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Four synchronous primary tumors in a male patient

1 Department of Pulmonary, Mercy Clinic, Fort Smith, AR, USA
2 Department of Internal Medicine, Faculty of Medicine, University of Jordan, Amman, Jordan
3 Department of Pathology, Mercy Clinic, Fort Smith, AR, USA, AR
4 Division of Pulmonary and Critical Care Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA

Correspondence Address:
Moh'd Al-Halawani,
Division of Pulmonary and Critical Care Medicine, SUNY Downstate Medical Center, Brooklyn, NY 11203
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_187_18

 > Abstract 

Multiple primary malignancies are defined as two or more primary malignant tumors diagnosed in one individual; they are further classified to synchronous or metachronous based on the period between each cancer diagnosis and the other. The diagnosis of four synchronous cancers is exceedingly rare. We report a case of a 72-year-old man, diagnosed with synchronous quadruple cancers, Hurthle cell carcinoma and papillary carcinoma of the thyroid, as well as squamous cell carcinoma and carcinoid tumor of the lung.

Keywords: Carcinoid tumor, Hurthle cell carcinoma, multiple cancers, papillary thyroid carcinoma, squamous cell carcinoma

How to cite this URL:
Abdeen Y, Al-Amer M, Taft E, Al-Halawani M. Four synchronous primary tumors in a male patient. J Can Res Ther [Epub ahead of print] [cited 2022 Aug 7]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=264216

 > Introduction Top

In recent decades, cancer has been transformed from a fatal disease to a treatable chronic disease and sometimes a curable one due to the advances in screening, diagnosis, and management of cancer. In some instances, patients present with more than one primary cancer either at the same time or within months or years from each other. These cancers are called multiple primary cancers.[1] The incidence of multiple primary cancers has been increasing in the last decades due to better diagnosis modalities, increased survival and life expectancies, and shared environmental and genetic risk factors between different cancers.[2],[3],[4],[5],[6] We report a case of a 72-year-old male patient with four synchronous primary cancers, papillary carcinoma and Hurthle cell carcinoma in the thyroid gland, and squamous cell carcinoma and carcinoid in the lung. To the best of our knowledge, this is the first report of these four cancers occurring synchronously.

 > Case Report Top

A 72-year-old Caucasian male with a history of hypertension, type 2 diabetes mellitus, a 25-pack-year smoking history who quits 25 years ago, and no personal history of cancer was admitted with nausea, vomiting, and abdominal pain. He denied cough, hemoptysis, or weight loss. Physical examination was significant for asymmetrical thyroid enlargement. Workup included a computed tomography (CT) scan of the abdomen that showed gallstones and an incidental lung nodule in the right lower lobe measuring 1.4 cm in diameter. This was followed by a CT scan of the chest that confirmed the presence of the right lower lobe nodule and revealed an additional 8-mm nodule in the same lobe as well as a right thyroid nodule measuring 3.8 cm in diameter. The patient was then sent for a positron emission tomography scan which showed hypermetabolic activity in the thyroid nodule of 3.7 standardized uptake values and no activity on the lung nodules.

The patient then underwent thyroid ultrasound and fine-needle aspiration of the right thyroid nodule which showed evidence of Hurthle cell carcinoma. The patient underwent multiple procedures to further investigate his findings, including subtotal thyroidectomy and laparoscopic cholecystectomy, followed by navigational bronchoscopy and biopsy of the right lower lobe 1.4-cm lung nodule. Pathology samples of the thyroid revealed the presence of papillary carcinoma in the left thyroid tissue [Figure 1] and confirmed the diagnosis of Hurthle cell carcinoma in the right thyroid tissue [Figure 2]. Cytology of the lung nodule showed atypical cells suspicious for squamous cell cancer of the lung [Figure 3]. Three weeks later, the patient underwent total thyroidectomy surgery with lymph node sampling which was negative for metastasis, along with right lower lung lobectomy with mediastinal sampling. Pathology confirmed the diagnosis of squamous cell carcinoma in the 1.4-cm lung nodule and showed carcinoid tumor in the 8-mm nodule that was found in the same lobe [Figure 4]. Mediastinal sampling was negative for malignancy. The patient tolerated the surgeries well and luckily had his tumors diagnosed at early stages. He was planned for radioiodine therapy as an outpatient and will be followed up with CT scans of the chest for lung tumor surveillance.
Figure 1: Papillary carcinoma of the left thyroid

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Figure 2: Hurthle cell carcinoma of the right thyroid

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Figure 3: Squamous cell carcinoma of the lung (left), with P40 staining (right)

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Figure 4: Carcinoid tumor of the lung (left), with synaptophysin staining (right)

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 > Discussion Top

Multiple primary cancers are considered in patients who present with two or more tumors in the same or a different organ. For epidemiological studies, tumors are considered multiple primary malignancies if they arise in different sites and/or have a different histology or morphology. It is important to follow strict definitions of multiple primaries to avoid considering multifocal tumors or metastasis as multiple primaries.[1]

The definitions of a multiple primary malignancy have evolved over time. Different studies utilize different definitions. The two most common definitions of multiple primaries currently used are provided by the Surveillance, Epidemiology, and End Results (SEER) project and the International Association of Cancer Registries and International Agency for Research on Cancer (IARC). Coyte et al. studied the impact of applying different definitions of multiple primaries.[2]

Multiple primary malignancies can be classified into synchronous or metachronous. The SEER database considers two tumors to be synchronous if they are diagnosed at the same time or within 2 months of each other and metachronous if after 2 months. The IARC considers a 6-month interval for the distinction between synchronous and metachronous rather than the 2-month interval utilized by the SEER recommendations.[7]

Multiple primary cancers are not a recent topic in the literature. It has been described as early as 1932 by Warren.[8] However, the incidence has been increasing since then.[3] Different studies report incidence in the range of 2.4%–17% within 20 years of follow-up.[1],[2] Most studies that report multiple primaries refer to patients who have two primary cancers. The incidence of triple and quadruple cancers is rare and therefore variable in the literature. Németh et al. reported an incidence of triple primary malignancy in 0.5% and quadruple primaries in 0.3% of patients with malignant tumors.[4] Watanabe et al. studied 5456 autopsy cases in the National Cancer Center of Japan and reported second primaries in 285 (5.2%) of the cases and only 58 (1.1%) triple or more cancers.[5] Antal and Vallent analyzed 719 patients with cancer, and multiple cancers were found in 53 (7.4%) cases. Forty-nine of those patients had two cancers and only four patients had three primary cancers.[6] Moreover, most of the reported triple and quadruple primary malignancies were metachronous rather than synchronous, as opposed to what we report in our case.

The rise in incidence is attributed to many factors including the advancement in diagnostic modalities, improved screening guidelines, better understanding of genetic cancer syndromes, and shared environmental risk factors for some cancers (for example, smoking). Moreover, improved survival of cancer patients and increased life expectancy allowed patients to survive long enough to develop multiple primary malignancies.[9],[10]

The role of genetics in the development of cancer has been studied widely and is still a topic of interest in research. In the recent years, more than 100 mutant genes have been shown to predispose patients to cancer, and even before identification of these genes, heritability in cancer patients was suspected based on a few factors including the sites of cancer, the age of onset of the disease, the presence of family history of the same cancer, and the presence of multiple cancers in the same patient.[11]

Multiple primary tumors sometimes present in highly specific pattern, indicating that they are almost certainly of genetic origin; these patterns are referred to as cancer syndromes. The genetic basis of multiple of these syndromes has been identified and widely studied. Examples of these syndromes include hereditary retinoblastoma syndrome (retinoblastoma and osteosarcoma); multiple endocrine neoplasia type 2a (medullary thyroid cancer and pheochromocytoma); von Hippel–Lindau disease (renal cancer, hemangioblastoma of the retina and central nervous system, and pheochromocytoma); hereditary breast and ovarian cancer syndrome; and Lynch syndrome (colon and endometrial cancer). In some other cases, cancers are statistically associated with each other, as they appear together more than expected, but the genetic basis for it is unknown.[11] To the best of our knowledge, our case does not fit with the patterns of any of the cancer syndromes described in the literature.

Multiple studies reported lung cancer as part of multiple primary cancers. Rosso et al. reported that in patients with lung cancer, 13.4% had multiple primaries.[12] In a retrospective study of 1769 patients with lung cancer by Sánchez et al., 22% of patients with lung cancer had multiple primaries, most of which were smoking related. They also reported that the incidence of the second primaries was great that what is expected in the general population matched for age and sex.[13] Bhaskarla et al., in an analysis of the second primary lung cancers in the SEER database, reported that the most common second cancers are also in the lung, especially if the first primary was small cell lung cancer.[14] Li et al. analyzed 5405 patients with lung cancer between 2005 and 2013. One hundred and eighty-five (3.4%) of the patients had multiple primary cancers. One hundred and seventy-five of them had one other primary cancer and ten patients had two other primary cancers and were excluded from the study to avoid misunderstanding. They reported that it was more common for the cancers to be metachronous (63.4%) than synchronous (36.6%), and they adopted the IARC 6-month interval period to distinguish synchronous from metachronous. In their study, the most common accompanying cancers were colon cancer (25/175), rectal cancer (18/175), esophageal cancer (25/175), and thyroid cancer (13/175). They also found a male predominance with a 2.5:1 ratio.[15]

Thyroid cancer is the most common endocrine malignancy, with a rising annual incidence of nearly 50% since the 1970s.[16] Papillary thyroid cancer is the most frequently diagnosed form of thyroid cancer, accounting for up to 80% of the cases.[17],[18] Multiple studies have reported an increased incidence of thyroid cancer after another primary malignancy at a different site. Moreover, other studies reported an increased rate of secondary malignancies among thyroid cancer survivors. A two-way positive association may be suggested by the previous notion. Murray et al. reported a 13.9% prevalence of synchronous or metachronous primary cancers in patients with papillary thyroid cancer. The most common overall cancers were breast, prostate, melanoma, leukemia, and lymphoma. The most common observed cancers in the synchronous group were renal cell carcinoma, melanoma, and oral cavity/pharyngeal cancers.[16] Lal et al. studied the risk of subsequent primary thyroid cancer in patients with one of ten common invasive malignancies. They demonstrated that there is an increased risk of subsequent thyroid cancer following nine out of the ten primary nonthyroid malignancies with bladder cancer being the exception. In their study, the standardized incidence ratio for subsequent primary thyroid cancer showed the highest elevation in patients with renal cell carcinoma (2.95), followed by leukemia (2.24), lymphoma (2.15), lung cancer (1.99), and melanoma (1.69).[19]

In general, a patient with cancer has a higher risk of developing a second primary cancer than the general population.[20] Moreover, as discussed earlier, patients with lung cancer may be at an increased risk of developing a second primary lung cancer, and they also may be at an increased risk of having thyroid cancer. In addition, patients with thyroid cancer may be at an increased risk of having lung cancer. However, and to the best of our knowledge, this is the first report of a case of two primary lung cancers and two primary thyroid cancers occurring synchronously.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

Vogt A, Schmid S, Heinimann K, Frick H, Herrmann C, Cerny T, et al. Multiple primary tumours: Challenges and approaches, a review. ESMO Open 2017;2:e000172.  Back to cited text no. 1
Coyte A, Morrison DS, McLoone P. Second primary cancer risk – The impact of applying different definitions of multiple primaries: Results from a retrospective population-based cancer registry study. BMC Cancer 2014;14:272.  Back to cited text no. 2
Demandante CG, Troyer DA, Miles TP. Multiple primary malignant neoplasms: Case report and a comprehensive review of the literature. Am J Clin Oncol 2003;26:79-83.  Back to cited text no. 3
Németh Z, Czigner J, Iván L, Ujpál M, Barabás J, Szabó G, et al. Quadruple cancer, including triple cancers in the head and neck region. Neoplasma 2002;49:412-4.  Back to cited text no. 4
Watanabe S, Kodama T, Shimosato Y, Arimoto H, Sugimura T, Suemasu K, et al. Multiple primary cancers in 5,456 autopsy cases in the national cancer center of Japan. J Natl Cancer Inst 1984;72:1021-7.  Back to cited text no. 5
Antal A, Vallent K. Cases of multiple tumors in our clinic. Orv Hetil 1997;138:1507-10.  Back to cited text no. 6
Amer MH. Multiple neoplasms, single primaries, and patient survival. Cancer Manag Res 2014;6:119-34.  Back to cited text no. 7
Warren S. Multiple primary malignant tumors, a survey of the literature and a statistical study. Am J Cancer 1932;16:1358-414.  Back to cited text no. 8
Bhatia S, Yasui Y, Robison LL, Birch JM, Bogue MK, Diller L, et al. High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: Report from the late effects study group. J Clin Oncol 2003;21:4386-94.  Back to cited text no. 9
Aydiner A, Karadeniz A, Uygun K, Tas S, Tas F, Disci R, et al. Multiple primary neoplasms at a single institution: Differences between synchronous and metachronous neoplasms. Am J Clin Oncol 2000;23:364-70.  Back to cited text no. 10
Cybulski C, Nazarali S, Narod SA. Multiple primary cancers as a guide to heritability. Int J Cancer 2014;135:1756-63.  Back to cited text no. 11
Rosso S, De Angelis R, Ciccolallo L, Carrani E, Soerjomataram I, Grande E, et al. Multiple tumours in survival estimates. Eur J Cancer 2009;45:1080-94.  Back to cited text no. 12
Sánchez de Cos Escuín J, Rodríguez López DP, Utrabo Delgado I, Gallego Domínguez R, Sojo González MA, Hernández Valle M, et al. Disease recurrence and second tumors in long-term survivors of lung cancer. Arch Bronconeumol 2016;52:183-8.  Back to cited text no. 13
Bhaskarla A, Tang PC, Mashtare T, Nwogu CE, Demmy TL, Adjei AA, et al. Analysis of second primary lung cancers in the SEER database. J Surg Res 2010;162:1-6.  Back to cited text no. 14
Li F, Zhong WZ, Niu FY, Zhao N, Yang JJ, Yan HH, et al. Multiple primary malignancies involving lung cancer. BMC Cancer 2015;15:696.  Back to cited text no. 15
Murray SE, Schneider DF, Bauer PS, Sippel RS, Chen H. Synchronous and antecedent nonthyroidal malignancies in patients with papillary thyroid carcinoma. J Am Coll Surg 2013;216:1174-80.  Back to cited text no. 16
Cooper DS, Ladenson PW. The thyroid gland. In: Gardner DG, Shoback D, editors. Greenspan's Basic & Clinical Endocrinology. 9th ed., Ch. 7. New York, USA: McGraw-Hill; 2011.  Back to cited text no. 17
Cobin RH, Gharib H, Bergman DA, Clark OH, Cooper DS, Daniels GH, et al. AACE/AAES medical/surgical guidelines for clinical practice: Management of thyroid carcinoma. American Association of Clinical Endocrinologists. American College of Endocrinology. Endocr Pract 2001;7:202-20.  Back to cited text no. 18
Lal G, Groff M, Howe JR, Weigel RJ, Sugg SL, Lynch CF, et al. Risk of subsequent primary thyroid cancer after another malignancy: Latency trends in a population-based study. Ann Surg Oncol 2012;19:1887-96.  Back to cited text no. 19
Mariotto AB, Rowland JH, Ries LA, Scoppa S, Feuer EJ. Multiple cancer prevalence: A growing challenge in long-term survivorship. Cancer Epidemiol Biomarkers Prev 2007;16:566-71.  Back to cited text no. 20


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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