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Case Records of the Massachusetts General Hospital

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Case 36-2015: A 27-Year-Old Woman with a Lesion of the

Konstantina M. Stankovic, M.D., Ph.D., Oon T. Tan, M.D., Ph.D., and Peter M. Sadow, M.D., Ph.D.​​

Presentation of Case

From the Departments of Otolaryngolo‑ Dr. Konstantina M. Stankovic: A 27-year-old woman was seen in an outpatient otolaryn- gy (K.M.S.) and Pathology (P.M.S.), Mas‑ gology clinic of the Massachusetts Eye and Ear Infirmary, which is affiliated with this sachusetts General Hospital, the Depart‑ ments of Otolaryngology (K.M.S., P.M.S.) hospital, because of a pruritic lesion of the left ear canal, with recurrent bleeding. and Laser and Reconstructive Surgery One year before this presentation, a ballooning lesion had developed in the pa- (O.T.T.), Massachusetts Eye and Ear Infir‑ tient’s left ear canal that partially occluded the lumen and was associated with mary, and the Departments of and Laryngology (K.M.S., O.T.T.) and Pa‑ pruritus and recurrent bleeding. An unknown was administered topi- thology (P.M.S.), Harvard Medical School cally into the ear canal, with improvement in both bleeding and pruritus. Two weeks — all in Boston. before this presentation, bleeding from the left ear canal recurred, with associated N Engl J Med 2015;373:2070-7. pruritus of both ear canals. The patient was seen by a physician at another clinic, DOI: 10.1056/NEJMcpc1410941 who prescribed an otic suspension (consisting of neomycin, polymyxin B sulfate, Copyright © 2015 Massachusetts Medical Society. and hydrocortisone) and a 5-day course of oral azithromycin, as well as topical clobetasol propionate ointment (0.05%) for pruritus; the symptoms did not improve, and the bleeding did not resolve. She was referred to the outpatient otolaryngology clinic of the Massachusetts Eye and Ear Infirmary. The patient reported brief episodes of sharp, stabbing otalgia on the left side, with episodes of disequilibrium that lasted for a few seconds and were not associ- ated with , , or changes in . She had not had recurrent otitis media during childhood, exposure to loud noises, or head trauma with loss of consciousness. She took no other and had no known . She worked in a health-related field. She did not smoke or drink alcohol. On examination, the patient appeared to be well, with no craniofacial dysmor- phism. A light pink raised lesion (approximately 1.0 cm by 1.0 cm by 0.5 cm), with a cobblestone appearance and several prominent vessels, was present on the pos- terior tragus of the left ear; on examination with an operating microscope, the lesion extended medially along the anterior wall of the external auditory canal. The , medial left ear canal, and entire right ear canal were normal. There was no tragal tenderness. A 512-Hz tuning fork was used to show that the Rinne test was positive bilaterally (with air conduction greater than ) and that, on the , the sound was located along the midline. The remainder of the

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examination of the nose, nasopharynx, mouth, Table 1. of Lesions of the External pharynx, larynx, neck, ears (for hearing acuity for Auditory Canal. conversational speech), and third through twelfth cranial nerves was normal, and there Infectious was no spontaneous . A culture of the Otitis externa (due to Pseudomonas aeruginosa) left external ear canal grew a moderate amount Inflammatory of coagulase-negative staphylococcus species. Top- Atopic dermatitis (eczema) ical nystatin–triamcinolone ointment was adminis- Insect bite tered to the left ear twice daily for 2 weeks, with- Sarcoidosis out improvement. One week later, the patient returned to the out- Kimura’s disease patient clinic. She reported near constant pruritus Idiopathic or reactive and bleeding that had increased in amount and Granuloma faciale frequency. The lesion in the left ear canal appeared Cutaneous lymphoid hyperplasia to be unchanged from the previous examination. Neoplastic A small crust covered the most medial aspect of Malignant the lesion. Squamous-cell carcinoma Nine days later, a diagnostic procedure was performed. Basal-cell carcinoma Ceruminous-gland carcinoma Differential Diagnosis Granulocytic sarcoma CD8+ T-cell lymphoproliferative disease of the ear Dr. Stankovic: I cared for this patient and am Benign aware of the diagnosis. The differential diagno- Lobular capillary hemangioma (pyogenic granuloma) sis of her pruritic, bleeding, painful lesion in Epithelioid hemangioma (angiolymphoid hyperplasia the left external auditory meatus includes in- with eosinophilia) fectious, inflammatory, idiopathic, and neo- plastic causes (Table 1). ment of the face and neck, which was not present Infectious and Inflammatory Processes in this patient. The most common infectious cause of a lesion Another relatively common inflammatory pro- in the ear canal is otitis externa, which is typi- cess that occurs in the ear canal is an insect bite. cally due to Pseudomonas aeruginosa. Features that Insect bites are characterized by discomfort, itch- support this diagnosis are the location of the ing, and focal pain; this patient had these symp- lesion and focal pain; the condition is not as- toms. However, the chronic nature of the patient’s sociated with a particular age or sex. However, symptoms and the absence of focal erythema, this diagnosis is unlikely because the lesion did warmth, and edema make an insect bite unlikely. not respond to topical or oral antibiotic agents Sarcoidosis, which is a chronic inflammatory and a culture of the ear canal did not grow any disease associated with noncaseating granulo- pathogens. mas, is a consideration in this case, because its A common inflammatory cause of a lesion in dermatologic manifestations include maculopap- the ear canal is atopic dermatitis (i.e., eczema). ular eruptions, subcutaneous nodules, and lupus This diagnosis is supported by the presence of pernio, a plaquelike violaceous lesion that occurs an intensely pruritic, erythematous lesion with in the ear or on the nose, cheek, or skin. How- scaly crusting and small, sometimes confluent ever, sarcoidosis is unlikely because it typically is vesicles. However, atopic dermatitis is typically systemic and has respiratory manifestations. In associated with asthma, allergic rhinitis, or other patients with sarcoidosis, skin involvement (seen atopic disorders; this patient did not have any of in 25% of patients) is much less common than these conditions. In addition, atopic dermatitis of involvement of the lungs (seen in 90%) or lym- the ear is typically a part of generalized involve- phoid tissues (seen in 75%).1

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Idiopathic and Reactive Processes carcinoma, which is much more common than Granuloma faciale is an uncommon, benign basal-cell or ceruminous-gland carcinoma. How- chronic skin condition that is usually considered ever, squamous-cell carcinomas of the external to be idiopathic but is sometimes thought to be auditory canal typically occur in patients with due to sun exposure. It is characterized by the chronic suppurative otitis media, which this presence of a single cutaneous nodule or multi- patient did not have. Furthermore, the patient’s ple cutaneous nodules, which are sometimes young age and the absence of a history of exces- covered with telangiectasias and commonly oc- sive sun exposure and of cranial-nerve deficits cur on the head and neck. Granuloma faciale is due to an invasive tumor make a malignant tu- much more common in persons of European mor unlikely. descent (such as this patient) than in those of Granulocytic sarcoma, also known as myeloid Asian or African descent. However, this diagno- sarcoma or chloroma, is a solid extramedullary sis is unlikely in this case because granuloma collection of myeloid leukemia cells that can oc- faciale typically occurs on areas that have been cur in the ear canal of an otherwise asymptom- exposed to the sun (including periauricular and atic patient.2 Although the onset of granulocytic helical areas); furthermore, the disease is usually sarcoma can precede that of acute myeloid leu- asymptomatic, is more common in men than in kemia by years,3 granulocytic sarcoma is un- women, and is associated with a median age at likely in this case because of the absence of a presentation of 45 years. myeloproliferative neoplasm, myelodysplastic syn- Another entity to consider is cutaneous lym- drome, or acute leukemia. phoid hyperplasia, a benign condition that is often considered to be idiopathic but is sometimes Benign considered to be reactive to jewelry, trauma, ar- An indolent CD8+ lymphoid proliferation of the thropod bites, folliculitis, or infection. It is not ear has been recognized as a distinct primary associated with a particular race but is twice as cutaneous T-cell lymphoproliferative disorder.4,5 common in women as in men, and two thirds of The lesion characteristically develops on the ex- cases occur before the patient is 40 years of age; ternal ear, grows slowly, and can be erythema- this patient’s demographic features are consis- tous and tender or painless. It is typically not in- tent with the diagnosis. Cutaneous lymphoid tensely pruritic or bleeding and commonly occurs hyperplasia is further supported by the nodular on the helix of the ; these features make nature, small size, and location of the patient’s the diagnosis unlikely in this case. lesion; a cutaneous lymphoid hyperplasia lesion Lobular capillary hemangioma, also known is typically less than 1 cm in diameter, and in as pyogenic granuloma, is a common, benign 70% of cases, it occurs on the face or other sites vascular tumor–like lesion involving the external on the head and neck, including the external ear. ear that may be due to trauma, hormones, or However, cutaneous lymphoid hyperplasia is typi- viral infection. The small, solitary nodular lesion cally associated with minimal symptoms, and the is prone to bleeding and ulceration (as was seen lesion is often red to purple. in this case). However, lobular capillary heman- gioma is unlikely because it is typically a glisten- Neoplasms ing red papule that evolves rapidly over a few A neoplastic cause of the lesion is supported by weeks, whereas the lesion seen in this case had the chronic and escalating nature of the patient’s a cobblestone appearance and evolved over many symptoms, along with the vascular markings on months. In addition, the incidence of lobular cap- the lesion. Both malignant and benign neoplasms illary hemangioma peaks in the second decade, should be considered. but this patient is in her third decade.

Malignant Epithelioid Hemangioma Malignant tumors of the external auditory canal An important diagnostic consideration in this are rare. The most common primary malignant case is epithelioid hemangioma, also known as tumor to occur in this location is squamous-cell angiolymphoid hyperplasia with eosinophilia. The

2072 n engl j med 373;21 nejm.org November 19, 2015 The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on June 27, 2016. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved. Case Records of the Massachusetts General Hospital appearance and location of the lesion, the asso- less commonly located in deep soft tissues. In ciated symptoms, and the patient’s age and sex the periphery of the lesion, the blood vessels are are all typical of this entity. Epithelioid heman- well formed, but in the center, the blood vessels gioma is an uncommon, benign neoplasm that are less well formed and often surround a single, is characterized by isolated or grouped papules, centrally located, larger vessel. The characteristic plaques, or nodules and occurs in the skin of the endothelial cells are plump, with ample eosino- head and neck, most commonly in the periauricu- philic cytoplasm and nuclei that may contain a lar skin, forehead, and scalp.6 An isolated lesion, prominent nucleolus. Epithelioid hemangiomas which is typically 0.5 to 2.0 cm in diameter, occurs have cuboidal-to-hobnail (tombstone-like) pro- in 80% of cases. The lesion is characteristically jection into the vascular lumina; they have a pruritic, painful, and prone to bleeding. Several multilobular growth pattern and tend to be cir- studies indicate a higher incidence in women than cumscribed more often in subcutaneous tissue in men, and the median age at onset is 30 years than in the dermis, where they may be poorly (range, 20 to 50). circumscribed. They may occasionally have an In the past, epithelioid hemangioma was of- infiltrative pattern in deep soft tissue (which ten confused with Kimura’s disease, a chronic was seen in this case) and may have spindled, inflammatory disorder of unknown cause that is cellular areas and a fibromyxoid stroma. The most common in young men of Asian descent. neoplastic blood vessels are accompanied by a Kimura’s disease is clinically manifested by sub- variable inflammatory infiltrate that is com- cutaneous masses in the region of the head and posed largely of lymphocytes and eosinophils neck, often with associated lymphadenopathy. but also of mast and plasma cells; eosinophils Kimura’s disease is also associated with blood were not visible in this case. The inflammatory eosinophilia, elevated levels of IgE, and in some changes are most prominent at the periphery of cases, the nephrotic syndrome. The diagnosis of the lesion, and the surrounding lymphoid cuff Kimura’s disease is unlikely in this case. may have the appearance of being contained in For diagnostic and therapeutic purposes, I a lymph node.7-9 performed a wide local excision of the lesion and Because the depth of the tumor from the split-thickness skin grafting. surface can vary and the tumor can have indis- tinct borders, complete excision is difficult and Dr. Konstantina M. Stankovic’s recurrence is common. In this case, the tumor Diagnosis extends to the tissue margins, and thus the risk of recurrence is high. Epithelioid hemangioma. Discussion of Management Pathological Discussion Dr. Stankovic: The lesion recurred 2 months after Dr. Peter M. Sadow: The excision specimen was a it had originally been excised, which occurs in skin ellipse (1.2 cm by 1.0 cm by 0.3 cm), with up to 50% of patients. Since spontaneous resolu- focal scaled crust that was visible on the skin tion is rare, we discussed options for manage- surface and no grossly evident dermal lesion. The ment of recurrent epithelioid hemangioma. entire specimen was submitted for histologic ex- amination (Fig. 1A and 1B). The dermis contained Management of Recurrent Epithelioid discontinuous foci of tumor, consisting of blood Hemangioma vessels with plump, eosinophilic, epithelioid en- Options for drug therapy include intralesional dothelial cells and patchy clusters of lymphocytes. injections of glucocorticoids or interferon alfa-2b, These features are typical of epithelioid heman- topical treatment with imiquimod or tacrolimus, gioma. The tumor focally extended to the lateral and systemic administration of glucocorticoids, and deep-tissue edges. isotretinoin, or mepolizumab (anti–interleukin-5 Epithelioid hemangiomas are generally lo- antibody). The main advantage of drug therapies cated in the dermis or subcutaneous tissue and is a good cosmetic outcome. However, such

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A B

* *

C D

*

Figure 1. Excision Specimens from the External Auditory Canal. Hematoxylin and eosin staining of the original excision specimen (Panel A) shows discrete proliferations of eosino‑ philic, epithelioid cells (ovals), with slitlike vascular spaces filled with blood (arrows). At higher magnification (Panel B), plump, epithelioid endothelial cells are visible; they have round‑to‑oval, vesicular, cleared‑out nuclei (arrows) with prominent nucleoli, as well as capillary and venule (asterisks) formation. Hematoxylin and eosin staining of the excision specimens of the recurrent lesion (Panel C) shows a fibrotic dermis and the multifocal nature of the lesion (ovals), as well as the associated and perilesional mixed chronic inflammatory infiltrate (arrows). At higher magnifi‑ cation (Panel D), the inflammatory infiltrate is seen to contain a mixture of cell types — predominantly lymphocytes with scattered eosinophils (arrows) — clustering around an abnormal blood vessel, with some cells showing char‑ acteristic hobnail projection into the vascular lumen (asterisk). Immunohistochemical staining for mast‑cell tryptase (Panel D, inset) shows the presence of numerous mast cells.

therapies are not curative, rely on patient adher- Laser therapy typically requires multiple ence, and may be associated with systemic side treatments, and effectiveness is inversely corre- effects. lated with the depth of invasion or vessel size. Surgical options include laser therapy, cryo- Although radiation has been used to treat recur- surgery, electrosurgery, and reexcision with ei- rent epithelioid hemangioma because of good ther a traditional method or Mohs micrographic cosmetic outcome, it is associated with risks of surgery. The advantage of surgical treatment is osteoradionecrosis of the temporal bone, malig- that it addresses the vascular segment at the nant transformation of a benign lesion, and de- base of the lesion to minimize the likelihood of layed . disease recurrence. A disadvantage is postopera- The patient first elected to undergo mini- tive scarring, which could lead to stenosis of the mally invasive laser treatment. I performed one ear canal in this patient. treatment with a potassium titanyl phosphate

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(KTP) laser, which resulted in regression of the lesion. However, the lesion recurred 2 months KTP Pulsed-dye Alexandrite later, and over the next 18 months, multiple la- (532 nm) (585–595 nm) (755 nm) ser treatments (with KTP and pulsed-dye lasers) and an intralesional glucocorticoid injection were administered. Transient regression and re- EPIDERMIS lief of symptoms occurred, but with recurrence after 1 to 2 months and ultimate development of a second lesion.

I consulted Dr. Tan of the Laser Center at the DERMIS Massachusetts Eye and Ear Infirmary for consid- eration of combination therapy with surgical reexcision and laser treatment. SUBCUTANEOUS FAT

Laser Treatment for Epithelioid Hemangioma SUBCUTANEOUS MUSCLE Dr. Oon T. Tan: Although this patient had under- Figure 2. Depth of Penetration of Laser Beams by Wavelength. gone several treatments — including surgery, The depth of penetration of laser beams into the skin varies by wave‑ intralesional glucocorticoid injection, and laser length. The skin is a turbid medium that affects the absorption, scattering, therapy — that resulted in short periods of qui- transmission, and reflection of the delivered light beam. In patients with escence accompanied by relief of her symptoms, fair skin, light delivered at a wavelength of 532 nm will penetrate the skin the tumor persistently recurred. The failure of to a depth of 0.8 mm from the dermoepidermal junction, light delivered these treatments to eradicate the tumor sug- at a wavelength of 585 to 595 nm will penetrate to a depth of 1.3 mm, and light delivered at a wavelength of 755 nm will penetrate to a depth gested that we needed a more effective treatment of 1.5 to 1.8 mm. KTP denotes potassium titanyl phosphate. method. The treatment had to be tumor-specif- ic, inducing minimal damage to healthy adjacent tissues and preserving structures in the auditory chromophore. The wavelength that has maxi- canal that were located distal to the tumor. mum absorption by hemoglobin is approximate- Why had the KTP and pulsed-dye lasers been ly 585 to 595 nm, and thus the initial choice of ineffective in eradicating the epithelioid heman- the pulsed-dye laser was appropriate. However, gioma? A unique aspect of the laser beam is its the depth of penetration at this wavelength was ability to penetrate the skin to different depths insufficient to destroy the deepest aspect of the as a function of its wavelength (Fig. 2).10 For tumor, and so we decided to use a more deeply example, the KTP laser, which has a wavelength penetrating, vascular-specific laser, the Alexan- of 532 nm, will penetrate the skin to a depth of drite laser, which has a wavelength of 755 nm 0.8 mm from the dermoepidermal junction,11 and penetrates the skin to a depth of 1.5 to 1.8 mm whereas the pulsed-dye laser, which has a wave- from the dermoepidermal junction.14 length of 585 to 595 nm, will penetrate to a Together with Dr. Stankovic, we developed a depth of approximately 1.3 mm.12 In this case, it protocol for performing a complete excision of seemed likely that neither the KTP laser nor the the lesion (Fig. 3A and 3B) and treating the site pulsed-dye laser had penetrated deeply enough of the excision intraoperatively with a combina- to completely destroy the epithelioid hemangio- tion of the Alexandrite laser (a 12-mm section for ma lesions and that tumor remnants had per- 20 msec, with a wavelength of 755 nm, at 22 J per sisted beyond the treated margins. square centimeter) and the pulsed-dye laser (a 7-mm Another aspect of laser therapy to consider is section for 20 msec, with a wavelength of 595 nm, selective photothermolysis, a technique used to at 9 J per square centimeter). A split-thickness skin concentrate the laser beam on a selected chro- graft was placed over the treated site, and the mophore.13 The vascular channels of epithelioid area was packed with a pressure dressing. Five hemangioma contain red cells; therefore, in this additional combined laser treatments were deliv- case, hemoglobin was the selected endogenous ered at 4-week intervals.

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A Pathological Discussion

Dr. Sadow: Two years after the original excision had been performed, two excision specimens of Tumor the recurrent lesion were obtained from the left ear canal that were designated as anterior and superior (Fig. 1C and 1D). The anterior specimen measured 1.5 cm by 1.0 cm by 0.2 cm, and the superior specimen measured 1.0 cm by 0.4 cm by 0.2 cm. The anterior specimen had extensive tumor involvement, which focally extended to both lateral and deep-tissue margins. The tumor on the superior specimen appeared to have been completely excised. Eosinophils were rare. The B stroma immediately adjacent to the tumor con- tained a lymphoid-rich inflammatory infiltrate with plasma cells that were positive for IgE. Staining for tryptase and CD117 showed numer- ous mast cells (Fig. 1D); mast cells are often seen in epithelioid hemangioma and may explain the patient’s itching. Dr. Stankovic: The patient was seen for follow-up 7 months after the combination treatment with reexcision, Alexandrite and pulsed-dye lasers, and split-thickness skin grafting. There was no evi- C dence of recurrence at the treated site (Fig. 3C). However, a small satellite lesion, measuring 5 mm in diameter, was noted lateral and superior to the original lesion. The patient underwent one treat- ment with the Alexandrite and pulsed-dye lasers. At follow-up 10 months after this treatment, the lesion was asymptomatic and unchanged in size and had no vascular markings.

Anatomical Diagnosis

Figure 3. Photographs of the Excision Site. Epithelioid hemangioma. Panel A shows the lesion in the external auditory canal before treatment. Panel B shows the site after surgical This case was presented at Otolaryngology Grand Rounds. excision. Panel C shows the site after combined surgical No potential conflict of interest relevant to this article was reported. and laser treatment; the lesions were completely cleared. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

References 1. Newman LS, Rose CS, Maier LA. Sar- 4. Géraud C, Goerdt S, Klemke CD. Pri- primary cutaneous T-cell lymphoma? Am coidosis. N Engl J Med 1997;​336:​1224-34. mary cutaneous CD8+ small/medium- J Surg Pathol 2007;​31:​1887-92. 2. Case Records of the Massachusetts sized pleomorphic T-cell lymphoma, ear- 6. Medscape. Angiolymphoid hyperpla- General Hospital (Case 36-2010). N Engl J type: a unique cutaneous T-cell lymphoma sia with eosinophilia (http://emedicine​ Med 2010;363:​ 2146-56.​ with a favourable prognosis. Br J Derma- .medscape​.com/​article/​1082603-overview). 3. Neiman RS, Barcos M, Berard C, et al. tol 2011;​164:​456-8. 7. Effat KG. Angiolymphoid hyperplasia Granulocytic sarcoma: a clinicopatholog- 5. Petrella T, Maubec E, Cornillet-Lefeb- with eosinophilia of the auricle: progres- ic study of 61 biopsied cases. Cancer 1981;​ vre P, et al. Indolent CD8-positive lym- sion of histopathological changes. J Lar- 48:1426-37.​ phoid proliferation of the ear: a distinct yngol Otol 2006;​120:​411-3.

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8. Mariatos G, Gorgoulis VG, Laskaris et al. Correlations between light penetra- using pulsed irradiation. J Invest Derma- G, Kittas C. Epithelioid hemangioma tion into skin and the therapeutic out- tol 1989;92:​ 868-71.​ (angiolymphoid hyperplasia with eosino- come following laser therapy of por- 13. Anderson RR, Parrish JA. Selective philia) in the oral mucosa: a case report twine stains. Lasers Med Sci 2002;​17:​ photothermolysis: precise microsurgery and review of the literature. Oral Oncol 70-8. by selective absorption of pulsed radia- 1999;​35:​435-8. 11. Bouchier-Hayes DM, Anderson P, Van tion. Science 1983;​220:​524-7. 9. Saiji EGL, Hornick JL. Epithelioid Appledorn S, Bugeja P, Costello AJ. KTP 14. Saleh N, Badr Y, Shokeir H, et al. and epithelial-like tumors. In:​ Hornick laser versus transurethral resection: ear- Comparative study between Ruby, Alexan- JL, ed. Practical soft tissue pathology: ​a ly results of a randomized trial. J Endou- drite and Diode lasers in hirsutism. Egyp- diagnostic approach. Philadelphia:​ Else- rol 2006;20:​ 580-5.​ tian Dermatol 2005;​1:​5 (http://www​.edoj​ vier, 2013:160-2.​ 12. Tan OT, Murray S, Kurban AK. Ac- .org.eg/​ vol001/​ 00102/​ 05/​ paper​ .pdf).​ 10. Ackerman G, Hartmann M, Sherer K, tion spectrum of vascular specific injury Copyright © 2015 Massachusetts Medical Society.

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