|Year : 2019 | Volume
| Issue : 3 | Page : 106-109
Two nights in one day: A case report of paraganglioma in sickle cell disease and a review of the literature
Okeoghene G Egigba1, Clement Odigie Osime1, Victor Ekanem2, Paul Jibril3
1 Department of Surgery, University of Benin Teaching Hospital, Benin City, Edo State, Nigeria
2 Department of Pathology, University of Benin Teaching Hospital, Benin City, Edo State, Nigeria
3 Department of Pathology, National Hospital, Abuja, Nigeria
|Date of Submission||20-May-2019|
|Date of Acceptance||06-Nov-2019|
|Date of Web Publication||6-Jan-2020|
Clement Odigie Osime
Department of Surgery, University of Benin Teaching Hospital, PMB 1111, Ugbowo, Benin City, Edo State
Source of Support: None, Conflict of Interest: None
Background: Sickle cell disease (SCD) is a chronic lifelong disease seen typically in Sub-Saharan Africans, the Mediterranean region and parts of Asia. The condition may be associated with other clinical entities.
Aim of Presentation: We present a case of malignant variant of paraganglioma in a 34-year-old SCD patient to highlight the fact that some very rare clinical entities may be found in this category of patients.
Case Report: Miss B.O. was a 34-year-old SCD patient who presented with features of an intra-abdominal mass. Incisional biopsy done from a mass arising from the left adrenal gland confirmed a malignant variant of paraganglioma. Post-exploratory laparotomy, the patient's clinical state deteriorated and she died 25 days after surgery.
Conclusion: Malignant variant of a paraganglioma, a very rare clinical condition, may be found in SCD patients.
Keywords: Malignant paraganglioma, rare condition, sickle cell disease
|How to cite this article:|
Egigba OG, Osime CO, Ekanem V, Jibril P. Two nights in one day: A case report of paraganglioma in sickle cell disease and a review of the literature. Port Harcourt Med J 2019;13:106-9
|How to cite this URL:|
Egigba OG, Osime CO, Ekanem V, Jibril P. Two nights in one day: A case report of paraganglioma in sickle cell disease and a review of the literature. Port Harcourt Med J [serial online] 2019 [cited 2020 Aug 9];13:106-9. Available from: http://www.phmj.org/text.asp?2019/13/3/106/275077
| Introduction|| |
Sickle cell disease (SCD) is a chronic lifelong disease seen mostly in Sub-Saharan Africans, the Mediterranean region and parts of Asia. It is due to a mutation in the gene coding for the beta chain of haemoglobin (Hb)., Affected people have the abnormal HbS, which causes the red blood cells to be malformed and sickle shaped., It is among the most common genetic disorders seen in Africa, the United Kingdom and in many other countries., Several reports indicate an increase in the risk of malignancy in SCD. This increased risk involves both the more common haematological cancers as well as solid tumours.,,,,,,,,,
There is, however, a dearth of data on the range of cancers involved. Solid tumours are rare and include colon cancer (relative risk [RR] 2.8, 1.2–5.5), non-melanoma skin cancer (RR 4.4, 1.3–12.2), kidney cancer (RR 5.4, 2.3–11.5) and thyroid cancer (RR 5.1, 1.3–15.4).
Paragangliomas are an extremely rare type of solid tumours derived from cells of the extra-adrenal paraganglia which are rudiments of the autonomic nervous system. They have an incidence of 2–8 cases per million persons per year and a prevalence of 1:6500–1:2500. Although mostly benign, 10%–15% will undergo malignant change.,, Phaeochromocytomas are the most common subtype.
They are highly heritable when compared to most other cancers with 40% showing germline mutations in one or more of up to thirty possibly causative genes., Up to a quarter of these develop under conditions of the hereditary tumour syndrome, mostly the Von Hippel–Lindau gene.
Paraganglioma in an SCD patient, therefore, represents the coexistence of two distinct pathologies of with strong genetic basis.
This case report intends to draw attention to the possibility of a genetic link between the two and to provoke further research into the possibility that there are linked genetic or epigenetic mechanisms as explanation for this finding.
| Case Report|| |
A 34-year-old female applicant, known SCD (HbSS) patient for more than 22 years presented to our facility on 11 February 2018 with a 1-year history of generalised abdominal swelling. The swelling was of insidious onset, progressive but has been much more rapid over the last 2 months.
There is associated moderate, dull-aching, constant and generalised pain. There was also occasional constipation, anorexia and weight loss. These symptoms were very similar to the features of SCD, and she has had for almost two decades.
She has about three to four sickle cell crises yearly, latest crisis was 7 weeks before and treatment usually included rehydration, blood transfusion, antibiotics, analgesics and antimalarials. She is not aware of family history of cancer, no prior irradiations and has never been on hydroxyurea.
On examination, she was chronically ill-looking, warm to touch, dehydrated, pale, icteric with sickle cell habitus.
Abdomen was distended, had generalised scarifications, moved with respiration and was soft.
There was a mass in the left half of the abdomen and entire pelvis and measured 25 cm by 14 cm. It was firm, tender, nodular and fixed. There was guarding, rebound tenderness, ascites but no hepatosplenomegaly. Bowel sounds were absent.
Rectal examination revealed a bulging, firm and tender anterior rectal wall. Examining finger was stained with melaena.
Her pulse was 106/min, blood pressure was 100/60 mmHg and heart sounds 1 and 11 were present.
Respiratory rate was 28/min, SPO2 was 98% and admitting packed cell volume was 22%.
Other systems were essentially normal.
An impression of peritonitis following bleeding intra-abdominal tumour was made.
She was resuscitated with intravenous fluids, transfused four units of blood, antibiotics and analgesics.
A nasogastric tube and urethral catheter were passed and blood samples were collected for complete blood count, serum electrolytes, urea and creatinine. Informed consent was obtained for laparotomy. At surgery, findings were 800 ml of bloody ascitic fluid, huge intra-abdominal mass occupying pelvis and left half of the abdomen up to hypochondrium displacing gut to the right upper abdomen. Mass is retroperitoneal, fixed and nodular, and there were many mesenteric and omental lymph nodes.
Ascitic fluid was collected for microscopy, culture and sensitivity, and peritoneum was suctioned dry. Biopsy was taken from the mass and abdomen closed in layers.
Post-operatively, we continued intravenous fluids, antibiotics, blood transfusion, analgesics and a dose of tranexamic acid, 500 mg. The abdominal wound did well, but her clinical state was poor and her performance status as assessed by the Eastern Co-operative Oncology Group system remained poor. She had features of sepsis, anaemia and progressive organ failure until her demise 9 weeks after presentation.
[Figure 1]a, [Figure 1]b, [Figure 1]c (H and E) show the photomicrograph of the slides showing the nest or insular pattern of paraganglioma.
[Figure 1]d, [Figure 1]e, [Figure 1]f, [Figure 1]g (immunohistochemistry) show clusters of delicate fibrovascular stroma separating relatively uniform polygonal cells into nest and clusters giving it the Zellballen pattern. These cells are surrounded by sustentacular cells.
| Discussion|| |
SCD is caused by a mutation in the gene coding for the beta chain of Hb located in the short arm of chromosome 11. It was first scientifically described in 1910 by James Herrick and is now the most common genetic disorder in many countries.,
Similarly, paraganglioma is a strongly heritable disease when compared to other cancers.,
The coexistence of paraganglioma and SCD, two distinct pathologies with very strong genetic basis immediately throws up many possibilities. This is more plausible when weighed against the backdrop of ongoing research on associations between different diseases especially on how carriers of certain abnormal genes may have increased or reduced risk of suffering certain cancers.,,
Suggested aetiopathogenetic mechanisms for this altered cancer risk in SCD include malignant transformation of tissues chronically damaged by the cytopathological consequences of SCD such as chronic inflammation, the finding of elevated proangiogenic markers associated with vascular complications of SCD  and transmission of carcinogenic viruses via blood transfusion in SCD.
Hydroxyurea, widely used in the management of SCD, has also been widely reported as a possible cause of increased cancer risk in such patients. It inhibits DNA synthesis and repair and in vitro suppresses complete DNA repair, thus promoting the accumulation of mutations and chromosomal damage.,, These effects were well-recognised mechanisms in carcinogenesis. It is also very probable that the severe and prolonged immunosuppression pre- and post-bone marrow transplantation therapy in SCD predisposes to cancer.,,
It is possible, therefore, that SCD alters a person's cancer risk by both genetic and epigenetic interactions that eventually lead to the development of cancer, especially those cancers with a very strong genetic basis. This possibility and the underlying aetiopathogenetic mechanisms will become clearer with advancements in research more so as the life expectancy of SCD patients continues to improve. In a review by Thomas et al., of the 85 deaths amongst SCD patients, 11 cases were from various types of malignancies. One of the cases was that of extra-adrenal metastatic paraganglioma. Similarly, Seminog et al. and Wilzén et al. noted in their reviews that the risk of some malignancies tended to be higher in patients with SCD., In their conclusions, the authors suggested the need for further studies at genetic and molecular levels to determine the basis for such risk.
Of note in the index case is that the presenting complaint of abdominal distension and pain are identical to the usual clinical features of SCD and so were attributed to the latter for a very long time until the abdominal mass was well advanced. This also holds true for most of the other features of cancers such as jaundice, anorexia, weight loss and bone pains, all of which may delay a thorough evaluation for cancer in an SCD patient. Asa et al. in their study reported the findings in paragangliomas located in unusual locations and suggested a high index of suspicion coupled with thorough examination and investigations.
| Conclusion|| |
Several reports strongly suggest an altered risk of cancer in SCD through genetic and epigenetic mechanisms. Over time, more research will validate or disprove this finding and shed more light on the range of cancers involved, especially those with strong underlying genetic basis like paraganglioma. The extensive overlap of symptomatology between SCD and intra-abdominal cancers will also receive greater attention so that the index of suspicion for possible cancer in the SCD patient will be raised.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest
| References|| |
Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 2010;376:2018-31.
Goldin AG, Kelty KC, Beard MF. Sickle cell anemia terminating in acute myeloblastic leukemia. Ann Intern Med 1953;39:920-8.
Samal GC. Sickle cell anemia with acute myeloid leukemia – (A case report). Indian Pediatr 1979;16:453-4.
Salmassi S, Currie ET, Bolf EC, Hernandez M, Kasprisin DO. Management of Hodgkin's disease in a patient with sickle cell anemia. Cancer 1981;48:252-4.
Paydas S. Sickle cell anemia and hematological neoplasias. Leuk Lymphoma 2002;43:1431-4.
Schultz WH, Ware RE. Malignancy in patients with sickle cell disease. Am J Hematol 2003;74:249-53.
Dawkins FW, Kim KS, Squires RS, Chisholm R, Kark JA, Perlin E, et al.
Cancer incidence rate and mortality rate in sickle cell disease patients at Howard university hospital: 1986-1995. Am J Hematol 1997;55:188-92.
Labi M, Haponik EF, Welsh RA, Summer WR. Alveolar cell carcinoma complicating sickle cell anemia: A chance occurrence? Am J Hematol 1989;32:222-5.
Tawfik OW, Moral LA, Richardson WP, Lee KR. Multicentric bilateral renal cell carcinomas and a vascular leiomyoma in a child. Pediatr Pathol 1993;13:289-98.
Shokunbi WA, Campbell OB, Ogunbiyi JO. Malignant haemangioendothelioma of bone in a HbSC disease patient – A case report. Afr J Med Med Sci 1996;25:293-6.
Stricker RB, Linker CA, Crowley TJ, Embury SH. Hematologic malignancy in sickle cell disease: Report of four cases and review of the literature. Am J Hematol 1986;21:223-30.
Seminog OO, Ogunlaja OI, Yeates D, Goldacre MJ. Risk of individual malignant neoplasms in patients with sickle cell disease: English national record linkage study. J R Soc Med 2016;109:303-9.
Chen H, Sippel RS, O'Dorisio MS, Vinik AI, Lloyd RV, Pacak K, et al.
The North American neuroendocrine tumor society consensus guideline for the diagnosis and management of neuroendocrine tumors: Pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas 2010;39:775-83.
Jansen JC, van den Berg R, Kuiper A, van der Mey AG, Zwinderman AH, Cornelisse CJ, et al.
Estimation of growth rate in patients with head and neck paragangliomas influences the treatment proposal. Cancer 2000;88:2811-6.
Granger JK, Houn HY. Head and neck paragangliomas: A clinicopathologic study with DNA flow cytometric analysis. South Med J 1990;83:1407-12.
Scholz T, Schulz C, Klose S, Lehnert H. Diagnostic management of benign and malignant pheochromocytoma. Exp Clin Endocrinol Diabetes 2007;115:155-9.
Mannelli M, Castellano M, Schiavi F, Filetti S, Giacchè M, Mori L, et al.
Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab 2009;94:1541-7.
Gimenez-Roqueplo AP, Dahia PL, Robledo M. An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res 2012;44:328-33.
Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, et al.
Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002;346:1459-66.
Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, et al.
Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 2005;23:8812-8.
Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anaemia. Arch Int Med 1910;6:517-21.
Fleming AF. Haematologic disease. In: Strickland GT, editor. Hunter's Tropical Medicine and Emerging Infectious Diseases. 8th
ed. Philadelphia: W.B. Saunders Company; 2000. p. 1192.
Goldacre M, Kurina L, Yeates D, Seagroatt V, Gill L. Use of large medical databases to study associations between diseases. QJM 2000;93:669-75.
Goldacre MJ, Wotton CJ, Seagroatt V, Yeates D. Cancers and immune related diseases associated with Down's syndrome: A record linkage study. Arch Dis Child 2004;89:1014-7.
Turner MR, Goldacre R, Goldacre MJ. Reduced cancer incidence in Huntington's disease: Record linkage study clue to an evolutionary trade-off? Clin Genet 2013;83:588-90.
Antwi-Boasiako C, Frimpong E, Gyan B, Kyei-Baafour E, Sey F, Dzudzor B, et al.
Elevated proangiogenic markers are associated with vascular complications within Ghanaian sickle cell disease patients. Med Sci (Basel) 2018;6. pii: E53.
Vamvakas EC, Blajchman MA. Deleterious clinical effects of transfusion-associated immunomodulation: Fact or fiction? Blood 2001;97:1180-95.
Snyder RD. The role of deoxynucleoside triphosphate pools in the inhibition of DNA-excision repair and replication in human cells by hydroxyurea. Mutat Res 1984;131:163-72.
Li JC, Kaminskas E. Progressive formation of DNA lesions in cultured Ehrlich ascites tumor cells treated with hydroxyurea. Cancer Res 1987;47:2755-8.
Najean Y, Rain JD. Treatment of polycythemia Vera: Use of 32P alone or in combination with maintenance therapy using hydroxyurea in 461 patients greater than 65 years of age. The french polycythemia study group. Blood 1997;89:2319-27.
Phillips LN, Krishnamurti L, Rytting H, Olson TA. Ovarian sertoli-leydig tumor after bone marrow transplant for sickle cell disease. Pediatr Blood Cancer 2018;65:e27367.
Stricker TP, Kumar V. Neoplasia. In: Kumar V, Abbas AK, Fausto N, Mitchell RN, editors. Robbins Basic Pathology. 8th
ed. Philadelphia: Saunders Elsevier; 2007. p. 516-22.
Sanford DE, Goedegebuure SP, Eberlein TJ. Tumour biology and tumour markers. In: Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice. 20th
ed. Philadelphia: Elsevier; 2017. p. 689-97.
Thomas T, Thomas D, French K, Binder AM. Malignancy in patients with sickle cell disease: A single centre observational study. Blood 2016;128:4867-71.
Wilzén A, Rehammar A, Muth A, Nilsson O, Tešan Tomić T, Wängberg B, et al.
Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes. Int J Cancer 2016;138:2201-11.
Asa SL, Ezzat S, Mete O. The diagnosis and clinical significance of paragangliomas in unusual locations. J Clin Med 2018;7. pii: E280.