Cutaneous leiomyoma of the nipple: also consider hereditary leiomyomatosis and renal cell cancer

Background

Cutaneous leiomyoma is an uncommon, benign tumour of smooth muscle tissue. Its exact incidence is unknown (1). It may be accompanied by local pain. Leiomyomas are divided into 3 types: piloleiomyoma, angioleiomyoma and genital leiomyoma. Piloleiomyoma and angioleiomyoma arise from the smooth muscle tissue of, respectively, the arrector pili muscle of the pilosebaceous unit and the arterial and venous vessel wall. Genital leiomyoma, which originates from the smooth muscle tissue of the scrotum, penis and vulva, is the least common (2). A leiomyoma of the nipple, arising from the areolar erectile smooth muscle tissue, is rare. In the literature it is often classified as a genital leiomyoma, whereas histologically it more closely resembles piloleiomyoma and is better regarded as a separate type (2-5).

 In the case of multiple cutaneous leiomyomas, one should be alert to the syndrome of hereditary leiomyomatosis and renal cell cancer, or "hereditary leiomyomatosis and renal cell carcinoma" (HLRCC). In this syndrome, renal cell carcinoma occurs in addition to leiomyomas of the skin and uterus (2, 6).

 In the case of multiple cutaneous leiomyomas, one should be alert to the syndrome of hereditary leiomyomatosis and renal cell cancer, or "hereditary leiomyomatosis and renal cell carcinoma" (HLRCC).

 Case report

A 42-year-old woman attended the dermatology clinic with a nodule on the right nipple that had been present for 2 years and was accompanied by pain. The patient described it as a severe pain triggered by friction or cold. She also complained of dryness and fissures of the nipple. The patient had already been applying lanolin cream.

 Clinically, there was a clear asymmetry between the two nipples (fig. 1A and 1B). The right nipple was firm and nodularly swollen, with a yellowish hyperkeratotic crust (fig. 1A).

Fig. 1: Clinical photographs of both nipples from the patient record. A: Right nipple with the hyperkeratotic crust with which the patient presented at the clinic. B: Left, unaffected nipple. Photograph from the patient record.

 Differential diagnosis

There is a broad differential diagnosis for painful cutaneous nodules. First, when the lesion is located on the nipple, Paget’s disease must be ruled out (8). Clinically, however, this tends to have an erythematosquamous or erosive-crusted appearance (9). In rare cases, a cutaneous leiomyoma can progress to a leiomyosarcoma. This presents with a large or increasing diameter, ulceration, an irregular shape and/or increasing pain (10). For painful cutaneous nodules, the following cutaneous tumours should also be included in the differential diagnosis: eccrine spiradenoma, neuroma, dermatofibroma, angiolipoma, neurilemmoma, endometrioma, glomus tumour, granular cell tumour and fibromatosis. Other, non-painful tumours are trichoepithelioma, lipoma, cylindroma, eccrine poroma, angiofibroma, tuberous sclerosis or fibroadenoma (1, 11). To complete the diagnostic picture, steatocystoma, dermal naevus, keloid, epidermoid cyst, neurofibroma, myoid hamartoma, myoepithelioma or liposarcoma may also be considered (1, 2, 6, 9, 11). The distinction between these differential diagnoses must be made histologically.

 Course of the case

A punch biopsy of the right nipple was taken. Histopathological examination showed a dermal proliferation of interlacing bundles of spindle cells with eosinophilic cytoplasm and cigar-shaped nuclei. No significant cytonuclear atypia, necrosis and/or mitoses were identified. Lactiferous ducts are entrapped within the tumour (fig. 2A and 2B). The tumour was positive for desmin and SMA (fig. 2C and 2D).

Fig. 2: Histological images of the biopsy. A-B: Histopathological images of haematoxylin and eosin staining. C-D: Immunohistochemical staining for smooth muscle actin (SMA). E-F: Immunohistochemical staining for fumarate hydratase (FH).

Immunohistochemical staining for fumarate hydratase was positive; hence there was no loss of fumarate hydratase expression (fig. 2E and 2F). Ki-67 staining showed no significantly increased proliferative activity in the smooth muscle tissue. 

According to the guidelines, genetic testing for HLRCC should be offered when HLRCC is clinically suspected (see below) or when there is a positive family history of HLRCC (9). In this particular case, the family history was negative. Although the patient did not meet the criteria, it was nevertheless decided together with her  to schedule genetic testing in the future. At the time of publication, this result was not yet known.

An abdominal ultrasound showed no renal tumours and no large uterine leiomyomas. The additional transvaginal ultrasound performed by the gynaecologist was reassuring.

Excision was advised as treatment, but the patient preferred clinical follow-up only.

Discussion

Clinically, cutaneous leiomyomas are firm, smooth, skin-coloured to erythematous or hyperpigmented papular nodules of 2 to 20 mm; solitary or grouped. They appear mainly on the extensor surfaces of the limbs, on the trunk, on the face and on the neck (10). Around 90% of these lesions cause itching or pain, either spontaneously or induced by exposure to cold, direct contact, emotion or pressure (1, 6).

On dermoscopy they most closely resemble dermatofibromas, with a hypopigmented centre and a peripheral brown or pink reticular pigment network. The pale centre is structureless or contains cloudy white areas, which can be explained by the proliferation of smooth muscle cells and collagen. Vascular structures are sometimes visible (1, 12).

Leiomyomas of the nipple occur more often in middle-aged women than in men, with a sex ratio (F:M) of 3:1 (11, 13). Genital leiomyomas are usually solitary, painless lesions (6). Leiomyomas of the nipple, by contrast, are usually described as painful; in the study by Marcoval et al., 30% of nipple leiomyomas were reported as painful (7). Our patient likewise had nipple pain on exposure to cold or friction. There is usually neither nipple discharge nor nipple retraction (11). A punch biopsy is required to establish the diagnosis of cutaneous leiomyoma.

Histopathological examination with positive immunohistochemical staining for smooth muscle actin (SMA) and desmin (2, 11) confirms the diagnosis of cutaneous leiomyoma.

Immunohistochemical screening for HLRCC consists of demonstrating negative staining for fumarate hydratase (FH), which is indicative of a mutation and loss of expression of this enzyme and, consequently, of the presence of intracellular accumulation of S-(2-succino)-cysteine (2SC) in the leiomyoma (2).

Immunohistochemical staining for FH in cutaneous leiomyomas in patients with HLRCC has a sensitivity of 70-83% and a specificity of 75-97.6% (5, 14). Positive staining for 2SC  has a sensitivity of 83-92% and a specificity of 67-75%;  however, the commercial availability of this stain is limited (15). Immunohistochemical staining has been proposed as a triage tool ahead of costly genetic testing for HLRCC in new diagnoses of cutaneous leiomyoma (5, 14). A diagnosis of multiple cutaneous leiomyomas, however, indicates a high probability of HLRCC and is therefore sensitive enough to proceed directly to genetic testing (5, 7, 14). In the study by Marcoval et al., the diagnosis of HLRCC was confirmed in 72.73% of patients with multiple piloleiomyomas (7). Further research is needed into the association between FH and 2SC and HLRCC in solitary cutaneous leiomyomas (14, 15). Ouchene et al. propose adding a solitary cutaneous leiomyoma with negative FH staining to the major criteria for HLRCC (16).

The definitive diagnosis of HLRCC is made by demonstrating a germline variant in the fumarate hydratase gene through genetic testing.

The lifetime risk of renal cell cancer in carriers of the fumarate hydratase mutation is 15-20% (9). As these are aggressive tumours with a high metastatic potential, it is important to rule out or confirm the diagnosis of HLRCC (7).

According to the guidelines, genetic testing for HLRCC should be considered when multiple cutaneous leiomyomas are present, at least 1 of which has been confirmed histologically. This counts as a major criterion. Genetic testing is also recommended in the case of a positive family history of HLRCC or when 2 or more of the following minor criteria are present: a solitary cutaneous leiomyoma and a family history of HLRCC, severe symptomatic uterine fibroids before the age of 40, type II papillary renal cell cancer before the age of 40, or a first-degree relative who meets one of the above major and minor criteria.

In addition, the occurrence of severe symptomatic uterine leiomyomas before the age of 40 in second-degree relatives may also be relevant (6, 9, 17).

Conclusion

Cutaneous leiomyoma is a rare, benign tumour of smooth muscle tissue. It can be recognised by solitary or multiple, often painful, firm, skin-coloured or erythematous papular nodules. The diagnosis is made by means of a punch biopsy and histopathological examination with immunohistochemical staining for smooth muscle actin (SMA) and desmin. Negative fumarate hydratase staining and positive S-(2-succino)-cysteine staining can indicate a fumarate hydratase mutation. When hereditary leiomyomatosis and renal cell cancer is suspected, genetic testing is indicated in order to screen for renal cell carcinoma in good time  , both in the  patient and in their family.

Acknowledgements

We thank pathologist Isabelle Lambert (labo Dermpat) for interpreting and providing the histological images.

Disclosures

Conflict of interest

The authors declare no conflict of interest.

Funding

No funding was received for this manuscript.

Liability and copyright

All authors hereby declare that they agree to the rules imposed regarding liability and copyright.

Patient consent

Written informed consent was obtained from the patient/patients for publication of this case report.

Affiliations

A.L. Jakers (1), D. Van Den Daele (2), G. Voet (3, 4)

(1) Trainee physician, Clinique Dermatologie Gent.

(2) General practitioner, Clinique Dermatologie Gent.

(3) Dermatologist, Clinique Dermatologie Gent.

(4) Correspondence address: G. Voet, Clinique Dermatologie Gent, Hippoliet Lippensplein 24A, 9000 Gent; email: griet.voet@dermatologiegent.be.

English abstract

Cutaneous leiomyoma of the nipple and exclusion of hereditary leiomyomatosis renal cell cancer

Cutaneous leiomyomas are rare, benign tumors of the smooth muscle tissue. Leiomyomas present as firm, smooth, skin-colored to erythematous or hyperpigmented papulonodular lesions from 2 to 20 mm; solitary or grouped. They are often associated with itchiness or pain. Multiple cutaneous leiomyomas can be associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). This syndrome constitutes a predisposition for cutaneous leiomyomas, uterine leiomyomas and renal cell carcinomas. The combination of only cutaneous and uterine leiomyomas is called Reed’s Syndrome.

We discuss the case of a 42-year-old female with a painful nodulus on the right nipple for 2 years. Positive immunohistochemical staining for smooth muscle actin (SMA) and desmin confirmed the diagnosis leiomyoma. There was no loss of fumarate hydratase expression on immunostaining. Ultrasound of pelvis and abdomen and transvaginal ultrasound showed no apparent kidney or uterine leiomyomas. Genetic testing for HLRCC was planned.

The importance in recognizing cutaneous leiomyomas lies in being able to screen for HLRCC. Patients with HLRCC should have screening and lifelong surveillance for uterine leiomyomas and renal cell cancer. 

Summary

Cutaneous leiomyomas are rare, benign tumours of smooth muscle tissue. Clinically, cutaneous leiomyomas can be recognised as firm, smooth, skin-coloured to erythematous or hyperpigmented papular nodules of 2 to 20 mm; solitary or grouped. Itching or pain is common. Multiple cutaneous leiomyomas are associated with the hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). This syndrome carries a predisposition to multiple cutaneous and uterine leiomyomas and renal cell carcinoma.

We present a case report of a 42-year-old woman with a painful nodule on the right nipple that had been present for 2 years. Histopathological examination confirms the diagnosis of leiomyoma by means of positive immunohistochemical staining for smooth muscle actin (SMA) and desmin. Immunohistochemically, there was no loss of fumarate hydratase expression. A screening ultrasound of the abdomen and pelvis and a transvaginal ultrasound showed no leiomyomas in the kidneys or uterus. Genetic testing for HLRCC was scheduled.  

Recognising and diagnosing cutaneous leiomyomas matters for both the patient and their family, with a view to detecting HLRCC. If HLRCC is diagnosed, the patient can be screened for uterine leiomyomas and renal cell carcinoma in good time and then followed up for life.

References

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Citation

Cite this article as: Jakers A, Van Den Daele D, Voet G. Cutaan leiomyoom van de tepel en uitsluiting hereditair leiomyoma renaalcelcarcinoom syndroom. Tijdschr Geneesk 2026: 82 (doi: 10.47671/TVG.82.25.045).