Metastatic esophageal squamous cell carcinoma with paraneoplastic Raynaud phenomenon: a case report

Introduction

Raynaud phenomenon (RP) is transient ischemia resulting from episodic vasospasm and most often affects the digits (1). RP has an estimated global prevalence of nearly 5% with the majority of cases considered primary, or idiopathic (2). Primary RP is most commonly seen in patients younger than 40 years old, and the development of RP later in life raises concern for an underlying secondary etiology (1). Secondary causes of RP include autoimmune disorders, occupational exposures, vasculopathy, and certain drugs (1). Paraneoplastic acral vascular syndrome (PAVS) represents a spectrum of vascular disorders including RP and is an important cause of secondary RP (3,4). PAVS is more commonly associated with solid tumors, metastatic disease, and adenocarcinoma, and has been reported in a variety of organs (3). Esophageal malignancies have been associated with development of PAVS, including a case of acrocyanosis associated with esophageal squamous cell carcinoma (SCC) (5,6). While PAVS has been described in the setting of esophageal SCC (6), we present a novel case with an initial presentation of secondary RP and progression to digital ischemia. We present this article in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-24-259/rc).

Case presentation

A 61-year-old Caucasian male with history of hypertension, hyperlipidemia, and alcohol use disorder presented with dysphagia and discoloration of digits. He had developed RP with triphasic reaction 3 months prior to admission. Two weeks after these symptoms began, he noted black discoloration of the fingertips which progressed to ulceration. He was prescribed nifedipine, 30 mg daily, by his primary care physician with no improvement in symptoms. Concomitantly, he developed weight loss, anorexia, and dysphagia to solids. His symptoms progressed to overt digital ischemia, and his dysphagia progressed to liquids, which prompted him to seek medical treatment. He denied family history of Barrett’s esophagus, esophageal malignancy, colon cancer, and autoimmune disease. His medications included lisinopril and recently initiated nifedipine. He had no significant occupational exposures and reported no tobacco use or illicit substance use. He was admitted to the hospital for further diagnostic evaluation and treatment.

At the time of admission, the patient had normal hemodynamics and was afebrile. His exam was notable for an erythematous macular rash covering the back and torso, and dry gangrene of the left 2^nd and 3^rd and right 2^nd, 3^rd, and 5^th digits without evidence of sclerodactyly (Figure 1). Peripheral pulses were intact. No skin thickening or sclerosis was noted and his oral aperture was normal in size. Initial chemistry profile and blood counts were within normal limits. Rheumatology and gastroenterology specialists were consulted for further evaluation.

Figure 1 Findings on physical examination of the right hand revealing dry gangrene of the 2^nd, 3^rd, and 5^th digits.

Given the rapidly progressive nature of his gastrointestinal symptoms and older age of onset for RP, a work-up for secondary causes was initiated. Laboratory evaluation was notable for erythrocyte sedimentation rate 8 mm/h (reference: 1–19 mm/h), C-reactive protein 1.4 mg/dL (reference: <0.5 mg/dL), positive antinuclear antigen with ≥1:2,560 titer in a speckled pattern, and Sjögren’s syndrome-related antigen A 2.9 antibody index (AI) (reference: 0.0–0.9 AI). Additional evaluation, including rheumatoid factor, cryoglobulins, anti-cyclic citrullinated peptide antibodies, antineutrophilic cytoplasmic antibodies, anti-double-stranded DNA (dsDNA) antibodies, ribonucleoprotein (RNP) antibodies, Smith antibodies, anti-scleroderma-70 antibodies, Sjögren’s syndrome-related antigen B antibodies, anti-Jo-1 antibodies, anti-centromere antibodies, and anti-RNA polymerase III antibodies, was unremarkable. Complements were within normal limits. Ankle-brachial indices in the bilateral upper extremities revealed pressure gradients between the wrist and fingers suggestive of mild occlusive disease.

Computed tomography of the chest, abdomen, and pelvis with intravenous contrast was conducted for initial evaluation of dysphagia and weight loss and to assess for occult malignancy as an etiology of secondary RP. Imaging revealed marked wall thickening of the distal esophagus extending to the gastroesophageal junction and extensive upper abdominal and retroperitoneal lymphadenopathy (Figure 2). An endoscopic evaluation with esophagogastroduodenoscopy was pursued on the basis of these findings and revealed a large, fungating, circumferential, and ulcerated mass from 35 to 40 cm from the incisors (Figure 3). Pathology revealed moderately-to-poorly differentiated invasive SCC. Concomitant development of dysphagia and RP with exclusion of other secondary etiologies resulted in a diagnosis of metastatic esophageal SCC with paraneoplastic RP. Endoscopic ultrasound and a positron emission tomography scan was planned for the outpatient setting to formally complete staging. Patient was discharged with an increased dose of nifedipine to 90 mg and outpatient subspecialty follow-up. He reported improvement in RP after discharge but did not seek further oncologic care and was later lost to follow-up. Therefore, although presumed to be metastatic based upon cross-sectional imaging findings, final tumor-node-metastasis (TNM) staging was not completed.

Figure 2 Computed tomography imaging with intravenous contrast of the abdomen and pelvis revealing marked thickening of the distal esophagus in transverse section (A) and extensive upper abdominal and retroperitoneal lymphadenopathy in coronal section (B).

Figure 3 Procedural images from endoscopic evaluation for etiology of dysphagia and correlation with imaging findings revealing a large, fungating, and circumferential mass from 35 to 40 cm from the incisors. Pathology was consistent with moderately-to-poorly differentiated SCC. SCC, squamous cell carcinoma.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

PAVS represents a spectrum of presentations including acrocyanosis and RP. Although rare, clinicians should consider occult malignancy with PAVS when evaluating for secondary causes of RP, especially among older adults (4). While a heterogenous spectrum of paraneoplastic syndromes in esophageal cancer has been described (7), PAVS and other vascular phenomenon are not commonly reported. We present a case of PAVS manifesting as secondary RP in the setting of metastatic esophageal SCC that shares many commonalities with previously reported cases of PAVS. Our patient developed RP and initial manifestations of malignancy concurrently, which is typical among cases of PAVS (8). Moreover, RP progressed rapidly to digital ischemia, which has been previously described for PAVS and is not characteristic of primary RP (3). Antinuclear antigen was positive with high titer in our case, which has been reported to occur in 24% of cases of PAVS (5).

The primary distinction between our case and existing literature is the underlying histology of malignancy. Indeed, roughly half of descriptions of PAVS have occurred in the context of adenocarcinoma (9). Although SCCs are not commonly described, there are reports in the literature of both lung (10) and esophageal SCC (6) with associated PAVS. The previously reported case of acrocyanosis secondary to esophageal SCC describes a patient with a 1-day history of acrocyanosis without subsequent progression to digital ischemia. The diagnosis of malignancy was made during evaluation of seemingly unrelated symptoms (6). In contrast, our patient presented months after initially developing RP and progressed to digital ischemia by the time of presentation. The period of antecedent RP and presence of overt digital ischemia is therefore novel among cases of PAVS secondary to esophageal SCC. There are additional reports of esophageal malignancy with PAVS, however, these cases presented with non-SCC histology (5).

Unfortunately, our patient was lost to follow-up after the initial diagnosis and we are unable to comment on response to cancer-directed therapy. However, prior cases of PAVS and digital ischemia associated with malignancy generally describe an improvement in symptoms following treatment of underlying malignancy (9,10). Specific treatments for digital ischemia and RP, including calcium channel blockade (10), and prostaglandins (8) have also been described for severe or refractory symptoms.

Conclusions

PAVS is a rare paraneoplastic syndrome that has been described in a variety of malignancies, and should be considered for patients presenting with RP, digital ischemia, or acrocyanosis at the time of cancer diagnosis. This is only the second case to our knowledge to describe PAVS in the setting of esophageal SCC and is the first with secondary RP as an initial manifestation and to describe progression to digital ischemia. This subtle, yet important distinction further highlights the importance of considering malignancy during evaluation for secondary RP.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-24-259/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-24-259/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-24-259/coif). R.V. serves as a steering committee member for short bowel syndrome therapies at VectivBio (Basel, Switzerland), but reports no conflicts of interest as it pertains to the content of this manuscript. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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