Breast Mass Isn't Cancer, but Why Is It Growing So Quickly?

A 30-year-old woman presents to the hospital in Turin, Italy, with a mass in her left breast. She explains that not long ago the lump was small, but it has rapidly increased in size. She has no family history of breast disease or ovarian cancer.

She notes that since the age of 2, she has had a general learning disability and epilepsy, as a result of neonatal hypoxia. To treat her neurological conditions, she has been taking sodium valproate, phenobarbital, clonazepam, and risperidone.

The patient is of normal weight, with a body mass index of 21. She notes that she did not begin menstruating until age 22; she had received combination hormone therapy with estrogen-progestin before then, but it had not produced the hoped-for effect of inducing the start of menstrual flow. She has not been pregnant.

Physical examination identifies a 3-cm fixed and firm lump with a undefined border, located below her left nipple areola complex. Clinicians perform an ultrasound, which reveals a solid, nonhomogenous lesion measuring 20×10 mm in size in left Q3-5. Color-doppler evaluation finds evidence of mild peripheral vascularization, irregular margins, and ductal ectasia without acoustic shadowing (figure).

Clinicians suspect a probable history of bilateral reactive axillary lymphadenopathy, and note fibrous mastopathy signs and fibroadenomas in both breasts. The ultrasound finding suggests malignancy, and an ultrasound-guided core needle biopsy is performed. Histopathology reports a benign fibroepithelial node, enriched in vascular space, suggestive of pseudoangiomatous stromal hyperplasia (PASH).

At the time the patient is diagnosed, her menstrual cycle is irregular, with normal menstrual flow occurring approximately every 40 to 60 days, she notes.

Because of the dimension of the breast mass, clinicians perform a lumpectomy; surgeons note that the lump is hardly dissociable from the adjacent tissue. After resection, the tumor is found to measure 25 mm. The patient is discharged the following day. Pathology confirms hamartoma-like fibroepithelial lesion with PASH features.

Follow-up

At 32 months follow-up, there is no disease recurrence.

Discussion

Clinicians reporting this case of PASH urge awareness of the hormonal risk factors associated with this benign stromal lesion, so that a suspected PASH lesion can be reported to the pathologist to ensure that it is distinguished from invasive cancer. This is essential to allow conservative management where possible, the authors emphasize.

First described by Vuitch, et al. in 1986, PASH is an uncommon benign breast lesion that generally presents as a fast-growing palpable lesion or gynecomastia. While the origins remain unclear, it appears to be associated with hormone (primarily progesterone) stimulation.

The nuclei of PASH stromal cells express high-density progesterone receptors, while expression of estrogen receptors is more variable. Histologically, PASH is characterized by a complex network of angulated and slit-like spaces lined by endothelial-like spindle cells and surrounded by dense collagenous stroma. Proliferation of fibroblasts and myofibroblasts and collagen over-secretion create a solid tissue with cystic areas resembling ectatic vessels (pseudo-vascular spaces).

Diagnosis

The authors of the case report note that although PASH as a main pathological finding is rare, incidental microscopic PASH is found in up to 23% of consecutive breast specimens. Diagnosis can be challenging – preoperative core biopsy fails to diagnose PASH in approximately 35% of cases. Furthermore, ultrasound imaging is nonspecific, as the lesion tends to appear as a hypoechoic ovoidal mass with regular margins.

As a benign entity, PASH must be histopathologically differentiated from low-grade angiosarcoma, the authors emphasize. This is based on histology with immunohistochemical staining support for CD31 and Factor VIII: angiosarcoma is CD31 and Factor VIII positive, whereas PASH is negative for these antibodies.

Treatment

A multidisciplinary approach is the best way to manage breast lesions, including PASH, the clinician authors note. Although treatment of PASH usually involves surgical excision, a "watch and wait" strategy can be applied if a diagnosis is made on core biopsy and the mass is less than 2 cm in size. Lumps that increase rapidly in size require surgical excision to assess the patient for ductal carcinoma in situ.

Although PASH can be found in about 25% of benign and malignant breast lesions, it is not associated with an increased cancer risk; in fact, it appears to be protective, the authors explain, although there have been two reported cases of synchronous tumoral PASH in the breast and axillary tissue.

Nevertheless, the authors caution, patients treated for PASH are more prone to ipsilateral breast cancer prevalence more than 5 years after PASH biopsy; PASH recurs in about 9-21% of cases -- probably due to the persistence of a residual mass after surgery.

In this patient, the combination of medications she was taking may have led to the development of PASH; progesterone is metabolized by cytochrome P450, which is inhibited by clonazepam, while valproate and risperidone are also metabolized by cytochrome P450. This may have set up a "competition" for the cytochrome between the multidrug therapy and progesterone, leading to an increased level of progesterone that may have stimulated PASH growth.

A hormonal etiology is also supported by the higher prevalence of PASH in premenopausal women (many of whom may be actively taking oral contraceptive pills), in 24-47% of men with gynecomastia, and by a reported case of PASH in a transgender man during hormone therapy or during pregnancy, the authors said.

Noting that PASH affects premenopausal women – most commonly those ages 41-50, according to one case series – or menopausal women taking hormone-replacement therapy, the case authors suggest that anti-hormonal therapy could theoretically reduce PASH mass. They cite a case report that proposes tamoxifen as an alternative approach to management of PASH, adding, however, that given the paucity of evidence, there is no support for anti-hormonal therapy as adjuvant therapy.

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