A case of raised CA 19-9 in a patient with desmoplastic fibroblastoma of the upper limb

Carbohydrate antigen 19–9 (CA 19–9) is a tumor marker widely accepted as the most useful blood test in diagnosing and monitoring pancreatic cancer. However, CA 19–9 may also be raised in other conditions such as colorectal, hepatic, lung, and ovarian carcinoma as well as benign conditions such as hepatobiliary and pulmonary diseases. CA 19–9 is rarely elevated above 200 U/ml in benign conditions with values exceeding 1000 U/ml being highly suggestive of malignancy. The mechanism of secretion in both malignant and benign conditions remains unclear. Desmoplastic fibroblastoma (DF) is a benign soft tissue tumor. CA 19–9 has not been reported in association with DF previously. We present a case of raised serum CA 19–9 in a 71-year-old male attributed solely to DF in his left cubital fossa. The patient’s CA 19–9 level rose from 56 U/ml at the time of presentation to 3763.8 U/ml over a period of 9 months. Post-DF excision, the CA 19–9 level decreased to 1464 U/ml at 1 month, 162.3 U/ml at 2.5 months, and 24U/ml, within normal range, at 7 months post-surgery. CA 19–9 levels continued to remain at 24 U/ml 1.5 years post-tumor excision. The CA 19–9 level in this patient was highly elevated which is unusual in association with a benign tumor. The rate of decrease in CA 19–9 level post-excision was in keeping with that reported after pancreatic cancer resections. This is the first case of DF in association with raised CA 19–9.

Desmoplastic fibroblastoma, CA 19–9, Tumor markers, Benign soft tissue tumor, Biochemistry

Desmoplastic fibroblastoma (DF), or collagenous fibroma, is a benign fibrous soft tissue tumor. There are no reports of DF associated with biochemical markers. Carbohydrate antigen 19–9 (CA 19–9) is a sialylated Lewis blood group antigen and a well-known tumor marker commonly elevated in patients with pancreatic cancer. However, CA 19–9 is also known to be raised in hepatic, pulmonary, gynecologic, endocrine, and splenic diseases [1]. CA 19–9 has a normal range of 0–37 U/ml, overall sensitivity of approximately 85% and 90% specificity for pancreatic cancer. For diagnosis, an antigen level exceeding 200 U/ml in a non-jaundiced patient and correlated with a pancreatic mass on CT scan is strongly predictive of cancer [2]. Ritts et al. reported that typically, 78% of patients with pancreatic cancer have antigen levels exceeding the normal range, and 56% of these patients have levels greater than 500 U/ml [2]. Tumors have been found to be unresectable in 96% of patients with pancreatic adenocarcinoma whose CA 19–9 blood levels exceed 1000 U/ml [3]. Although the association of CA 19–9 with pancreatic cancer is well established, it has not been associated with DF. Case report We present a case of raised serum CA 19–9 in a healthy 71-year-old Chinese male which was attributed to DF in his left cubital fossa. The patient presented to a general orthopaedic clinic with pain and dysaesthesia of the left forearm. Examination did not show a dermatomal distribution of symptoms or evidence of local forearm swelling or tenderness. X-rays and MRI of the cervical spine were performed but did not reveal any attributable cervicogenic cause for his symptoms. The patient was subsequently referred to a neurologist for further investigation. Serum tumor markers were performed as part of investigation. The indication for the test was unclear but may have been part of a commercial health screening package. The patient’s serum CA 19–9 was elevated at 56 U/ml. His baseline CA 19–9 had been within normal limits at 33 U/ml at a routine health screening check 1 year prior. The patient had been worked up negative for rheumatological and connective tissue disorders as well as diabetes mellitus. Due to the elevated CA 19–9 levels, the patient was referred to a gastroenterologist and general surgeon. CT scans of the thorax, abdomen, pelvis, MRI of the abdomen, oesophago-gastroduodenoscopy (OGD), and colonoscopy were ordered but did not show any pancreatic or hepatobiliary cause for the elevated CA 19–9. At this point, no causes had been found for the patient’s symptoms or elevated CA 19–9 levels. The patient’s arm symptoms continued to worsen over a period of 9 months from his initial presentation. A repeat serum CA 19–9 showed an increase to 3763.8 U/ml. A recheck to exclude a spurious reading showed that CA 19–9 values were still elevated at 3561.6 U/ml. Re-examination of the left forearm now revealed a mass at his antecubital fossa. MRI of his forearm revealed a well-defined 2.0 × 1.0 × 3.0 cm ovoid lesion which was closely associated with the anterior capsule of the elbow and neurovascular bundle at the cubital fossa. The lesion was isointense on T1-weighted and heterogenous, displaying areas of central and peripheral high signal intensity on T2-weighted sequences (Figs. 1, 2). There was perilesional edema which may represent inflammatory changes. Post-contrast administration, there were central foci of low-intermediate enhancement (Fig. 3). A repeat MRI abdomen showed no pancreatic or hepatic abnormalities. A whole-body positron emission tomography (PET)-CT scan showed an incompletely characterized, mildly fluorodeoxyglucose (FDG) avid soft tissue mass near the left antecubital fossa but no other focal suspicious FDG activity elsewhere. An incisional biopsy of the left cubital fossa tumor was performed for which the histology suggested DF. After this definitive pathological diagnosis, the patient subsequently underwent a marginal excision of the tumor. A lobulated, dense, whitish fibrous tumor tissue, (measuring 4.7 × 3.0 × 1.2 cm) which was abutting but not involving the median nerve, was excised (Fig. 4 – 5). Light microscopic examination of the excised specimen revealed a circumscribed and lobulated hypocellular tumor (Fig. 6) composed of spindle cells appearing stellate in some areas and devoid of nuclear atypia or mitotic activity (Fig. 7). The features were those of DF. Immunohistochemical study on CA 19–9 expression on the specimen was negative. The patient had uneventful post-operative recovery with resolution of upper limb symptoms. CA 19–9 values decreased to 1464 U/ml at 1 month and 162.3 U/ml at 2.5 months post-surgery. Subsequently, the next follow-up was only at 7 months post-surgery and the CA 19–9 level was within the normal range at 24 U/ml and at 1.5 years post-surgery continued to remain at 24 U/ml. The CA 19–9 values and related timeline for this patient is reflected in Fig. 8.

DF tumors typically present as a painless mass on the trunk or extremity. Progressive increase in size has been observed and tumors have been reported from 1 to 20 cm in maximum diameter [4]. Occasionally, patients may present with sensorimotor neurological deficit, with nerve entrapment being a frequent feature [5]. Complete surgical excision is the recommended treatment [6]. The differential diagnosis of DF includes other infiltrative tumors, such as desmoid-type fibromatosis, neurofibroma, and low-grade fibromyxoid sarcoma and it is essential to confirm the diagnosis prior to definitive treatment [7]. In investigating the link between DF and CA 19–9, it is worth considering the mode of production, secretion and metabolism of the tumor marker. The CA 19–9 antigen is a tumor associated antigen, but it is not tumor-specific. Its synthesis is via normal human pancreatic and biliary ductular cells, along with gastric, colonic, endometrial, and salivary epithelia [8]. It is widely accepted as the most useful blood test in diagnosing and treating pancreatic cancer in patients. CA 19–9 is detected via a monoclonal antibody that binds to specific carbohydrate groups newly shed from pancreatic cells in the event of oncogenic transformation. The concentration of serum CA 19–9 is the result of the rate of antigen production by malignant and normal tissues balanced by its rate of clearance from the blood. As a glycoprotein, CA 19–9 is cleared via hepatic metabolism and excreted in bile [9]. Based on a retrospective review of all patients who had elevated CA 19–9, Pavai et al. [8] showed that malignant conditions with elevated CA 19–9 included colorectal, pancreatic, hepatic, lung, and ovarian carcinoma. Benign conditions with increased CA 19–9 were predominantly diseases of the hepatobiliary system, as well as pulmonary diseases, end stage renal failure and polymyositis. The tumor marker is rarely elevated higher than 200 U/ml in benign conditions with the exception of liver cirrhosis and cholecystitis. Values exceeding 1000 U/ml are highly suggestive of malignancy. Slight elevations above the upper normal limit of CA 19–9 are frequently found in the population [1, 10]. Kim et al. analyzed 192 who had raised CA 19–9 levels unrelated to malignancy and found that the cause for raised antigen levels were unknown in 45 (23.4%) cases and proposed an algorithm for a systematic approach to CA 19–9 elevation without evidence of malignant or pancreatobiliary diseases [1]. Our patient had pre-excision CA 19–9 levels of 3763.8 U/ml, which was suspicious of malignancy, however, there have been numerous reports where CA 19–9 levels have far exceeded 1000 U/ml in benign conditions such as chronic bronchitis, benign mucinous cystadenoma, ureteric calculi induced hydronephrosis, various pancreato-hepatobiliary diseases [11, 12], and even heavy tea consumption [13]. Other than metastatic disease [11], there have been no reports of any malignant or benign primary tumors of the limbs with associated CA 19–9 elevation. A survey of serum CA 19–9 levels in autoimmune diseases also revealed elevated levels in some patients with systemic lupus erythematosus (SLE), Sjogren’s syndrome, thyroiditis, mixed connective tissue disease, dermatomyositis papillary carcinomas, and approximately 50% of follicular adenomas and carcinomas [14, 15]. Treatment with oral prednisone resulted in a reduction in CA 19–9 to normal values after 6 months in some patients supporting the role of an inflammatory process in the pancreatic parenchyma [16]. Elevation of CA 19–9 can be attributed to the imbalance between increased production and decreased clearance or degradation. Proposed mechanisms of CA 19–9 elevation in benign diseases include inflammation and proliferation of non-tumorous tissue, such as in pancreatitis, cholangitis, bronchiectasis, idiopathic pulmonary fibrosis, ovarian cyst, and endometriosis; blockage of excretion of CA 19–9 in diseases such as obstructive jaundice and bronchitis; and when metabolic malfunction is present in diseases such as hepatitis, diabetes mellitus, and chronic glomerulonephritis [1]. Kim at el proposed that elevated CA 19–9 levels in patients with benign diseases can be associated with inflammation and their findings of an increased erythrocyte sedimentation rate (ESR) further supported their hypothesis [17]. Furthermore, CA 19–9 has been proposed as an adhesion molecule in synovial inflammation [18]. In this case report where immunohistochemical staining was negative for CA19-9 in the excised DF specimen, we can postulate that elevated CA 19–9 levels in the patient could have been via an indirect effect rather than by direct secretion by the tumor. Due to MRI findings of perilesional edema and the close proximity of the tumor to the anterior elbow capsule, we could postulate that there could have been irritation and inflammation of surrounding tissue and synovial capsule that may have given rise to raised CA 19–9 levels. However, more research and data are required to prove this hypothesis. For pancreatic cancer, CA 19–9 is also a helpful prognostic indicator post-surgical resection. Patients who normalize their CA 19–9 postoperatively live longer than patients who do not [19]. Pre-treatment CA 19–9 concentrations below 2000 U/ml has been shown to have a longer median survival compared to those with levels exceeding 2000 U/ml [20]. There have been attempts to quantify the half-life of serum CA 19–9. Rapellino et al. [21] report that clinical half-life of serum CA 19–9 levels in patients after colorectal cancer resection is slightly longer than1 day with a variation from less than 1 day to 3 days. Yoshimasu et al. [22] describes a biphasic elimination pattern for CA 19–9 in 40 patients who underwent radical resection for intrathoracic malignancies. The author calculated the half-life of CA 19–9 as 0.4—0.6 days in the first compartment and 2.7—6.8 days in the second compartment. The author describes the first compartment of biphasic elimination to reflect the amount of tumor marker contained in the blood, and the second compartment to reflect that contained in extravascular fluid. Căinap et al. suggest the half-life of CA 19–9 being 1 to 3 days [23], whereas Murai et al. suggested that half that to be 10.9 days in diabetic patients [24]. Montgomery et al. [25] measured pre- and post-operative CA 19–9 levels in 32 patients who underwent resection of pancreatic adenocarcinoma. Patients with CA 19–9 levels returning to normal (< 37 U/ml) post-resection, had a longer overall survival and disease free interval than those who’s levels did not return to normal. In these subset of patients, the post-operative time period in which the levels returned to normal ranged from 2 months to 1 year and the authors postulated that this variation might be due to post-operative pancreatic inflammation or ductal irritation as well as differences in production, secretion and metabolism of CA 19–9 between individuals. CA 19–9 levels fell after complete resection of the tumor and rose with recurrence and increasing tumor burden in the majority of patients. However, no reproducible parameters for CA 19–9 elevations that defined recurrence could be identified. The author postulated this to the differences in the biologic behavior of individual tumors and differences in production, secretion and metabolism of CA 19–9 in individuals. In our case report, the patient was seen at 1, 2.5, and 7 months post-excision of tumor and CA 19–9 values were recorded during each follow-up. Although the CA 19–9 levels had normalized at 7 months post-op, we believe this could have occurred much earlier. However, due to logistical restrictions, we could not follow-up the patient between 2.5 and 7 months post-op and hence were not able to conclusively show this earlier normalization. From the available data, the half-life of CA19-9 in this case report was between 13.2 and 20.6 days. Although the half-life of CA 19–9 did not behave similarly to that described by Rapellino, Yoshimasu, and Căinap [21–23], the CA 19–9 fell at a pace closer to that described by Murai [24] and with a similar trend as described by Montgomery (25) in patients who had levels returning to normal after pancreatic adenocarcinoma resection. This is the first case report of a benign limb soft tissue tumor and an associated elevation in CA 19–9 levels. The mechanism of CA 19–9 production in DF is unclear. More evidence is required to investigate if there is a direct association between DF and CA 19–9 or indirect mechanisms such as surrounding soft tissue inflammation. Author contributions All authors contributed equally in the literature review, manuscript writing, review, and approval of the version submitted for publication. Kumaran Rasappan (KR) is the corresponding author of this study and as such, takes responsibility for the integrity of the data in the study and the accuracy of the content provided. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declarations Conflict of interest The authors report no financial and personal conflicts of interest in this work. Statement of informed consent The patient mentioned in this case report was informed that data, including any necessary clinical photographs, from the case would be submitted for publication, and gave their informed consent. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

- 1.Kim S, Park BK, Seo JH, Choi J, Choi JW, Lee CK, et al. Carbohydrate antigen 19–9 elevation without evidence of malignant or pancreatobiliary diseases. Sci Rep. 2020;10(1):1–9. doi: 10.1038/s41598-019-56847-4. [DOI] [PMC free article] [PubMed] [Google Scholar] - 2.Ritts RE, Pitt HA. CA 19–9 in pancreatic cancer. Surg Oncol Clin N Am. 1998;7(1):93–101. doi: 10.1016/S1055-3207(18)30286-2. [DOI] [PubMed] [Google Scholar] - 3.Haglund C, Roberts PJ, Kuusela P, Scheinin TM, Mäkelä O, Jalanko H. Evaluation of CA 19–9 as a serum tumour marker in pancreatic cancer. Br J Cancer. 1986;53(2):197. doi: 10.1038/bjc.1986.35. [DOI] [PMC free article] [PubMed] [Google Scholar] - 4.Miettinen M, Fetsch JF. Collagenous fibroma (desmoplastic fibroblastoma): a clinicopathologic analysis of 63 cases of a distinctive soft tissue lesion with stellate-shaped fibroblasts. Hum Pathol. 1998;29(7):676–682. doi: 10.1016/S0046-8177(98)90275-1. [DOI] [PubMed] [Google Scholar] - 5.Fong F, Odell E, Simo R. Collagenous fibroma (desmoplastic fibroblastoma) of the neck presenting with neurological symptoms. Head Neck Pathol. 2009;3(1):47–50. doi: 10.1007/s12105-008-0098-6. [DOI] [PMC free article] [PubMed] [Google Scholar] - 6.Gong L-H, Liu W-F, Ding Y, Geng Y-H, Sun X-Q, Huang X-Y. Diagnosis and differential diagnosis of desmoplastic fibroblastoma by clinical, radiological, and histopathological analyses. Chin Med J (Engl) 2018;131(1):32–36. doi: 10.4103/0366-6999.221274. [DOI] [PMC free article] [PubMed] [Google Scholar] - 7.Yang GY, Malik NK, Chandrasekhar R, Ma W-W, Flaherty L, Iyer R, et al. Change in CA 19–9 levels after chemoradiotherapy predicts survival in patients with locally advanced unresectable pancreatic cancer. J Gastrointest Oncol. 2013;4(4):361. doi: 10.3978/j.issn.2078-6891.2013.045. [DOI] [PMC free article] [PubMed] [Google Scholar] - 8.Pavai S, Yap SF. The clinical significance of elevated levels of serum CA 19–9. Med J Malaysia. 2003;58(5):667–672. [PubMed] [Google Scholar] - 9.Pearce S, Thornes H, Carr D, Tanner A. Diagnostic pitfall; interpretation of CA 19–9 concentrations in the presence of hepatic dysfunction. Gut. 1994;35(5):707–708. doi: 10.1136/gut.35.5.707. [DOI] [PMC free article] [PubMed] [Google Scholar] - 10.Ventrucci M, Pozzato P, Cipolla A, Uomo G. Persistent elevation of serum CA 19–9 with no evidence of malignant disease. Dig Liver Dis. 2009;41(5):357–363. doi: 10.1016/j.dld.2008.04.002. [DOI] [PubMed] [Google Scholar] - 11.Ballehaninna UK, Chamberlain RS. The clinical utility of serum CA 19–9 in the diagnosis, prognosis and management of pancreatic adenocarcinoma: an evidence based appraisal. J Gastrointest Oncol. 2012;3(2):105–119. doi: 10.3978/j.issn.2078-6891.2011.021. [DOI] [PMC free article] [PubMed] [Google Scholar] - 12.Wang X, Qi X, Li H, Shao X, Guo X. An extremely increased CA19–9 level due to common bile duct stone: a case report. AME Med J. 2017;2(2):18. doi: 10.21037/amj.2017.02.02. [DOI] [Google Scholar] - 13.Howaizi M, Abboura M, Krespine C, Sbai-Idrissi MS, Marty O, Djabbari-Sobhani M. A new cause for CA19. 9 elevation: heavy tea consumption. Gut. 2003;52(6):913–914. doi: 10.1136/gut.52.6.913. [DOI] [PMC free article] [PubMed] [Google Scholar] - 14.Schmid KW, Ofner C, Ramsauer T, Hittmair A, Tötsch M, Ladurner D, et al. CA 19–9 expression in subacute (de Quervain’s) thyroiditis: an immunohistochemical study. Modern Pathol. 1992;5(3):268–272. [PubMed] [Google Scholar] - 15.Qian JIN, Zheng J, Xianrong XU, Yeming HU, Ying Z, Weihua XU, et al. Value of serum carbohydrate antigen 19–9 and carcinoembryonic antigen in evaluating severity and prognosis of connective tissue disease-associated interstitial lung disease. Arch Rheumatol. 2018;33(2):190. doi: 10.5606/ArchRheumatol.2018.6419. [DOI] [PMC free article] [PubMed] [Google Scholar] - 16.Safadi R, Ligumsky M, Goldin E, Ilan Y, Haviv YS, Nusair S. Increased serum CA 19–9 antibodies in Sjögren’s syndrome. Postgrad Med J. 1998;74(875):543–544. doi: 10.1136/pgmj.74.875.543. [DOI] [PMC free article] [PubMed] [Google Scholar] - 17.Kim H-R, Lee C-H, Kim YW, Han SK, Shim Y-S, Yim J-J. Increased CA 19–9 level in patients without malignant disease. Clin Chem Lab Med. 2009;47(6):750–754. doi: 10.1515/CCLM.2009.152. [DOI] [PubMed] [Google Scholar] - 18.Szekanecz E, Sandor Z, Antal-Szalmás P, Soós L, Lakos G, Besenyei T, et al. Increased production of the soluble tumor-associated antigens CA19–9, CA125, and CA15–3 in rheumatoid arthritis. Ann N Y Acad Sci. 2007;1108:359–371. doi: 10.1196/annals.1422.037. [DOI] [PubMed] [Google Scholar] - 19.Steinberg W. The clinical utility of the CA 19–9 tumor-associated antigen. Am J Gastroenterol. 1990;85(4):350–355. [PubMed] [Google Scholar] - 20.Duffy MJ. CA 19–9 as a marker for gastrointestinal cancers: a review. Ann Clin Biochem. 1998;35(3):364–370. doi: 10.1177/000456329803500304. [DOI] [PubMed] [Google Scholar] - 21.Rapellino M, Piantino P, Pecchio F, Ruffini E, Cavallo A, Scappaticci E, et al. Disappearance curves of tumor markers after radical surgery. Int J Biol Markers. 1994;9(1):33–37. doi: 10.1177/172460089400900107. [DOI] [PubMed] [Google Scholar] - 22.Yoshimasu T, Maebeya S, Suzuma T, Bessho T, Tanino H, Arimoto J, et al. Disappearance curves for tumor markers after resection of intrathoracic malignancies. Int J Biol Markers. 1999;14(2):99–105. doi: 10.1177/172460089901400207. [DOI] [PubMed] [Google Scholar] - 23.Căinap C, Nagy V, Gherman A, Cetean S, Laszlo I, Constantin A-M, et al. Classic tumor markers in gastric cancer. Current standards and limitations. Clujul Med. 2015;88(2):111–115. doi: 10.15386/cjmed-409. [DOI] [PMC free article] [PubMed] [Google Scholar] - 24.Murai J, Soga S, Saito H, Otsuki M, Kitada T, Saisho Y, et al. Study on the mechanism causing elevation of serum CA19-9 levels in diabetic patients. Endocr J. 2013;60(7):885–891. doi: 10.1507/endocrj.EJ12-0364. [DOI] [PubMed] [Google Scholar] - 25.Montgomery RC, Hoffman JP, Riley LB, Rogatko A, Ridge JA, Eisenberg BL. Prediction of recurrence and survival by post-resection CA 19–9 values in patients with adenocarcinoma of the pancreas. Ann Surg Oncol. 1997;4(7):551–556. doi: 10.1007/BF02305535. [DOI] [PubMed] [Google Scholar]