implications for family mutations; MEN3 is characterized by the members because first-degree relatives have a occurrence of MTC and pheochromocytoma in 50% risk of developing the disease and can often association with a marfanoid habitus, mucosal be identified by MEN1 mutational analysis. neuromas, medullated corneal fibers and MEN1 is characterized by the occurrence of intestinal autonomic ganglion dysfunction, parathyroid, pancreatic islet and anterior pituitary leading to megacolon. tumors. Some patients may also develop MEN4 due to cyclin-dependent kinase inhibitor carcinoid tumors, adrenocortical tumors, (CDNK1B) mutations. Each MEN type is meningiomas, facial angiofibromas, associated with the occurrence of specific collagenomas and lipomas. Patients with MEN1 tumors. MEN4, which is also referred to as have a decreased life expectancy, and the MENX, is characterized by the occurrence of outcomes of current treatments, which are parathyroid and anterior pituitary tumors in generally similar to those for the respective possible association with tumors of the adrenals, tumors occurring in non-MEN1 patients, are not kidneys, and reproductive organs [2]. as successful because of multiple tumors, which may be larger, more aggressive, and resistant to The sellar region is a site of various types of treatment, and the concurrence of metastases. tumors, are the most common, The prognosis for MEN1 patients might be arise from epithelial pituitary cells and account improved by presymptomatic tumor detection for 10-15% of intra cranial tumors, tumor >10 and undertaking treatment specific for MEN1 mm are macro adenoma and those < 10 mm are tumors. Thus, it is recommended that MEN1 micro adenomas, most pituitary adenomas are patients and their families should be cared for by micro adenomas. Most of the pituitary adenomas multidisciplinary teams comprising relevant are diagnosed accidentally, as they don’t have specialists with experience in the diagnosis and any physical symptoms and signs [5]. treatment of patients with endocrine tumors [8].

Criteria for diagnosis MEN type 1 Epidemiology There is a lack of evidence from the clinical trials The incidence of MEN1 as estimated from to evaluate methods of diagnosis and screening random postmortem studies is 0.25%, and is 1– for the tumors or treatment of MEN1 [8]. A 18% in patients with primary diagnosis of MEN1 may be established in an hyperparathyroidism, 16-38% in patients with individual by one of the three criteria (Figure - , and less than 3% in patients with 1) [6]: on the basis of the occurrence of two or pituitary tumors [3, 6, 7]. The disorder affects all more primary MEN1- associated endocrine age groups, with a reported age range of 5 to 81 tumors (i.e. , yr [3, 6, 7]. MEN1 is inherited as an autosomal enteropancreatic tumor, and pituitary adenoma) dominant disorder with a high degree of (Figure - 1) ) [6, 9, 10]. The occurrence of one

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E.A. Ashok Kumar, M. Ravi Teja Raidu. A rare case of invasive pituitary macroadenoma with hemorrhage in MEN 1 syndrome - A case report. IAIM, 2021; 8(4): 106-117.

of the MEN1-associated tumors in a first-degree asymptomatic and has not yet developed serum relative of a patient with a clinical diagnosis of biochemical or radiological abnormalities MEN; and identification of a germline MEN1 indicative of tumor development (Figure - 1). mutation in an individual, who may be

Figure – 1: Basis for MEN1 diagnosis [6].

CLASSIFICATION  grade 2 = tumor extends to space between the Hardy’s classification [20, 21] intercarotid line and the lateral tangent Upper panel shows the classification of sphenoid  grade 3 = tumor extends lateral to the lateral bone invasion tangent Grade 0: intact with normal contour; o 3A = above the intracavernous ICA into Grade I: intact with bulging floor; the superior cavernous sinus compartment Grade II: intact, with enlarged fossa; o 3B = below the intracavernous ICA into Grade III: localized sellar destruction; the inferior cavernous sinus compartment Grade IV: diffuse destruction.  grade 4 = complete encasement of Only grade III and IV tumors are considered intracavernous ICA invasive. Lower panel depicts a classification of the Figure – 2: Knosp classification staging [22]. suprasellar extension of an adenoma which may be symmetrical or asymmetrical Grade A: suprasellar cistern only; Grade B: recess of the third ventricle; Grade C: whole anterior third ventricle; Grade D: intracranial extradural; Grade E: extracranial extradural (cavernous sinus) [20, 21].

Knosp classification staging (Figure – 2) [22] These lines are used to define 4 grades of tumor invasion:  grade 0 = medial to medial tangent Treatment  grade 1 = tumor extends to space between the The treatment for each type of MEN1-associated medial tangent and the intercarotid line endocrine tumor is similar to the respective tumors occurring in non-MEN1 patients.

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E.A. Ashok Kumar, M. Ravi Teja Raidu. A rare case of invasive pituitary macroadenoma with hemorrhage in MEN 1 syndrome - A case report. IAIM, 2021; 8(4): 106-117.

However, the treatment outcomes of MEN1- pricking type and was associated with associated tumors are not as successful as those photophobia and phonophobia. She also had one in non-MEN1 patients, for several reasons. First, episode of projectile vomiting, contained food MEN1-associated tumors, with the exception of particles and was blood tinged. She had pituitary NET, are usually multiple, thereby associated symptoms like giddiness, sweating, making it difficult to achieve a successful generalized weakness and body pains, tingling surgical cure. For example, MEN1 patients often sensation over both the upper and lower limbs develop multiple submucosal duodenal were present. No history of fever, loss of gastrinomas, thereby reducing surgical cure rates consciousness, involuntary movements, loss of compared with similar sporadic solitary tumors, appetite, pain abdomen, loose stools .Patient such that only approximately 15% of MEN1 developed blurring of vision and pain on eye patients, compared with 45% of non-MEN1 movements the next day. Patient is a K/C/O patients, are free of disease immediately after Diabetes Mellitus since 2 years and on surgery, and at 5 yr this decreased to glyciphage. approximately 5% in MEN1 patients, compared with 40% in non-MEN1 patients [6, 11-14]. Past history: Patient had a history of head injury MEN1 patients also develop multiple parathyroid 9 years ago, after which she had headache on and tumors, and subtotal parathyroidectomy has off. Underwent surgery for Renal Calculi 9 years resulted in persistent or recurrent hypercalcemia ago. No history of HTN, thyroid disorders or within 10 yr in 20 – 60% of MEN1 patients, as epilepsy. No significant family history. opposed to 4% in non-MEN1 patients [6, 15, 16]. Menstrual history: menorrhagia since 1 year. Secondly, occult metastatic disease is more prevalent in MEN1 patients with NET than in On investigation - Hb-10 g%, RBC count 7.2 patients with sporadic endocrine tumors. For mill/cumm, WBC count 8600 cells/cumm with example, metastases are present in up to 50% of Neutrophils - 72%, Lymphocytes - 24%, patients with MEN1-associated , Eosinophils - 2%, Basophils - 0%, Monocytes - whereas less than 10% of non-MEN1 2%, Platelet count – 2.4 lakhs/cu mm. ESR 1st hr insulinomas metastasize. Thirdly, MEN1- - 20 mm, Blood Urea 19 mg%, Serum associated tumors may be larger, aggressive, and Creatinine - 0.7 mg, Complete Urine resistant to treatment. For example, 85% of Examination (CUE) – normal, Random Blood anterior pituitary tumors in MEN1 patients, as Sugar of 384mg/dl, Serum Electrolytes: Na – opposed to 64% in non-MEN1 patients, are 139 m mol/L, K – 4.3 m mol/L, CL – 105 m macroadenomas at the time of diagnosis; 30% of mol/L. LFT – Normal, Fasting Lipid Profile- anterior pituitary tumors in MEN1 patients have WNL, ECG-Sinus Tachycardia, Thyroid profile - invaded surrounding tissue (Hardy classification T3-1.12 ng/ml, T4-13.41 micro gm/dl, TSH-2.36 grades III and IV), compared with 10% in micro IU/ml, Anti TPO antibodies-0.44 IU/ml (N nonMEN1 patients; and more than 45% of = < 4.11), Anti Tg Ab – 3.08 IU/ml(N = < 5.61), anterior pituitary NET in MEN1 patients had anti-ds DNA – 15.6 (negative). USG thyroid persistent hormonal oversecretion after showed well defined echoic lesion with few appropriate medical, surgical, and radiotherapy cystic areas in right lobe of thyroid with minimal treatment, compared with between 10 and 40% peripheral and internal vascularity, to rule out in non-MEN1 patients [17-19]. parathyroid lesion. FNAC of thyroid gland - Moderate cellularity comprised of monomorphus Case report round and oval cells predomnantly arranged in A 38 year old female came to the hospital, with monolayered sheets with occsionally papillar complaints of sudden onset of right sided fragments. There is no evidence of intranuclear headache of one day duration, which was inclusions or nuclear grooving. Very scant

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E.A. Ashok Kumar, M. Ravi Teja Raidu. A rare case of invasive pituitary macroadenoma with hemorrhage in MEN 1 syndrome - A case report. IAIM, 2021; 8(4): 106-117. colloid with occasional cyst macrophages noted. revealed lt. ovarian cyst and hepatosplenomegaly Impression - Parathyroid . with fatty changes in the liver. CT scan brain (Figure - 3) showed: bulky pituitary gland with Serum cortisol (between 7-9 AM) – 4.29 ug/dl heterogenous alteration and expansion of sella (ref.4.30 – 22.4) , growth hormone 2.10ng/ml (up and extension into cavernous sinus. Pituitary to 8 ng/ml), FSH – 3.75 mIU ( follicular phase - Macroadenoma. Also showed sclerosis of 2.5 to 10.2 mIU /ml, mid cycle phase – 3.4 to Cranial vault with widening of diploeic space. 33.4 mIU /ml, luteal phase – 1.5 to 9.1 mIU /ml, MRI brain (Figure - 4) revealed heterogenously post-menopausal – 23.0 to 116.3 mIU /ml ), LH enhancing subtle T1 hyperintense mass lesion – 2.02 IU/L, Serum prolactin - 7.38 ng/ml (Ref. involving sellar and suprasellar region measuring N = 2.8 to 29.2), Serum Calcium - 11.8 mg/dl (N 15x23x22mm (pituitary gland and infundibulum) = 8.6 to 10.2), Serum PTH levels - 377 pg/ml which is suggestive of Pituitary Macroadenoma (N= 15 to 68 pg/ml). Ultrasound abdomen with hemorrhage.

Figure – 3: CT SCAN Axial Sections – showed bulky pituitary gland with heterogenous alteration and expansion of sella and extension into cavernous sinus. Pituitary Macroadenoma. Also showed sclerosis of Cranial vault with widening of diploeic space.

Figure - 4A: T2 FLAIR AXIAL.

Figure – 4B: T2 SAGITTAL.

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E.A. Ashok Kumar, M. Ravi Teja Raidu. A rare case of invasive pituitary macroadenoma with hemorrhage in MEN 1 syndrome - A case report. IAIM, 2021; 8(4): 106-117.

Figure – 4C: T2 AXIAL.

Figure – 4D: DWI.

Figure – 4E: T1 POST CONTRAST AXIAL.

Figure – 4F: T1 POST CONTRAST SAGITTAL & CORONAL.

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E.A. Ashok Kumar, M. Ravi Teja Raidu. A rare case of invasive pituitary macroadenoma with hemorrhage in MEN 1 syndrome - A case report. IAIM, 2021; 8(4): 106-117.

Figure – 4G: T2 SAGITTAL.

Figure – 4H: T2 FLAIR SAGITTAL.

Figure – 4I: T2 CORONAL &T2 FLAIR CORONAL.

Figure - 4(A,B,C,D,E,F,G,H,I): MRI revealed heterogenously enhancing subtle T1 hyperintense mass lesion involving sellar and suprasellar region measuring 15x23x22 mm (pituitary gland and infundibulum) which is suggestive of Pituitary Macroadenoma with hemorrhage.

A diagnosis of Invasive Pituitary After which patient was referred to neurosurgery Macroadenoma with Hemorrhage in MEN 1 centre Syndrome GRADE III - E (according to Hardy’s Staging) and GRADE III (according to Discussion Knosp’s Classification Staging ) and Renal A diagnosis of Invasive Pituitary Macroadenoma Calcular Disease P.O. Status, was made. Patient with Hemorrhage in MEN 1 Syndrome GRADE also had Parathyroid neoplasm apart from III - E (according to Hardy’s Staging) and Pituitary macroadenoma. GRADE III (according to Knosp’s Classification Staging) and Renal Calcular Disease P.O. Status, Treatment given was made. Patient also had Parathyroid neoplasm 1. Tab. Nimodipine 30 mg 2 tid apart from Pituitary macroadenoma. MEN 1 2. Tab. Glyciphage 500 mg 1 tid Syndrome itself is very rare, and hemorrhage in

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E.A. Ashok Kumar, M. Ravi Teja Raidu. A rare case of invasive pituitary macroadenoma with hemorrhage in MEN 1 syndrome - A case report. IAIM, 2021; 8(4): 106-117. the Pituitary Macroadenoma is still much more not be any clear genotype-phenotype correlation rarer. [17]. Fewer than 3% of patients with anterior pituitary tumors will have MEN1 [26]. Clinical The treatment for each type of MEN1-associated manifestations of these tumors in patients with endocrine tumor is generally similar to that for MEN1 are similar to those in patients with the respective tumors occurring in non-MEN1 sporadic pituitary tumors without MEN1 and patients. However, the treatment outcomes of depend on the hormone secreted and the size of MEN1-associated tumors are not as successful as the pituitary tumor. Thus, patients may have those in non-MEN1 patients, for several reasons. symptoms of hyperprolactinemia (e.g. First, MEN1-associated tumors, with the amenorrhea, infertility, and galactorrhea in exception of pituitary NET, are usually multiple, women, and impotence and infertility in men) or thereby making it difficult to achieve a have or Cushing’s disease. In successful surgical cure. addition, enlarging pituitary tumors may compress adjacent structures such as the optic Pituitary tumors chiasma or normal pituitary tissue and may cause Clinical manifestations and diagnosis visual disturbances, and/or hypopituitarism. In a The incidence of pituitary tumors in patients with MEN1 mutation carrier, who would be MEN1 varies from 15 to 50% in different series considered to be at high risk of developing [17, 18, 23, 24]. These occur from 5 yr of age to tumors, periodic biochemical monitoring should the ninth decade. MEN1 pituitary adenomas include measurement of serum prolactin and occur frequently in women, and significantly IGF-I levels, as well as MRI of the pituitary. In more of these were macroadenomas, i.e. diameter patients with abnormal results, hypothalamic- greater than 1 cm [18]. About one third of these pituitary testing should characterize further the pituitary tumors showed invasive features such nature of the pituitary lesion and its effects on the as infiltration of tumor cells through surrounding secretion of other pituitary hormones. normal juxtatumoral pituitary tissue on histology. Despite the apparent larger size, more aggressive Treatment behavior and reduced response to therapy, no Treatment of pituitary tumors in patients with increased prevalence of pituitary carcinoma is MEN1 consists of the use of therapies similar to observed in MEN1. Approximately 60% of those in patients without MEN1 and consists of MEN1-associated pituitary tumors secrete appropriate medical therapy (e.g. bromocriptine prolactin, 25% secrete GH, 5% secrete ACTH, or cabergoline for ; or octreotide or and the remainder appear to be non-functioning, lanreotide for somatotrophinoma) or selective with some secreting glycoprotein subunits [17, transsphenoidal adenomectomy if feasible, with 24], although the occurrence of non-functioning radiotherapy reserved for residual unresectable adenomas has been reported [25]. However, tumor tissue. However, pituitary tumors in pituitary tumors derived fromMEN1 patients MEN1 patients are more aggressive and less may exhibit immunoreactivity to several responsive to medical or surgical treatments [17, hormones, and particularly in the higher 18, 25, 27]. Thus, treatment in MEN1 patients occurrence of somatolactotrophinomas [17]. with hormonally secreting pituitary adenomas Infact, plurihormonal expression is more was significantly less effective in restoring the frequently observed in MEN1-associated hypersecretion of hormones to normal (MEN1 pituitary tumors compared with non-MEN1 vs. non-MEN1 patients) [18]. Furthermore, a pituitary tumors [17, 18]. Pituitary tumors, which separate analysis of the 85 in are usually prolactinomas, may be the first MEN1 patients revealed that treatment was manifestation of MEN1 in 15% of patients, and successful in normalizing plasma prolactin somatotrophinomas occur more often in patients concentrations in only 37 (44%) patients. It is older than 40 yr [3, 18, 23], although there may likely that surgery will be required more

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E.A. Ashok Kumar, M. Ravi Teja Raidu. A rare case of invasive pituitary macroadenoma with hemorrhage in MEN 1 syndrome - A case report. IAIM, 2021; 8(4): 106-117. frequently in the treatment of MEN1-associated parathyroidectomy (i.e. removal of 3.5 glands) than in non-MEN1 pituitary adenomas. has resulted in persistent or recurrent hypercalcemia within 10 to 12 yr after surgery in Parathyroid tumors 40 to 60% of patients, and in hypocalcemia Clinical manifestations and diagnosis requiring long-term therapy with vitamin D or its Primary hyperparathyroidism is the most active metabolite calcitriol in 10 to 30% of common feature of MEN1 and occurs in patients with MEN1 [15, 16, 32, 33]. These approximately 90% of all patients with MEN1 recurrence rates are markedly higher than those [3, 6]. Patients may have asymptomatic observed after parathyroidectomy in patients who hypercalcemia, nephrolithiasis, osteitis fibrosa do not have MEN1, in whom recurrent cystica, vague symptoms associated with hypercalcemia occurs in 4 to 16% and hypercalcemia (e.g. polyuria, polydipsia, hypocalcemia in 1 to 8% of patients. For total constipation, or malaise), or occasionally peptic parathyroidectomy with autotransplantation, both ulcers. Biochemical investigations reveal fresh and cryopreserved parathyroid tissue has hypercalcemia, in association with increased been used. To improve the outcome of circulating PTH concentrations. The parathyroid autotransplantation, one study has hypercalcemia is usually mild, and severe reported that the use of less tissue (e.g. hypercalcemia resulting in crisis or parathyroid approximately 10 fresh parathyroid pieces 1 cancers is rare. Additional differences in the mm3 in size) helps to reduce both the recurrence primary hyperparathyroidism associated with of hypercalcemia and the hypoparathyroidism MEN1, compared with features of the disorder in rates [34]. Subtotal parathyroidectomy is those patients without MEN1, include earlier age suggested as the initial treatment of primary at onset (20 to 25 yr vs. 55 yr), greater reduction hyperparathyroidism in MEN1, but total in bone mineral density [28], and an equal parathyroidectomy with autotransplantation may male/female ratio (1:1 vs. 1:3) [3, 6, 29]. also be considered in some cases. Total Preoperative imaging (e.g. neck ultrasound with parathyroidectomy may be reserved for those Tc99msestamibi parathyroid scintigraphy) is of with extensive disease either at first or at repeat limited benefit because all parathyroid glands surgery. Persistent hypocalcemia is treated with may be affected, and neck exploration is required oral calcitriol (1,25- dihydroxyvitamin D), irrespective of preoperative localization studies. although management of hypoparathyroidism can be challenging in some patients, even with Treatment the use of vitamin D and calcium replacement. Surgical removal of the abnormally overactive parathyroid glands in patients with MEN1 is the Conclusion definitive treatment, but it is controversial A diagnosis of Invasive Pituitary Macroadenoma whether to perform subtotal (3.5 glands) or total with Hemorrhage in MEN 1 Syndrome GRADE parathyroidectomy and whether surgery should III - E (according to Hardy’s Staging) and be performed at an early or late stage of the GRADE III (according to Knosp’s Classification disease. Open bilateral neck exploration is Staging) and Renal Calcular Disease P.O. Status, recommended, as opposed to minimally invasive was made. Patient also had Parathyroid neoplasm parathyroidectomy, because all four parathyroid apart from Pituitary macroadenoma. MEN 1 glands are usually affected with multiple Syndrome itself is very rare, and hemorrhage in adenomas or hyperplasia, although this the Pituitary Macroadenoma is still much more histological distinction may be difficult; rarer. is rarely found in patients withMEN1, and to date only three patients with There has been technological advances in the germline MEN1 mutations have been reported to diagnosis of MEN1, which include radiological have parathyroid carcinoma [30, 31]. Subtotal

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