Vulva

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2020, Case 14, and is a granular cell tumor of the vulva.

The information provided in this case was accurate and correct at the time of publication in 2020.

Any changes in terminology since the time of publication may not be reflected in this case.

This excision shows a dermal and subcutaneous non-encapsulated cellular lesion composed of monotonous granular cells without a discernable architectural pattern. The borders are infiltrative. Mitotic activity is not seen, and the nuclei are uniform without prominent nucleoli. The cytoplasm is strikingly granular and eosinophilic. Immunostains demonstrate strong immunoreactivity for S100, SOX10, calretinin, inhibin, and TFE3. Actin, desmin, MART1, HMB45, and p63 immunoreactivity are not seen. Electron microscopy performed for academic purposes demonstrates abundant myelin-like figures and secondary lysosomes. These findings represent a granular cell tumor (GCT).

The origin of GCTs have been controversial since their recognition as a distinct entity by Dr. Abrikosoff in 1926. GCTs may affect any body site but are classically described in the oral cavity/tongue, skin, breast, and vulva. GCTs are currently thought to be derived from Schwann cells and are characterized by a massive intracytoplasmic accumulation of lysosomes, yielding the typical granular appearance.

Immunohistochemically, GCTs express strong S100 and SOX10 positivity, and most also express CD68, calretinin, inhibin, vimentin, CD1a, and TFE3 to varying degrees. Negative immunostains include melanosome markers (HMB45, MART1), smooth muscle markers (actin, desmin), and all cytokeratins. TFE3 immunostaining is better known for its use in renal cell carcinoma with Xp11 translocation and alveolar soft part sarcoma. While rare, these tumors can enter into the differential diagnosis with GCTs (particularly malignant GCTs) due to the granular cytoplasm both entities display, and overlapping immunostaining. Thus, selecting an appropriate immunostain panel based on the histologic appearance is essential when dealing with granular lesions.

The vast majority of GCTs are benign and carry an excellent prognosis after surgical excision. However, approximately 1% - 2% of GCTs are malignant, demonstrating a high recurrence rate and metastases, with mortality rates reported at 40%. The “Fanburg-Smith” histologic criteria for malignancy in GCT diagnosis examined 6 factors: necrosis, spindling, high nuclear:cytoplasmic ratios, vesicular nuclei with large nucleoli, nuclear pleomorphism, and increased mitotic activity (greater than 2 mitoses per 10 high-power fields). GCTs exhibiting 3 or more criteria were considered malignant, those with 1 or 2 criteria were atypical and those with only focal nuclear pleomorphism without other criteria were considered benign. In the same study, increased Ki67 index (between 10% - 50%) and p53 expression also showed a statistically significant association with malignant categorization. Other studies list size greater than 5 cm, lower extremity location, rapid recent growth, older age, and female sex as additional risk factors for malignancy. Multicentricity was present in some benign and atypical GCT cases and therefore is not a criterion for risk stratification. The most common sites of metastasis are lung, bone, and lymph nodes.

GCTs are generally considered sporadic tumors; however, multiple GCTs have been associated with 2 rare inherited syndromes, namely LEOPARD syndrome and Noonan syndrome. LEOPARD syndrome is an inherited condition with abnormalities of the skin, heart, inner ears, and genitalia. The “LEOPARD” acronym stands for Lentigines, Electrocardiographic conduction defects, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of genitalia, Retarded growth, and Deafness. Noonan syndrome is an autosomal dominant disorder characterized by short stature, unusual facial characteristics, heart defects, and bony malformations of the rib cage.

Melanoma is the second most common vulvar malignancy, after squamous cell carcinoma, and usually presents in postmenopausal women. In contrast to granular cell tumors, vulvar melanomas have a high mortality rate, making early identification and appropriate treatment paramount. Melanomas typically do not show the abundant granular eosinophilic cytoplasm, show significant cytologic atypia, may show melanin pigment and are often associated with an intraepidermal melanocytic component. Immunostains for melanosome-specific markers (such as MelanA or HMB45) positive, which are negative in granular cell tumors. S100 and SOX10 can be positive in both melanomas and granular cell tumors.

Perivascular epithelioid cell tumors (PEComa) are thought to arise from perivascular epithelioid cells, which are hypothesized to originate from neural crest stem cells. PEComas may be aggressive with local or distant dissemination. These tumors show myomelanocytic differentiation and can occur in multiple anatomic locations, including the uterine corpus. Classic PEComas usually show a diffuse or nested spindle cell growth pattern sometimes in a radial distribution around blood vessels. It is uncommonly confused with GCT. However, epithelioid areas in PEComas can be prominent. PEComas display variable cytoplasmic granularity, variable mitotic rate and inconsistent cytologic atypia, all findings that can raise GCT in the differential diagnosis. PEComas, like granular cell tumors, can express S100 and TFE3 by immunohistochemistry. However, in keeping with their myomelanocytic differentiation, PEComas express both myogenic and melanocytic antigens and should be considered when actin, desmin, and/or caldesmon are co-expressed with HMB45, MelanA, and MiTF. Careful histologic analysis and an appropriate panel of immunostains allows for discrimination between these 2two entities.

Smooth muscle tumors, primarily leiomyomas (and rarely leiomyosarcomas), can display significant granular cell changes. In the vulvar area, these tumors are most common in the 4th to 5th decades and usually display the common smooth muscle growth patterns of intersecting fascicles of spindle-shaped cells. However, occasional tumors show a more nested, epithelioid pattern with granular cytoplasm. In circumstances where the granularity is sufficient to raise a differential with GCT, immunostains will easily discriminate leiomyoma from GCT. Actin, desmin, estrogen receptor, and progesterone receptor are typically positive in gynecologic smooth muscle tumors. Diffuse S100 staining, a hallmark of GCT, is not seen in smooth muscle tumors.

Squamous cell carcinoma is not easily confused with GCT when each tumor's histology is well-visualized via an adequate biopsy or excision. However, GCTs are often biopsied with a clinical suspicion of squamous cell carcinoma, and in clinical practice, biopsies and even excisions may be quite superficial, especially as GCT are often associated with overlying pseudoepitheliomatous squamous hyperplasia, which can be quite prominent and can mimic squamous cell carcinoma. A careful examination of the visible epithelial-stromal interface and ensuring adequacy sampling of the dermal lesion, is critical to an accurate diagnosis.

1. Granular cell tumors (GCTs) are positive for which panel of immunostains?
   
   
   1. Cytokeratin, MelanA, and actin
   2. SOX10, MelanA, and cytokeratin
   3. S100, SOX10, and actin
   4. S100, HMB45, and MiTF
   5. S100, SOX10, and TFE3
2. Benign GCTs are characterized by which of the following?
   
   
   1. 40% mortality rate
   2. An infiltrating growth pattern
   3. High mitotic index, and nuclear pleomorphism
   4. High rates of local recurrence
   5. Increased Ki67 (10% - 50%) proliferation index
3. Multiple GCTs may rarely arise in association with which genetic syndrome?
   
   
   1. Gardner syndrome
   2. LEOPARD syndrome
   3. Lynch syndrome
   4. Multiple endocrine neoplasia, type I
   5. Tuberous sclerosis

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2. Ordóñez, NG. Granular Cell Tumor: A Review and Update. Adv Anat Pathol. 1999;6(4):186-203.
3. Papalas JA, Shaco-Levy R, Robboy SJ, Selim MA. Isolated and Synchronous Vulvar Granular Cell Tumors: a clinicopathologic study of 17 cases in 13 patients. Int J Gynecol Pathol. 2010;29(2):173-180.
4. Singh VA, Gunasagaran J, Pailoor J. Granular Cell Tumour: Malignant or Benign? Singapore Med J. 2015;56(9):513-517.
5. Stemm M, Suster D, Wakely PE, et al. Typical and Atypical Granular Cell Tumors of Soft Tissue: A Clinicopathologic Study of 50 Patients. Am J Clin Pathol. 2017;148(2):161-166.

1. S100, SOX10, and TF3 (e)
2. An infiltrating growth pattern (b)
3. LEOPARD syndrome (b)