Acromegaly Associated with Leukemia: A Case Report
Subgroup: Volume 7, Issue 1, Winter
Date: March 2009
Type: Case Report
Start Page: 46
End Page: 50
- MH Adib Department of Medical Oncology, Kashan University of Medical Sciences, Kashan, I.R. Iran
- A Ebadi Department of Endocrinology, Department of Endocrinology, Kashan University of Medical Sciences, Kashan, I.R. Iran
City, Province: Kashan,
Country: I.R. Iran
Acromegaly is one of the most common clinical presentations of pituitary tu-mors. Some patients with this condi-tion may be affected by other benign or malignant neoplasms. There are a few reports of acromegaly in association with acute leukemias.
Case report: Reported here is a case of acromega-ly associated with Philadelphia positive acute lymphoblastic leukemial. The patient was a 61 year-old man, evaluated for complaints of bleed-ing from pilonidal cyst and weakness. He had typical acromegalic features. Laboratory tests showed he had pancytopernia and elevated IGF-1 levels. Imaging studies revealed he had a pitui-tary macroadenoma. The result of aspiration and biopsy of bone marrow and flowcytometric analysis confirmed the diagnosis of acute lym-phoblastic leukemia, Pre B cell type. Cytogenetic study of lymphoblasts revealed translocation of the 9 and 22 or Philadelphia chromosome.
Conclusion: It is suggested that the proliferative effect of growth hormone, as well as its anti-apoptotic activity related to IGF-1 may result in the increased incidence of neoplastic processes including acute leukemias in this group of pa-tients.
Keywords: Acromegaly; Acute lymphoblastic leukemia; Philadelphia chromosome
Acromegaly, a clinical syndrome caused by increased levels of growth hormones,1 has an incidence of 3-4 per one million people each year, the patients being aged between 40-45 years at time of diagnosis.2,3 The most com-mon cause of acromegaly is increased secre-tion of growth hormone from the pituitary somatotrop cells. Usually there is about a 12-year interval between the appearance of symptoms and diagnosis.4 This kind of pitui-tary adenoma is usually benign, and in 75% of the patients it is a macroadenoma.5 Some of the clinical findings in these patients are enlargement of distal endings, coarse face, large nose, increased dental spaces, joint dis-eases,6 increased bone density,5 cardiovascu-lar disorders including cardiomyopathy,7 heart failure,7,8 pituitary insufficiency,5 voice changes, hirsutism,5 enlarged visceral organs including the prostate,9 and increased inci-dence of some benign lesions, including ute-rine leiomyoma,10 and polyps in colon.11-13 Manifestations of soft tissue overgrowth in-clude macroglossia, deepening of the voice, and paresthesias of the hands due to carpal tunnel syndrome.14 It is also reported that acromegaly results in the increased chance of some cancers, including colon, stomach, eso-phagus, breast, and hematological malignan-cies13,15 with higher mortality than in the normal population. Some studies have shown that increased growth hormone level is asso-ciated with increased chance of leukemia, and lymphoma.16 It is reported that there is a 3.2 fold increase in incidence of malignant tumors in patients with acromegaly.17 The best test for the diagnosis of acromegaly is the measurement of IGF-1 blood level, which differs in various age groups.3 In addition, the measurement of growth hormone, in particu-lar its dynamic measurement, after glucose tolerance test is necessary for the documenta-tion of the disease. Magnetic resonance imag-ing (MRI) and dynamic CT scan demonstrate the lesion in most cases.5 Trans-sphenoidal resection of adenoma is the treatment of choice in patients with acro-megaly. The goal of treatment is to normalize IGF-1 level, and to return growth hormone levels to less than 1 gr/mL after glucose to-lerance test;1,2 in case this cannot be achieved, medical treatment and radiotherapy may also be considered.18 Acute Lymphocytic Leukemia (ALL) is a malignant disorder originating in a single B or T lymphocyte progenitor. The prolifera-tion and accumulation of blast cells in the bone marrow result in the suppression of he-matopoiesis and thereafter anemia, thrombo-cytopenia and neutropenia.19,20 The disease is most common in children, but can occur at any age.20 The relative lack of therapeutic success in adult ALL patients corresponds to a high frequency of cases with unfavorable genetic lesions, such as the BCR-ABL onco-gen resulting from the rearrangement of the chromosomes 9 and 22. BCR-ABL expres-sion is associated with an extremely poor prognosis in ALL patients despite treatment using contemporary protocols for high risk disease.21,23
In February 2006, a 61 year old man re-ferred to Shahid Beheshti University Hospital of Kashan University of Medical Sciences (KAUMS) for bleeding from a pilonidal cyst and pancytopenia; his history showed admis-sion to hospital for chest pain two months be-fore referring. He received two units of blood for his pallor. He also complained of sweat-ing in upper trunk, weakness, easy fatiguabil-ity, and bone pain. He had been diagnosed with diabetes since three years, and was on oral medications. He was smoking 40 ciga-rette packs/yr. He had also had several ad-missions in the past few months for his heart problem, and bleeding. He appeared very sal-low, with pale conjunctivae, and had typical acromegalic features, including prognatism, increased dental spaces, large nose (Fig. 1), broad fingers and toes. He had two skin tags at 6 and 12 o’clock on anus and 5 on neck and upper thoracic region. His liver span was 13 cm, but no splenomegaly, petechia, purpu-ra, or ecchymosis were detected. Lungs were clear. A systolic murmur grade 2/6 was audi-ble. Lab data on admission included: WBC: 2700 μl; Hb:9.6 g/dL; plt:16000 μL; FBS:417 mg/dL. His IGF-1 was 376 ng/mL normal values 78-258 for 50-70 year olds. His ran-dom growth hormone level was 75 ng/mL which two hours after glucose tolerance test was 20 ng/mL. A brain CT scan revealed a huge pituitary macroadenoma (Fig.2)
Fig.1. Photograph of the patient shows acro-megalic features such as prognatism, increased dental spaces and large nose
Fig. 2. Computerized tomography (CT) of brain shows pituitary macroadenoma
Fig. 3. Photograph of bone marrow aspirate shows lymphoblastic leukemia in which lym-phoblasts have fine chromatin, nuclear inden-tation and basophilic cytoplasm. (geimsa, magnification×100)
Analysis of bone marrow aspiration and bone marrow biopsy specimens showed dif-fuse infiltration of bone marrow with imma-ture cells with heterogenity in cell size and shape (Fig. 3) with fine chromatin, nuclear indentation and basophilic cytoplasm, a pic-ture more compatible with L2 subtype of acute lymphoblastic leukemia. In flowcyto-metric analysis, these cells had CD10 and CD19 antigens on the cell surfaces; hence re-sults of aspiration and biopsy of bone marrow and flowcytometric analysis confirmed the diagnosis of Acute Lymphoblastic Leukemia (ALL) pre B cell type. Cytogenetic study of bone marrow aspiration revealed the translo-cation of 9 and 22 or PhiladelPhia chromo-some (Fig. 4). After two courses of induction chemotherapy the patient attained complete remission; he however refused surgical treatment for his pituitary adenoma, and was hence treated with octreotide, and left the hospital in a good condition.
Fig. 4. Cytogenetic study of some marrow cells shows 46 chromosomes with translocation of chromosomes 9 and 22 compatible with phila-delphia chromosome
Although the role of growth hormone is well documented in some benign, as well as malignant processes such as uterine tumors, adenomatous polyps in colon, cancers of co-lon, stomach, esophagus, and breast, there is limited data available regarding this effect in hematological neoplasms. Cohen reported uterine leiomyoma in 81 per cent of patients with acromegaly.10 Velmhogen reported a five fold increase in adenomatous polyps of colon in comparison to normal populations.15 This premalignant lesion is seen in 30 per cent of acromegalic patients. It is reported that the stimulating effect of growth hormone results in the increased incidence of colonic adenocarcinomas.11-13 One study from Hong Kong reported two cases of leukemia in 106 acromegalic patients in a 15-year follow up period; one of the patients had ALL while the other had Acute Myeloblastic Leukemia (AML), suggesting a synergistic effect for growth hormone in the accurrence of leuke-mia.24 Popovic also has reported that in com-parison with nonfunctional adenomas and prolactinoma, acromegalic patients are more involved in such diseases as Hodgkin lym-phoma, ALL, AML, and thyroid, ovarian, breast, uterus, skin, pancreas, bladder, kid-ney, and colorectal cancers; he also reported three patients with two cancers, who had 3.39 times more risk of malignant tumors when compared with the normal population.25 Frandkin studied the effects of growth hor-mone in those treated for its deficiency and found that there is a 1.8% increased inci-dence of leukemia in these patients.26 The in-itiation and progression of ALL is driven by successive mutations that alter cellular func-tions, including an enhanced ability of self renewal, a subversion of control of normal proliferation, a block in differentiation and an increased resistance to death signals or apop-tosis.16,19 Many risk factors such as environ-mental factors, acquired genetic changes, ge-netic syndromes and alterations in host pharmacogenetics are known to be implicated in the induction of ALL in some patients but the relation of other risk factors with ALL needs to be explored.20 It seems that growth hormone with its proliferative and anti-apoptotic effects related to IGF-1 results in the increased incidence of malignant and non malignant diseases.17 These effects, as well as cardiovascular consequences of acromegaly, hence mandate surgical treatment of growth hormone secreting pituitary adenomas fol-lowed by appropriate medical treatment, and if needed radiotherapy. Also these patients should be thoroughly evaluated for occult malignancies. On the basis of this report and a review of literature, acromegalic patients have an in-creased incidence of certain solid tumors and hematological malignancies. Therefore in ad-dition to appropriate management of pituitary tumor, these patients must have regular fol-low ups and further evaluation for occult ma-lignancies.
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- Bengtsson BA, Edén S, Ernest I, Odén A, Sjögren B. Epidemiology and long-term survival in acro-megaly. Acta Med Scand 1988; 223: 327-35.
- Altstadt TJ, Azzarelli B, Bevering C, Edmondson J, Nelson PB. Acromegaly caused by a growth hormone-releasing hormone-secreting carcinoid tumor: case report. Neurosurgery 2002; 50: 1356-9.
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- Scillitani A, Chiodini I, Carnevale V, Giannatempo GM, Frusciante V, Villella M, et al. Skeletal in-volvement in female acromegalic subjects: The ef-fects of growth hormone excess in amenorrheal and menstruating patients. J Bone Miner Res 1997; 12: 1729-36.
- Minniti G, Moroni C, Jaffrain-Rea ML, Esposito V, Santoro A, Affricano C, et al. Marked im-provement in cardiovascular function after success-ful transsphenoidal surgery in acromegalic patients. Clin Endocrinol (Oxf) 2001; 55: 307-13.
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- Colao A, Marzullo P, Ferone D, Spiezia S, Cer-bone G, Marinò V, et al. Prostatic hyperplasia: An unknown feature of acromegaly. J Clin Endocrinol Metab 1998; 83: 775-9.
- Cohen O, Schindel B, Homburg R. Uterine lei-omyomata--a feature of acromegaly. Hum Reprod 1998; 13: 1945-6.
- Renehan AG, Shalet SM. Acromegaly and colorec-tal cancer: risk assessment should be based on population-based studies. J Clin Endocrinol Metab 2002; 87: 1909.
- Terzolo M, Reimondo G, Gasperi M, Cozzi R, Pi-vonello R, Vitale G, et al. Colonoscopic screening and follow-up in patients with acromegaly: a mul-ticenter study in Italy. J Clin Endocrinol Metab 2005; 90: 84-90.
- Ron E, Gridley G, Hrubec Z, Page W, Arora S, Fraumeni JF Jr. Acromegaly and gastrointestinal cancer. Cancer 1991; 68: 1673-7.
- Jenkins PJ, Sohaib SA, Akker S, Phillips RR, Spil-lane K, Wass JA, et al. The pathology of median neuropathy in acromegaly. Ann Intern Med 2000; 133: 197-201.
- Delhougne B, Deneux C, Abs R, Chanson P, Fie-rens H, Laurent-Puig P, et al. The prevalence of co-lonic polyps in acromegaly: A colonoscopic and pathological study in 103 patients. J Clin Endocri-nol Metab 1995; 80: 3223-6.
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- Biermasz NR, Pereira AM, Smit JW, Romijn JA, Roelfsema F. Morbidity after long-term remission for acromegaly: persisting joint-related complaints cause reduced quality of life. J Clin Endocrinol Metab 2005; 90: 2731-9.
- Gilliland DG, Tallman MS. Focus on acute leuke-mias. Cancer Cell 2002; 1: 417-20.
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- Kebriaei p, larson RA. progress and challenges in the therapy of adult acute lymphoblastic leukemia. Curr Opin Hematol 2003; 10: 284-9.
- Fletcher JA, Lynch EA, Kimball VM, Donnelly M, Tantravahi R, Sallan SE. Translocation (9;22) is associated with extremely poor prognosis in inten-sively treated children with acute lymphoblastic leukemia. Blood 1991; 77: 435-9.
- Au WY, Chow WS, Lam KS, Ko GT, Cockram CS, Kwong YL. Acute leukaemia in acromegaly patients. Br J Haematol 2000; 110: 871-3
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