—  SPECIALTY CONFERENCE  —

Pediatric Pathology

Case 1 - Childhood Asymmetric Labium Majus Enlargement

Sara O. Vargas
Children's Hospital
Boston, MA


Click on each slide thumbnail image for an enlarged view
Clinical summary
This 7-year-old girl presented with painless nontender swelling of the left labium majus that had been apparent for one year. The area was soft without overlying skin discoloration, and although no distinct mass was palpable, the left labium majus was noted to be distinctly larger than the right. Breasts were Tanner stage 1, and there were no early pubertal signs. FSH, LH, and estradiol were within normal limits. The abnormality was followed for 6 months and appeared to enlarge. Ultrasound examination failed to reveal a discrete mass, and the sonographic chang es were described as "extra soft tissue." MRI showed a somewhat circumscribed area (low in signal intensity on T1-weighted images, high in signal intensity on T2-weighted images, and enhancing fairly homogeneously with gadolinium) measuring approximately 4 x 2 x 2 cm. Given the concern for possible malignancy, excision was performed. In the operative report the surgeon stated, "There was no clear definable mass." The tissue was described as fatty and likened to a lipoma. There was no inguinal hernia.


Case 1 - Figure 1 -
Gross examination showed fibrofatty tissue without discrete lesional boundaries.
Case 1 - Figure 2 -
A sparsely cellular collection of round, oval, and spindled fibroblasts expanded fibrous septa and surrounded fat lobules, individual adipocytes, and blood vessels (original magnification, 10x).
Case 1 - Figure 3 -
Here, the fibroblasts were surrounded by an abundant pale matrix containing thin and thick collagen and elastic fibers (original magnification, 20x).



Case 1 - Figure 4 -
Many fibroblasts were slightly plump and showed amphophilic cytoplasm, often with bipolar cytoplasmic extensions (original magnification, 40x).
Case 1 - Figure 5 -
Nerves characteristically showed thick perineuria and myxoid change (original magnification, 20x).
Case 1 - Figure 6 -
More heavily collagenized areas alternated with less heavily collagenized areas. Defining any boundary of the abnormality was difficult (original magnification, 4x).



Case 1 - Figure 7 -
An elastic tissue stain highlighted numerous elastic fibers (original magnification, 40x).
Case 1 - Figure 8 -
Immunostaining for estrogen receptor highlighted a subset of the plump fibroblast nuclei (original magnification, 40x).


Pathologic findings
Gross examination showed a 4.5 x 3.3 x 1.0 cm fragment of pale tan fibroconnective tissue. Microscopically, the tissue consisted of the usual constituents of vulvar soft tissue, including fibrous tissue, fat, blood vessels, and nerves. The fibrous tissue component had unusual morphologic features. The fibroblasts were plump, often showing amphophilic cytoplasmic tails. They were set in an abundant pale myxoid matrix rich in elastic fibers. The pallor of the matrix varied, sometimes resulting in a pattern of light and dark bands appreciable at scanning magnification. The fat, blood vessels and nerves were fairly unremarkable, aside from being surrounded by the apparent expansion of fibrous tissue. Nerves showed myxoid change and perineurial thickening.

Diagnosis
Childhood Asymmetric Labium Majus Enlargement

Follow-up
The swelling recurred during the year after surgery but then regressed in the following year.

Discussion
This lesion is a typical example of childhood asymmetric labium majus enlargement (CALME), a lesion of pre- or early puberty that is probably more akin to asymmetric breast budding than to a neoplasm. CALME is a fairly commonly biopsied pediatric lesion. At Children's Hospital Boston, it constitutes 22% of all vulvar soft tissue lesions. It presents in a discrete age group, usually around age 8 (range, 3.9 to 13.2 years). Occasionally the enlargement may appear to be bilateral but asymmetric. Radiologic imaging and surgical exploration fail to reveal discrete boundaries. By MRI, the signal may be hypo-, iso- or hyperintense and may extend to the pubic ramus. Occasional patients referred for a clinically unilateral mass may have bilateral signal abnormalities on MRI. Surgery is most often undertaken with concern for a neoplasm, but occasionally for a suspected lymphatic malformation or inguinal hernia.

Histologically, the lesions show the usual constituents of vulvar soft tissue, with an expansion of the fibrous component. Sparsely to moderately cellular interconnected fibrous bands encircle fat lobules, blood vessels, and nerves. The bands contain plump fibroblasts in an abundant matrix with thin collagen fibers, frequent elastic fibers, and pale myxoid material. By comparison with age-matched controls, CALME shows expanded fibrous septa without disruption of the normal architecture. Both CALME and age-matched controls are immunopositive for estrogen receptors.

Ultrastructurally, CALME shows fibroblasts with abundant rough endoplasmic reticulum. Nuclear fibrous lamellae are prominent. The extracellular matrix contains precollagen, collagen, elastic fibers, and numerous proteoglycan granules. Cytogenetic analysis, performed in 3 cases, has demonstrated normal 46,XX karyotypes.

Recurrence of CALME is extremely common, probably occurring in excess of 50% of patients. In the patients without histologically documented recurrence, there was often a history of preceding inguinal hernia exploration or "lipoma" resection at the same site. Of note, in the one patient whose postoperative recurrence was followed with observation rather than re-excision, the lesion resolved spontaneously.

In the breast, physiologic maturational changes are well known, characterized by the Tanner staging system. Asymmetric breast swelling at puberty is a common and well recognized condition; it usually resolves to cosmetic satisfaction. Gynecomastia occurs in up to 80% of boys at puberty, may be unilateral or bilateral, and usually resolves spontaneously.

The labia majora (as well as breasts) are typically enlarged at birth due to maternal hormones; their rounded puffy character is lost after 2-6 weeks. Thickening, protrusion, and rugation of the labia majora and minora are said to precede other signs of puberty, usually 1-2 years before menarche. It seems clear that the vulva, like the breasts, is intrinsically subject to physiologic hormonal response. Many nonhuman mammalian species are known to show cyclic vulvar swelling in association with estrous cycles, stimulated by estrogen. Microscopic examination has shown the swollen tissue to consist of "normal fibroplasia", ultrastructurally showing the same extracellular matrix constituents as CALME. Until the description of CALME in 2005, asymmetric development of the human labia majora had not previously appeared in MEDLINE, nor in textbooks of pediatric gynecology or pathology.

The differential diagnosis of CALME may include labia minora hypertrophy, another vulvar lesion consisting predominantly of an expanded fibrous tissue component, with fibroblast morphology and matrix similar to CALME. Labia minora hypertrophy shows clinical differences from CALME. Among pediatric patients it is resected in the late teenage years, primarily for cosmetic reasons and never with the suspicion for a neoplasm.

Lesions characterized by edema may also enter the differential diagnosis of CALME. Postparacentesis vulvar edema can cause unilateral labium majus swelling after paracentesis or laparascopy when ascites or insufflation fluid may track into the vulva; this clinical scenario did not apply among CALME patients. Massive localized lymphedema, like CALME, occurs in the proximal medial extremities, often around the inguinal region, and often in patients with previous surgery at the same site. It is also characterized by an expansion of fibrous septa and an abundant pale matrix rich in "edema fluid." Lobules of mature fat are encircled by the fibrous tissue. However, massive localized lymphedema is described in morbidly obese patients and is characteristically extremely large (mean, 7.5 kg). Massive edema of the ovary, while involving a different organ, shares some features with CALME. It is characterized by an apparent proliferation of fibroblasts with a pale matrix and does not show disruption of the underlying architecture. It occurs in young women (6-33 years old), is most often unilateral, and appears to be hormone-related, often associated with menstrual disturbances or hyperandrogenism. Of note, massive edema of the ovary can be difficult to distinguish from ovarian fibromatosis. Lymphatic malformation is also in the differential diagnosis of CALME. Both may show increased hair on the affected side and an increase in fibrous tissue. However, CALME does not show the abnormal lymphatic channels and sclerosis that can be evident in lymphatic malformation.

Traumatic vulvar lesions may also be included in the differential diagnosis of CALME. At least one CALME patient was known to have had a contusive blow preceding the development of labium majus enlargement. Perineal nodular induration (also known as "third testicle of the cyclist" or "bicyclist's vulva"), nodular fasciitis, and post-operative spindle cell nodule have all been described in the vulva and are all characterized by a proliferation of fibroblasts. However, they are separable by different clinical factors and additional distinct histologic features. In patients with CALME in which the recurrence was examined histologically, it was identical to the primary resection specimen in all instances.

Infiltrative fibroblastic neoplasms may also enter the differential diagnosis of CALME. Aggressive angiomyxoma is one such lesion. It occurs in women of reproductive age, presents as an ill-defined swelling or mass, and grows along tissue planes without invading organs. It tends to be large (>10 cm) and may, like CALME, extend to the pubic ramus. Microscopically, aggressive angiomyxoma is characterized by sparse, evenly distributed small spindle to stellate cells with one or more eosinophilic cytoplasmic processes, small and uniform nuclei, a loose myxoid background with delicate wavy collagen fibrils, a prominent vascular component with dilated thin and thick-walled vessels haphazardly throughout the stroma, delicate smooth muscle bundles adjacent to blood vessels, and extravasated erythrocytes. Its fibroblasts are characteristically ER-positive. Ultrastructural examination shows the spindle cells to have fibroblastic-myofibroblastic differentiation and a lack of the fibrous nuclear lamina seen in CALME. Aggressive angiomyxomas may show chromosomal rearrangements involving chromosome 12q15 (site of HMGIC gene).

Fibroma or fibromatosis may also be included in the differential diagnosis of CALME. In fact, the lesion termed "prepubertal vulval fibroma" is undoubtedly the same lesion as CALME. In their recent paper, Iwasa and Fletcher interpret the process as an "infiltrative fibroblastic neoplasm with a tendency to recur when incompletely excised." Others have also alluded to the process in abstract form. While the fibroblasts of CALME have a poorly circumscribed "infiltrative" appearance, it is apparent that an expanded study of the process (including detailed clinical findings, thorough review of radiographic images, hormone receptor immunostaining, electron microscopic examination, comparison with vulvar tissue from age-matched controls, and cytogenetic analysis) provides for new conclusions about the lesion's pathogenesis that may spare patients potentially deforming surgery.

In the field of pediatric pathology, pathologists see the body as a whole, with an appreciation of normal growth and development and their variation. The case presented exemplifies this important aspect of our discipline.

References

CALME:

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Physiologic changes:
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Differential diagnosis:
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