Angiolymphoid Hyperplasia With Eosinophilia Associated With Pregnancy: A Case Report and Review of the Literature

A case of angiolymphoid hyperplasia with eosinophilia (ALH) is reported in a 33-year-old woman who developed an auricular nodule during the second trimester of her pregnancy. Angiolymphoid hyperplasia with eosinophilia usually occurs on the head and neck of young adults and is more common in women than in men. Characteristic histologie features of ALH present in this case included proliferation of thick-walled blood vessels lined by prominent endothelial cells, infiltration of the interstitium by chronic inflammatory cells (mainly eosinophils), and presence of lymphoid follicles with germinal centers. The auricular tumor was completely excised. Thirteen months after excision, the patient remains tumor free. Although there are not many case reports on ALH during pregnancy or involving use of oral contraceptive pills, sex hormones may play a role in the pathogenesis of ALH. This hypothesis, in the context of cases previously described in the literature, and the differential diagnosis of ALH are discussed.

(Arch Pathol Lab Med. 2005;129:1168-1171)

Angiolymphoid hyperplasia with eosinophilia (ALH) is a rare benign vascular tumor characterized by solitary or multiple red to brown papules or nodules found mainly on the head and neck of young adults between 20 and 40 years of age,1 with a mean age at onset of 30 to 33 years.2 It has also been described in other tissues, including liver, orbit, spleen, palate, bone, heart, and blood vessels.1,3 It is more common in women than in men1 and is associated with peripheral blood eosinophilia of 6% to 34% in about 20% of patients.2,4 The lesions are often pruritic or painful and may coalesce into confluent plaques that are chronic, with little propensity for spontaneous resolution. Itching is significantly greater when the tumor is larger than 2 cm in diameter.1 A history of trauma is found in some patients (9% in the study by Olsen and Helwig4). The interval between trauma and the onset of the lesion ranges from 7 months to 20 years, with a median interval of 30 months.4 Lesion growth, tumor pulsation, and bleeding are other common presentations.2,4 Most intradermal lesions are small, with diameters of 0.5 to 2 cm; subcutaneous lesions may be much larger, up to 5 to 10 cm in diameter.2,5 The tumor is generally intradermal or subcutaneous, but it may involve deep soft tissues and vessels.1 Peripheral blood eosinophilia, enlargement of regional lymph nodes, and arteriovenous shunts have been reported but are variable features.4 Herein, we report a case of ALH that presented as an auricular nodule during the second trimester of pregnancy in a 33- year-old woman.

REPORT OF A CASE

A 33-year-old woman in her fourth month of a single gestation presented with fullness and pain in the auricle of her right ear for 4 weeks. She was gravida 4, para 3. The 2 1.5-cm lesion was cauliflower-shaped, covered with intact skin, and described as “peculiar appearing.” Fluctuation was felt over the right auricular concha. The patient reported that the pain did not respond to Cortisporin eardrops. Her complete blood count was normal, and there was no peripheral blood eosinophilia. She was operated on, with the diagnosis of possible right auricular abscess. Under local anesthesia, the area beneath the lesion was explored with a syringe. No purulent material was found. Therefore, a 5 4 3-mm incisional biopsy from the center of the lesion was taken and submitted for frozen section diagnosis. Further exploration of the area failed to reveal any abscess cavity or purulent material. The frozen section diagnosis was “actinic keratosis and benign spindle cell lesion, probable neurilemmoma.” Because of the benign character of the lesion, the patient was advised to defer excision of the lesion until after her pregnancy. The patient was prescribed cephalexin monohydrate and hydrocodone bitartrate. The preliminary pathology report from the permanent sections was a benign lesion with probable arteriovenous malformation. The glass slides were sent for consultation to the M. D. Anderson Cancer Center, Houston, Tex. The consultants’ diagnosis was ALH.

One month after the incisional biopsy, the patient presented to the emergency department, complaining of 2-day pain in the same lesion area of her right ear. She was afebrile but was described by the physician as having swelling of her right ear. She was diagnosed as having otitis externa with possible abscess and was prescribed cephalexin monohydrate and hydrocodone bitartrate.

She returned for the definitive treatment about 6 months after her first presentation and 43 days after her normal vaginal delivery following an uneventful pregnancy. The size of the lesion at this time was approximately 3 2 cm. It is not known if the patient was breastfeeding or if the lesion was still growing. Under general anesthesia, the operating microscope was used to excise the lesion with margins of 2 to 3 mm. The specimen was a 3 2.2 1-cm gray-tan soft tissue, which consisted of a segment of skin with underlying subcutaneous tissue and cartilage. The cut surfaces were fleshy. The lesion was submitted for frozen section diagnosis to confirm the negative surgical margins. A full-thickness skin graft from the right supraclavicular fossa was used to close the defect. The patient was discharged and prescribed cephalexin monohydrate, bacitracin ointment, and hydrocodone bitartrate. The lesion had not recurred 13 months after the operation.

Figure 1. Tombstonelike arrangement of cells in a large vessel of angiolymphoid hyperplasia (hematoxylin-eosin, original magnification 400).

Figure 2. Cytoplasmic vacuoles in the prominent endothelial cells (hematoxylin-eosin, original magnification 400).

Figure 3. Perivascular and interstitial infiltration of lymphocytes, plasma cells, and eos/nophils (hematoxylin-eosin, original magnification 400).

Figure 4. Presence of lymphoid follicles with germinal centers (hematoxylin-eosin, original magnification 400).

Figure 5. A thick-walled vessel with CD34-positive endothelial cells (CD34 immunohistochemical stain, original magnification 400).

Characteristic histologie features of ALH were present in the patient’s lesion, including proliferation of thick-walled blood vessels, many of which were lined by prominent endothelial cells, with some containing cytoplasmic vacuoles (Figures 1 and 2). The endothelial cells had a “tombstone” appearance. Perivascular and interstitial infiltration of lymphocytes, plasma cells, and eosinophils was also present (Figure 3). Eosinophils, which usually comprise 5% to 15% of the infiltrate,2 made up about 10% of the infiltrate in this case. Many lymphoid follicles, most of them with germinal centers, were present in our patient’s lesion (Figure 4). Immunohistochemical staining for CD34 was positive (Figure 5) but was negative for estrogen and progesterone receptors.

COMMENT

First described by Wells and Whimster6 as “subcutaneous angiolymphoid hyperplasia with eosinophilia,” ALH is a benign vascular tumor. It has also been called epithelioid hemangioma, inflammatory angiomatous nodule, atypical or pseudopyogenic granuloma, and histiocytoid hemangioma. There has been confusion in differentiating between ALH and Kimura disease. Kimura et al7 in 1948 in Japan indicated that Kimura disease was first described in the Chinese literature. They described the disease as an “unusual granulation combined with hyperplastic change of lymphatic tissue.” Kimura disease is prevalent among young men of Asian descent. It presents as lymphadenopathy with or without an associated soft tissue mass and involvement of major salivary glands. Although the skin lesions in Kimura disease also commonly occur on the head and neck, they are located deeper than ALH lesions, usually in subcutaneous tissues. Peripheral eosinophilia is almost always present in Kimura disease, but it is only present in about 20% of ALH cases. Elevated serum IgE is usually present in Kimura disease but is rare in ALH.1,8

Microscopically, lesions in Kimura disease lack the epithelioid endothelial cells that are the morphologic hallmark of ALH.9 Sclerosis, vascularization of the germinal centers, polykaryocytes, eosinophilic abscess, necrosis of the germinal centers, IgE-bearing dendritic cells in the germinal centers, and postcapillary venule proliferation are consistent features of Kimura disease. Kimura disease can also be distinguished from ALH by the presence of dense hyaline fibrosis in the affected lymph nodes.1,8

Angiolymphoid hyperplasia with eosinophilia has different presentations, resulting in various clinical impressions. In a study of 116 patients by Olsen and Helwig,4 the most common clinical diagnoses were epidermal cysts and angiomas. Consistency, color, shape, size, and growth rate of the lesion are some of the factors that lead to prebiopsy diagnoses of scalp nodule or mass, pyogenic granuloma, lipoma, lymph node, and Kaposi sarcoma.4 Histologically, the differential diagnoses of ALH include benign and malignant vascular lesions of the skin, as well as various reactive conditions dominated by lymphocytes and eosinophils. If the clinical presentation of ALH is considered along with its typical microscopic features, then one can exclude other vascular and reactive lymphoidconditions, such as cavernous hemangioma, pyogenic granuloma, venous lake, capillary aneurysm, Kaposi sarcoma, angiomatous lymphoid hamartoma, granuloma faciale, eosinophilic granuloma, polyarteritis nodosa, pseudolymphoma (eg, insect bite, lymphocytic infiltration of Jessner, and lymphocytoma cutis), cutaneous angiosarcoma, and epithelioid hemangioendothelioma.4

Histologically, cavernous hemangioma has large cavernous vascular spaces separated by scant stroma, but prominent endothelial cells and inflammatory infiltrate are not present. Although proliferating capillaries and acute and chronic inflammatory infiltrates are present in pyogenic granuloma, its marked edema and absence of tombstonelike endothelial cells help differentiate it from ALH. Venous lake has a single large dilated space or several connecting dilated spaces that have thin walls and are lined by a single layer of flattened endothelium and scant stroma. Capillary aneurysm is considered a precursor of venous lake and has similar histologie features. In the early stage of Kaposi sarcoma, dilated and sometimes irregular and angulated blood vessels with interspersed infiltrate of lymphocytes, plasma cells, and macrophages are seen, but plump endothelial cells and eosinophilic infiltration are not present. The later stage of Kaposi sarcoma, which is more cellular and may be composed of plump spindle cells, is rarely confused with ALH. Germinal center vascularization may be seen in the hyaline vascular type of angiomatous lymphoid hamartoma, but these germinal centers are generally atrophie and there are no eosinophilic infiltrates. Vasculitic changes, extravasated red blood cells, and hemosiderin deposition are often seen in granuloma faciale but not in ALH. Eosinophilic granuloma usually involves bone, and Langerhans histiocytosis is the characteristic feature of the lesion. In polyarteritis nodosa, inflammation occurs through the entire arterial wall, not just in the interstitium. Although mixed inflammation is present in pseudolymphoma, prominent endothelial cells of ALH are not seen. Cutaneous angiosarcoma is a malignant vascular neoplasm that affects older persons, presenting as slow- growing multiple red nodules on the face and scalp. It shows local invasion and distal metastatic spread. Microscopically, all degrees of differentiation of cutaneous angiosarcoma may be found, from mainly vascular channels with plump anaplastic but distinguishable endothelial cells to undifferentiated solid spindle cell tumors producing no blood vessels. Unlike ALH, cutaneous angiosarcoma does not show tissue eosinophilia.10 Finally, epithelioid hemangioendothelioma presents as a soft tissue mass in adults, and histologically it has short cords and nests of slightly pleomorphic endothelial cells surrounded by a myxoid matrix. Unlike ALH, epithelioid hemangioendothelioma has no tissue eosinophilia.11

Rarely does ALH regress spontaneously. Therefore, treatment is generally necessary. Different treatment modalities have been used, but about 30% of ALH lesions recur, although none have been reported to metastasize, to our knowledge. Intralesional injections of glucocorticoids, interferon alfa-2a, and cytotoxic agents, as well as cryotherapy electrodesiccation, and pulse-dye or long-pulse turntable dye laser, are among the modalities used. Deep surgical excision of ALH lesions has been reported to have the most favorable results, with no reported recurrence after 1-year follow-up.12 Our patient was treated with surgical excision, and after 13 months, she was still tumor free.

Four patients have been reported to develop ALH for the first time during the first trimester of pregnancy. Two of these patients had single nodules, and the other two had multiple lesions. A fifth patient, who had multiple asymptomatic lesions for years, had an increase in the size of lesions during her pregnancy.4 Gardner et al13 reported a case of ALH presenting as a pruritic mass on the right cheek that began when the patient became pregnant and grew rapidly during her pregnancy. Moran et al3 reported a case of ALH that arose at the junction of the soft and hard palates and enlarged during the first trimester of pregnancy. Two ALH cases have been reported by Moy et al.5 The ALH lesion in one of these cases resolved after discontinuation of oral contraceptive pills. The ALH lesions in the other patient increased in size during pregnancy. She also developed new ALH lesions, and all of her lesions decreased in size by half during the postpartum period. Biopsy specimens of the tumors in these 2 patients before remission were found to express a significant amount of estrogen and progesterone receptors, compared with no detection in their normal skin.

Our patient developed ALH during her pregnancy. The tumor increased in size throughout the pregnancy. The mass was 3 2 cm approximately 1 month after pregnancy, compared with 2 1.5 cm at her first presentation in the fourth month of the pregnancy. It is not known if the tumor stopped growing or decreased in size after the pregnancy. The histologie features of her lesion are typical for ALH. Her lesion was positive for CD34, a sensitive marker for endothelial differentiation. Immunohistochemical stains for estrogen and progesterone were negative in our patient. However, the occurrence of the disease during pregnancy suggests that sex hormones might have had a role in this case. Moy et al5 used monoclonal antibody assay to measure estrogen and progesterone receptor molecules with occupied or unoccupied binding sites. This method is more sensitive than the method we used, which is a nuclear stain. Although the number of ALH cases reported during pregnancy or involving use of oral contraceptive pills is limited, there are multiple findings that suggest the hypothesis that sex hormones may play a role in the pathogenesis of ALH. Higher prevalence of the dis ease among women and occurrence of the disease in association with sex hormones are two important observations. The high number of estrogen and progesterone receptors in the tumor cells of some patients5 and regression of the lesions after discontinuation of the effect of sex hormones are additional noteworthy findings. Further studies are needed to evaluate ALH more closely.

We thank Robert E. Lyon, DO, and Hamed Jafar-Nejad, MD, for reviewing the manuscript and for their helpful comments.

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Neda Zarrin-Khameh, MD, MPH; James E. Spoden, MD; Rue M. Tran, MD

Accepted for publication May 12, 2005.

From the Department of Pathology (Drs Zarrin-Khameh andTran)and Division of Otolaryngology, Department of Surgery (Dr Spoden), Texas Tech University Health Sciences Center, Lubbock.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Neda Zarrin-Khameh, MD, MPH, Department of Pathology, Texas Tech University Health Sciences Center, 3601 4th St, Lubbock, TX 79430 (e-mail: neda.zarrinkhameh@ttuhsc.edu).

Copyright College of American Pathologists Sep 2005