Raynaud\u27s phenomenon of the tongue after radiation therapy with or without chemotherapy is an exceedingly rare complication. Symptoms are similar to Raynaud\u27s disease of other sites and involve pallor and discomfort on exposure to cold temperatures that resolve with rewarming. Presentation occurs approximately 18-24 months after radiotherapy on average and can usually be managed effectively with lifestyle modification and pharmacotherapy. Here, we present a case of lingual Raynaud\u27s following surgery and adjuvant radiation therapy in a patient with squamous cell carcinoma of the oral cavity

Kabbani, Loay S

Murphy, Nicholas

Shepard, Alexander D

Siddiqui, Farzan

English

Henry Ford Health System Scholarly Commons

Henry Ford Health Henry Ford Health Scholarly Commons Radiation Oncology Articles Radiation Oncology 8-30-2022 Lingual Raynaud's Phenomenon after Surgical and Radiotherapeutic Intervention for Oral Squamous Cell Carcinoma Nicholas Murphy Loay S. Kabbani Alexander D. Shepard Farzan Siddiqui Follow this and additional works at: https://scholarlycommons.henryford.com/radiationoncology_articles Case ReportLingual Raynaud’s Phenomenon after Surgical andRadiotherapeutic Intervention for Oral SquamousCell CarcinomaNicholas J. Murphy ,1 Loay S. Kabbani,2 Alexander D. Shepard,2 and Farzan Siddiqui 31Wayne State University School of Medicine, 540 E. Canfield Ave. Detroit, MI 48201, USA2Department of Surgery, Henry Ford Hospital, 2799 W Grand Blvd Detroit, MI 48202, USA3Department of Radiation Oncology, Henry Ford Hospital, 2799 W Grand Blvd Detroit, MI 48202, USACorrespondence should be addressed to Farzan Siddiqui; fsiddiq2@hfhs.orgReceived 4 June 2022; Accepted 9 August 2022; Published 19 August 2022Academic Editor: Muzaffer SindelCopyright © 2022 Nicholas J. Murphy et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.Raynaud’s phenomenon of the tongue after radiation therapy with or without chemotherapy is an exceedingly rare complication.Symptoms are similar to Raynaud’s disease of other sites and involve pallor and discomfort on exposure to cold temperatures thatresolve with rewarming. Presentation occurs approximately 18-24 months after radiotherapy on average and can usually bemanaged effectively with lifestyle modification and pharmacotherapy. Here, we present a case of lingual Raynaud’s followingsurgery and adjuvant radiation therapy in a patient with squamous cell carcinoma of the oral cavity.1. IntroductionRaynaud’s phenomenon (RP) is a vasospastic process thattypically affects the digits of the hands, causing painful dis-coloration on exposure to cold temperatures or strong emo-tions [1]. It is estimated that 3-5% of the general populationis affected by RP with a predilection for females and those inmore northerly regions [1]. Classically, it presents in threephases beginning with pallor, which represents the initialvasoconstrictive ischemic phase. After a prolonged periodof ischemia, the second phase of a cyanotic blue color resultsfrom the presence of desaturated blood in the affected part.With recovery, there is a final hyperemic phase of vasodila-tion which produces a red color. This classic color progres-sion from white to blue to red is only infrequently present.Episodes of vasospasm usually last from minutes to one hourbut can last multiple hours [1].The precise mechanism for RP has not yet beenelucidated but current thinking points to a combination ofprobable neural and vascular factors. The neural pathwayinvolves sympathetic nervous system stimulation by coldtemperatures or stress. The resulting release of norepineph-rine activates vascular smooth muscle alpha adrenoreceptorsleading to vasoconstriction. However, local factors can over-ride this neural response as seen in patients with local anes-thesia of sympathetic nerves or postsympathectomy who canstill experience episodes of RP [1]. Another postulatedmechanism for RP is production of reactive oxygen species(ROS) by mitochondria in response to cold temperatures[1]. Signaling through the Rho/Rho-kinase pathway leadsto translocation and subsequent activation of α2C-adrenore-ceptors causing vasoconstriction [1].Small artery occlusive disease (e.g., vasculitis) is morecommonly implicated in secondary RP, which is associatedwith collagen vascular diseases such as systemic sclerosis[1]. Some of the vascular causes include endothelial celldamage, disparate vasoactive substance production, intra-vascular narrowing, and increasing vasoconstriction [1].Once exposed to cold, these factors increase the body’s nat-ural vasoconstrictive response leading to the classical paleskin of affected areas [1, 2].Development of management strategies has been ham-pered by the complex etiology of RP and a poor understand-ing of its exact mechanisms. Many therapies have been triedHindawiCase Reports in Vascular MedicineVolume 2022, Article ID 1567581, 4 pageshttps://doi.org/10.1155/2022/1567581with varying degrees of success. They are broadly dividedinto nonpharmacologic and pharmacological interventions.Treatment is stratified based on severity, beginning withnonpharmacological approaches for mild symptoms. Theseinclude lifestyle modification to avoid triggers such as keep-ing the affected areas warm with clothing and avoidingexposure to cold temperatures [1]. Smoking cessation isalways advised, if applicable [1]. For more severe symptoms,vasodilator therapy is added, typically beginning withdihydropyridine calcium channel blockers—nifedipine beingthemost studied and drug of choice [1]. Other potential agentsinclude alpha-1 adrenoreceptor antagonists (prazosin),angiotensin-converting enzyme inhibitors, nitric oxide, pros-taglandin analogs, phosphodiesterase inhibitors, selectiveserotonin reuptake inhibitors, antioxidants, botulinum toxinA, endothelin receptor antagonists, and Rho inhibitors [1].Alternative approaches include herbal remedies such asGinkgo biloba extract and rosemary oil, acupuncture, transcu-taneous nerve stimulation, and sympathectomy amongothers [1].Although the primary regions affected by RP are thedigits of the hands and feet, rarely affected regions includethe nose, ears, lips, and nipples. Raynaud’s of the tongue isexceedingly rare and to date is only described in a handfulof case reports.2. CaseA 63-year-old postmenopausal female with a history ofhypertension, hyperlipidemia, and former 25 pack-yeartobacco use presented with squamous cell carcinoma of theoral cavity pathological stage IVA (pT1N2bM0). She hadundergone wide local excision of an alveolar ridge lesionwith, left neck dissection of levels I-IV, and reconstructionwith a right radial forearm free flap; the margins were nega-tive, and there was no extranodal extension. She subse-quently completed postoperative radiation therapy to adose of 60Gy in 30 fractions using intensity-modulated radi-ation therapy (IMRT) to the areas shown in Figures 1(a) and1(b). At follow-up, 19 months after radiation, she continuedto suffer from xerostomia and diminished taste sensation butshowed no evidence of disease based on clinical and radio-logic examination. Approximately two years after comple-tion of radiation, in the month of October, she began tonotice intermittent lingual pallor. She reported that the tipand anterior 1/4 of her tongue predominately on the left sidebegan to tingle and turn white, lasting 10-15 minutes andoccurring two to three times per day as shown in Figure 2.This change occurred mostly with exposure to cold ambienttemperatures and resolved with rewarming. Interestingly, itdid not occur with drinking cold beverages. There were nomotor, sensory, balance, or hearing changes or similar symp-toms in the digits of the hands or feet. She had no history ofRaynaud’s disease, cerebrovascular accident, transientischemic attack, or other neurologic disease. Physical exam-ination revealed no visible abnormality of the tongue andflexible laryngoscopy was unremarkable. A computedtomography angiogram of the head and neck done to inves-tigate possible vascular causes showed no significant extra-cranial arterial occlusive disease or aneurysm. She wasreferred to vascular surgery for further evaluation, and labo-ratory studies were ordered, showing an ESR 4mm/Hr, CRP0.2mg/dL, PT 12.9 sec, PTT 25 sec, INR 0.97, DRVVT35 sec, and lupus anticoagulant negative. Her presentationwas noted to be most consistent with Raynaud’s phenome-non of the tongue, and a trial of nifedipine extended release30mg daily was started. During follow-up several weekslater, she reported significant improvement in the frequencyand severity of symptoms and was tolerating treatment,though attacks continued to occur intermittently when out-doors in cold temperatures.3. DiscussionRaynaud’s phenomenon of the tongue is exceedinglyuncommon and often occurs in the setting of primary Ray-naud’s disease of the digits. There have been at least 22 casesof lingual involvement reported in the literature, usuallyassociated with systemic sclerosis, Sjögren’s syndrome, orother connective tissue disorders [3–8]. Of the lingual Ray-naud’s cases found in the literature, four were identifiedwithout preexisting connective tissue disease all occurringafter the use of radiotherapy for head and neck squamouscell carcinomas [2, 9–11]. In three cases, there was no his-tory of Raynaud’s disease affecting the digits and in all cases,radiotherapy had occurred between 18 and 54 months priorto the onset of symptoms. One of the patients was noted tohave a smoking history while the other three were eithernonsmokers or not specified. Nicotine is noted to be a riskfactor for Raynaud’s disease and was potentially a contribut-ing factor in our patient [1].Interestingly, 2/4 cases involved male patients, while typ-ical RP tends to affect females more than males. One riskfactor for RP is the hormone estrogen, which potentiatesvasoconstriction occurring via alpha adrenoreceptors [1].Further evidence for this factor comes from estrogen therapyincreasing the risk of RP in postmenopausal women [1]. Ourpatient was not on estrogen therapy. Raynaud’s phenome-non can result from either increased vasoconstriction orimpaired vasodilation or a combination of the two in smallarteries. Underlying arterial occlusive disease can be a majorcontributing factor. Arteries narrowed by such a processhave a lower “critical closing pressure,” and normal cold-induced vasoconstriction can lead to temporary vessel clo-sure. Radiation leads to a progressive obliterative endarteritisof small vessels which makes them prone to such changesand may be a contributing factor to the rare occurrence ofRP [2]. Additionally, radiation damage to the endotheliumdisrupts normal chemical mediators of vasorelaxation. Theresult is exaggerated vasoconstriction, both in intensity andduration, to normal adrenergic-mediated stimuli (e.g., coldor stress) and impaired vasodilation leading to the classicsymptoms of RP [2]. Surgery is also likely a contributing fac-tor from scarring leading to compression of small arterialbeds [11].Non-RT-associated cases in this group of lingual Raynaud’spatients tended to occur in younger people and females, often2 Case Reports in Vascular Medicinewith a previously diagnosed systemic sclerosis with digitalRaynaud’s symptoms [3–8].Treatment of our patient using calcium channel blockerswas apparently effective, though other options ranging fromlifestyle changes of avoiding colder temperatures up torecurrent botulinum toxin injections seemed acceptable [2,9–11]. Three of the other cases demonstrated stable diseasewith nonpharmacologic management, leading to ongoingintermittent pain attacks that were reported as self-limitingand tolerable [2, 9, 10]. One patient was treated with fiftyunits of botulinum toxin injected along the sternocleidomas-toid muscle, which provided complete resolution of thepatient’s discoloration, paresthesia, and dysphagia for 3months until symptoms gradually returned [11]. Repeatinjections reportedly had similar effect to the first [11].Overall, the treatment paradigm for lingual Raynaud’s afterRT seems to mirror the general consensus for primaryRaynaud’s disease. Severity of symptoms and patientpreference for intervention should be the main consider-ations until further data in this specific patient populationbecome available.4. ConclusionIn summary, lingual Raynaud’s phenomenon is a rare com-plication of radiation therapy to the oral cavity. Althoughthe exact mechanism is currently unknown, the etiology islikely related to radiation-induced small artery damageresulting in an exaggerated vasoconstrictive response to nor-mal adrenergic stimulation. Treatments can be effective inmitigating symptoms and include lifestyle changes andpharmacologic intervention.Data AvailabilityThe cases discussed in this report may be accessed at theprovided references. There is no additional unreleased data.DisclosureThis study is performed as part of employment with HenryFord Health System.Conflicts of InterestThe authors declare that there is no conflict of interestregarding the publication of this article.References[1] I. Nawaz, Y. Nawaz, E. Nawaz, M. R. Manan, andA. Mahmood, “Raynaud’s phenomenon: reviewing the patho-physiology and management strategies,” Cureus, vol. 14, no. 1,article e21681, 2022.[2] C. B.Westbury, K. J. Harrington, P. Rhys-Evans et al., “Raynaud'sphenomenon after radical radiotherapy for tumours of the head60.060.057.060.054.051.3(a)60.0 60.060.060.057.057.060.051.354.054.054.054.0 54.0(b)Figure 1: (a, b) Dose lines of radiotherapy treatment showing irradiated regions of the oral cavity.Figure 2: Picture of the oral tongue demonstrating left-sidedtongue pallor.3Case Reports in Vascular Medicineand neck,” Postgraduate Medical Journal, vol. 79, no. 929,pp. 176-177, 2003.[3] B. Lioger and E. Diot, “Raynaud's phenomenon of the tongue:uncommon presentation of a classical sign,” QJM: An Interna-tional Journal of Medicine, vol. 106, no. 6, pp. 583-584, 2013.[4] S. Chatterjee, “Raynaud phenomenon causing lingual pallorand dysarthria,” Canadian Medical Association Journal,vol. 188, no. 15, pp. E396–E396, 2016.[5] V. Grémain, L. Richard, V. Langlois, and I. Marie, “Raynaud'sphenomenon of the tongue,” Joint, Bone, Spine, vol. 84, no. 2,article 231, 2017.[6] J. Cohen, M. Lia Palomba, and L. Morris, “Raynaud’s phenom-enon of the tongue,” The Journal of Rheumatology, vol. 40,no. 3, article 1093, 2013.[7] E. Casey and N. Lawton, “Progressive systemic sclerosispresenting with Raynaud’s phenomenon in the tongue andsensory trigeminal neuropathy,” Rheumatology, vol. 11, no. 3,pp. 131–133, 1971.[8] M. Perry, S. Surtee, and Z. Nawaz, “Raynaud's of the tongue,”Internal Medicine, vol. 4, no. 8, 2017.[9] A. Mittal and A. Mittal, “Raynaud's of the tongue followingchemoradiation for squamous cell carcinoma of the orophar-ynx,” Molecular and Clinical Oncology, vol. 6, pp. 187-188,2017.[10] A. F. Ghiam and J. Cho, “Lingual Raynaud phenomenon,”Canadian Medical Association Journal, vol. 187, no. 15,pp. 1160–1160, 2015.[11] S. Boukovalas, A. C. Mays, and J. C. Selber, “Botulinum toxininjection for lower face and oral cavity Raynaud phenomenonafter mandibulectomy, free fibula reconstruction, and radia-tion therapy,” Annals of Plastic Surgery., vol. 82, no. 1,pp. 53-54, 2019.4 Case Reports in Vascular Medicine

Lingual Raynaud\u27s Phenomenon after Surgical and Radiotherapeutic Intervention for Oral Squamous Cell Carcinoma

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Lingual Raynaud\u27s Phenomenon after Surgical and Radiotherapeutic Intervention for Oral Squamous Cell Carcinoma

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