Malignant Melanoma of the Vulva



Fig. 8.1
Clinical vulvar melanomas present often as large lesions, with variegate pigmentation and irregular borders. Multifocality is not uncommon in vulvar melanomas





Dermoscopy


Dermoscopy may be used as a noninvasive examination of vulvar melanocytic lesions and can play a role in selection of suspicious pigmented lesions in need of a biopsy. The dermoscopic criteria for benign and malignant lesions on the vulva are not very well established, mainly due to the lack of large case series of such lesions. A recent study revealed that in vulvar melanomas, 60 % of cases had a multicomponent pattern by dermoscopy [7]. The same study revealed that there may be an irregular dermoscopic pattern in vulvar melanomas, with white or white-blue veil, irregularly distributed dots and globules, and atypical vascular pattern [7].


Location


Melanoma can occur on the keratinized surfaces of the vulva, but more often affects the modified mucous membranes of the vulva and the true mucous membranes of the vestibule and the vagina. In one of the large retrospective studies, more than half of the patients presented with melanoma involving the vulvar mucosa (labia minora, urethra, clitoris, introitus, vagina), and in 21 % of the patients, the melanoma was on the epidermal site of the vulva (labia majora or mons pubis). Overall, the most common location is on the labia minora, followed by the labia majora. It is important to emphasize that 20 % of the patients may have multifocal disease at the diagnosis [8]. In rare instances, melanomas can occur on the distal aspect of the urethra and may be visible at the urethral meatus at clinical examination [9].



Epidemiology


The female genitalia and especially the vulvar region have one of the highest densities of melanocytes in the body. Approximately 3 % of all melanomas in women occur in the genital region. Among the female genital tract, the most common is vulvar melanoma (76.7 %), followed by vaginal (19.8 %), while cervical melanoma is least common [10]. Despite the sun-protected location and apparent rare incidence, vulvar melanomas are in fact more frequent than other types of cutaneous melanomas, when accounting for the region’s surface in rapport with the entire body surface [11, 12]. The annual incidence of vulvar melanoma is approximately 0.1 per 100,000 per year in the United States. According to one of the largest studies to date using data from the Surveillance, Epidemiology, and End Results (SEER) database, vulvar melanomas occur most often in middle-aged to elderly (median age of 68), postmenopausal white women [13, 14]. Childhood vulvar melanoma is extremely rare [15].

Vulvar melanoma can occur in all skin types. In comparison with nongenital cutaneous-counterpart melanomas, 3.6 % of vulvar melanomas affect black patients, in contrast with only 0.6 % of cutaneous melanomas [14]. As in cutaneous melanomas, family history of melanoma correlates with an increased incidence in vulvar melanoma and may be identified in up to 15 % of cases [16].


Histopathology


When reporting the diagnosis of melanoma, certain prognostic factors and characteristics are usually noted. We will present those parameters with specific comments regarding vulvar melanoma.


Histological Subtypes


Considering that melanomas involve primary the mucosal aspect of the vulva, the majority of melanomas arising in this anatomic region are mucosal/acral-lentiginous type, followed by superficial spreading and nodular types. Desmoplastic melanomas, usually occurring in sun-damaged skin of elderly people, are rarely reported in the vulvar area [17]. Vulvar melanomas arise most commonly de novo, but in approximately 5 % of cases, especially in those affecting the cutaneous aspect of the vulva, they may be associated with a preexisting nevus [18].

Mucosal/acral-lentiginous melanoma is characterized by a poorly circumscribed, asymmetrical proliferation of cytologically atypical melanocytes (i.e., cellular pleomorphism, with high nuclear/cytoplasmic ratio, irregular nuclei, and frequently prominent nucleoli). The junctional component may be composed of nests of melanocytes, but more often there are numerous single cells with confluent, lentiginous growth pattern, and prominent pagetoid upward migration (Fig. 8.2a). When invasive, the dermal melanocytes have similar histomorphology with the junctional ones and fail to demonstrate maturation growth pattern with depth. Mitotic figures may be identified within the dermal melanocytes. Lymphovascular and perineural invasion is more commonly seen in this type of melanoma in comparison with cutaneous melanomas.

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Fig. 8.2
(a) Vulvar melanoma is characterized by a proliferation of cytologically atypical melanocytes with numerous single cells with confluent, lentiginous growth pattern, and prominent pagetoid upward migration. (b) Vulvar superficial spreading melanomas occur on the cutaneous aspect of the vulva and are characterized by a predominately nested melanocytic proliferation, with a lesser degree of pagetoid upward migration

Vulvar superficial spreading melanomas that occur on the cutaneous aspect of the vulva are characterized by a poorly circumscribed, asymmetrical proliferation of atypical melanocytes, mostly having a nested growth pattern. The superficial spreading-type melanoma has a lesser degree of pagetoid upward migration, when compared with the mucosal/acral-lentiginous type (Fig. 8.2b).

Nodular melanoma is defined by an invasive component of melanoma in which the melanoma in situ (intraepithelial) does not extend for three or more rete ridges from the invasive component. In deeply invasive lesions, the tumor cells may show a higher degree of heterogeneity, frequently displaying both epithelioid and spindle cell histology.


Clark Level


In vulvar melanomas, the Clark level assessment is only valid for melanomas arising on the cutaneous aspect of the vulva (similarly used as in nongenital cutaneous melanomas). Clark level is not applicable for the mucosal type of vulvar melanomas since the Clark levels are related to cutaneous and not mucosal structures. The anatomic levels of melanoma invasion are: level I, melanoma in situ; level II, invasion into the superficial papillary dermis; level III, invasive melanoma fills and expands the papillary dermis; level IV, invasion into the reticular dermis; and level V, infiltration into subcutaneous adipose tissue. It has been reported that the assessment of Clark levels II, III, and IV has a very high interobserver variability. Moreover, in melanomas with polypoid growth pattern, the tumor may be deeply invasive by Breslow thickness but still a Clark level III. In these cases, there is no significant prognostic value of the Clark level, and the thickness of the tumor dictates the clinical behavior. Currently, the Clark level is no longer recommended to be used as a staging criterion, since it is not an independent prognostic factor when mitotic rate is included in the analysis [19].

In the largest case series of vulvar melanoma, the median Clark level when reported was IV, highlighting that these tumors are usually diagnosed when they are relatively advanced [8, 18].


Tumor Thickness


Breslow proposed in 1970 that measuring the vertical thickness of cutaneous melanoma is a good tool to predict the metastatic potential of this tumor. Until today, this measurement is the single most important prognostic factor for melanoma clinical behavior. Moreover, the evaluation of this parameter has the least interobserver variability. The Breslow thickness is measured from the top of the epidermal granular layer to the deepest melanocyte of the invasive component. When there is tumor-induced ulceration, the measurement should be done from the base of the ulceration to the deepest aspect of the invasive component of melanoma.

The term of “Breslow thickness” should be reserved for vulvar melanomas occurring in the cutaneous aspect of the vulva; for mucosal melanomas, only the term “thickness” is considered appropriate since the term “Breslow” was not intended for mucosal sites [20].

Involvement of follicular or adnexal structures by melanoma in situ, even if they are situated deeper in the dermis, should not be considered for the measurement of melanoma thickness. On the other hand, the presence of perineural invasion by melanoma (relatively commonly seen in mucosal type of vulvar melanoma), in our opinion, should be measured and reported as part of the Breslow thickness.

Several large case series of vulvar melanoma report that the median Breslow thickness ranges from 3.2 to 4.4 mm [8, 21].


Radial and Vertical Growth Phase


The definition of radial and vertical growth phases is based on the concept that tumor progression implicates different evolutionary steps that can be identified on histological examination and helps predict the tumor metastatic potential. By definition, all in situ melanomas have only radial growth phase. When melanoma invades into the dermis or submucosa, it may still have only radial growth phase (single cells or small nests within the dermis, without mitotic figures).

Vertical growth phase has been defined as “tumorigenic” growth, when the dermal nests are larger than any nest in the junctional component of the lesion or when mitotic figures can be identified within the dermal melanocytes. It has been reported that the metastatic potential of a melanoma strongly correlates with the presence of vertical growth phase, but it seems that the predictive power of vertical growth phase is likely related to the presence of the dermal mitotic figures rather than the size of the dermal tumoral nests.


Mitotic Figures


The counting of mitotic figures should be done only in the invasive component of melanoma. Currently, the preferred method is to report the mitotic count per square millimeter (usually represents 4 and ½ consecutive high-power fields at a magnification of 40×, but it depends on the size of the field in that particular microscope). It has been reported that a high mitotic rate correlates with a poor survival rate. In one of the largest case series of vulvar melanoma, the average of mitotic figure per square millimeter was reported to be 6.6 [21].


Ulceration


The presence of ulceration is regarded as an independent prognostic factor for melanoma-associated survival. Survival rates of patients with an ulcerated melanoma are lower than those of patients with a non-ulcerated melanoma of similar thickness. Thus, the presence of ulceration results in upstaging the lesion. The presence of ulceration and possibly its width should be always reported. It is also important to recognize the difference between tumor-related ulceration (due to “epidermal consumption and attenuation”) and ulceration due to trauma, since the latter is probably not associated with such an impaired prognosis (Fig. 8.3). Therefore, morphologists should be very cautious before reporting ulceration in re-excision specimens (in which the cause for ulceration may be surgical trauma).

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Fig. 8.3
Presence of ulceration is an independent prognostic factor for melanoma-associated survival and its presence should be reported. Histologically, it is characterized by the absence of the epidermis with fibrin deposition and neutrophilic aggregates


Lymphovascular Invasion


The presence of tumor cells in lymphovascular spaces is considered a major prerequisite for metastatic spread (Fig. 8.4a). Several authors have reported that vascular invasion in melanoma may be associated with an increased risk of relapse, lymph node metastasis, distant metastases, overall survival, and disease-free survival. However, other authors showed that this feature is not an independent factor in predicting prognosis in patients with melanoma. This apparent discrepancy may be due to the difficulty of identifying this feature on hematoxylin and eosin sections alone. Previous reports on immunohistochemical detection of lymphovascular invasion and correlation with metastatic rate have yielded conflicting results. More recently, studies have shown that immunohistochemical detection of lymphovascular invasion using anti-D2-40, a monoclonal antibody against podoplanin, in melanomas thicker than 1 mm, correlates with sentinel lymph node status and survival (Fig. 8.4b). Therefore, we suggest that such analysis might be incorporated in the routine work-up of primary cutaneous melanoma thicker than 1 mm. In one of the largest case series of vulvar melanomas, vascular invasion of tumor cells did not reach the significance level as a predictor of survival in the univariate analyses [18].

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Fig. 8.4
(a) Lymphovascular invasion is characterized by the presence of tumor cells in lymphovascular spaces. (b). D2-40 immunohistochemical study can highlight the vascular spaces and can be used as an aid in identification of lymphovascular invasion


Perineural Invasion


Infiltration of nerves by tumor cells should also be recorded (Fig. 8.5). Some types of melanomas, such as desmoplastic or spindle cell melanomas, have a high propensity for perineural invasion. This feature is also relatively commonly seen in mucosal melanomas.

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Fig. 8.5
Perineural invasion is relatively commonly seen in mucosal melanomas, such as vulvar melanoma


Microscopic Satellitosis


Microsatellites are defined as discrete tumor aggregates, designated as having the diameter larger or equal to 0.05 mm in largest dimension and are separated from the main tumor by normal (not fibrosis or inflammation) dermal collagen or subcutaneous fat. Only few studies have evaluated the role of microsatellites as prognostic factors in cutaneous melanomas and so far there is no definite published data in this regard in vulvar melanomas. It is controversial whether their presence is an independent prognostic factor, but they do appear to correlate with a higher risk of local recurrence and with an increased frequency of regional lymph node metastasis (from 12 % to 53 %) in tumors thicker than 1.5 mm.


Regression


Histologically, it can be recognized by the presence of dermal fibrosis, vascular proliferation, inflammatory infiltrate, and the presence of melanophages in association with complete or partial loss of melanocytes. There may be also thinning of the overlying epidermis with loss of rete ridges (Fig. 8.6). The regression changes can range from focal to extensive and can be partial or complete. The correlation of regression with prognosis is controversial. Although most studies have not found a significant role for regression in determining survival, others suggested that the metastatic rate is higher in thin melanomas with extensive regression. One of the possible explanations is that a regressed lesion was previously thicker, and the assessment of current thickness is an underestimate of the tumor’s metastatic potential [22].

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Fig. 8.6
Regression can be recognized by the presence of dermal fibrosis, vascular proliferation, inflammatory infiltrate, and presence of melanophages in association with complete or partial (as in this case) loss of melanocytes


Tumor-Infiltrating Lymphocytes


The host immune response is recognized by the presence of a lymphocytic inflammatory infiltrate. It can be “brisk,” “non-brisk,” and “minimal” (“absent”) and is usually measured by the extent of the lymphocytic infiltrate surrounding the invasive dermal component of melanoma. The presence of a brisk inflammatory infiltrate has been reported that correlates with improved survival. However, the assessment of this feature is observer dependent, mainly due to the lack of a uniform definition of host response in terms of type and location of the infiltrate.


“Multifocality” of Vulvar Melanoma


“Multifocality” of vulvar melanomas, especially those arising on the mucosal aspect, is a well-known characteristic with a significant impact in the capability to obtain tumor-free surgical margins. Multifocality is defined as multiple foci of melanoma separated by intact epithelium, or arising on follow-up, but not in the vicinity of the surgical scar. In one study, six of nine (66 %) vulvar melanomas had more than one focus of melanoma: one had multiple primary melanomas both at the time of diagnosis and during follow-up period, one had multiple foci of melanoma but had no local recurrences, and three had secondary melanomas during follow-up.

Interestingly, in a recent study, almost half of the patients had atypical melanocytic hyperplasia adjacent to primary melanoma [21]. Verschraegen et al., in their recently published series, raise the suggestion of a “field effect” in vulvar melanomas; some patients having atypical melanocytic hyperplasia at the surgical margins as well as in noninvolved mucosa, and local recurrences in these patients were described.


Prognostic Factors, 2009 AJCC Staging, and Its Applicability on Vulvar Melanomas


The understanding of prognostic factors and their clinical significance in cutaneous melanomas is continuously evolving. The American Joint Committee on Cancer (AJCC) adopted in 2002 a version of the melanoma staging system on the basis of an analysis of 17,600 patients in AJCC Melanoma Staging Database. Recently, in November 2009, a new version of AJCC Melanoma Staging and classification has been released, based on an expanded sample size of the Melanoma Staging Database (over 30,000 patients) and multivariate analysis of different independent prognostic factors [19].

There is variability between different institutions and pathologists regarding the routine reports of histological parameters in melanomas. Some of the reports contain only minimal information (such as tumor thickness and presence or absence of ulceration) while others are very comprehensive. In such detailed reports, although some of the information provided might not be of immediate relevance to a given patient, its importance might become apparent at a later date, especially when used in conjunction with information gathered from large number of patients in prospective or retrospective studies. As an example, mitotic count is now included as an essential histopathological element in the newest version of AJCC Melanoma Staging and classification.

In contrast with the 2002 AJCC Melanoma Staging, the mitotic rate replaces the level of invasion (Clark) in defining T1 categories of cutaneous melanomas. The presence of one or more mitotic figures per square millimeter is now used as one of the two criteria (along with ulceration) for defining T1b-stage melanoma. A possible drawback of applicability of this criterion may be in cases in which there is a very small dermal component. However, it is not recommended by AJCC or College of American Pathologists (CAP) to perform multiple, serial sections with the intent to detect mitotic figures. The tumor thickness is the primary determinant for T staging in both 2002 and 2009 AJCC recommendations for melanoma staging. In the newer 2009 AJCC, recommendation immunohistochemical detection of nodal metastases is included and has to be performed in all the cases in which a metastasis is not obvious in the initial hematoxylin- and eosin-stained sections examined. In such cases, the markers that can be used for immunohistochemical studies may be MART1, Melan A, or HMB45. The number of nodal metastases is the primary determinant for N staging and there is no lower threshold of staging N+ disease (isolated tumor cells and very small tumor deposits should be scored N+). The TNM staging categories for cutaneous melanomas (including vulvar melanoma) that are currently recommended are included in Table 8.1.


Table 8.1
2009 AJCC melanoma pathologic staging






































































































Stage

T (tumor)

N (lymph nodes)

M (metastases)

0

Tis (in situ)

N0

M0

IA

T1a (thickness < 1 mm, without ulceration, <1 mitosis/square mm)

N0

M0

IB

T1b (thickness <1 mm, with ulceration and/or 1 or >1 mitoses/square mm)

N0

M0

OR

T2a (thickness 1–2 mm, without ulceration)

IIA

T2b (thickness 1–2 mm, with ulceration)

N0

M0

OR

T3a (thickness 2–4 mm, without ulceration)

IIB

T3b (thickness 2–4 mm, with ulceration)

N0

M0

OR

T4a (thickness >4 mm, without ulceration)

IIC

T4b (thickness >4 mm, with ulceration)

N0

M0

IIIA

T1–T4a

N1a (1 lymph node with micrometastasis)

M0

OR

N2a (2–3 lymph nodes with micrometastases)

IIIB

T1–T4b

N1a (1 lymph node with micrometastasis)

M0

OR

N2a (2–3 lymph nodes with micrometastases)

IIIB

T1–T4a

N1b (1 lymph node with macrometastasis)

M0

OR

N2b or N2c (2–3 lymph nodes with macrometastases or in transit metastases/satellites without lymph node involvement)

IIIC

T1–T4b

N1b (1 lymph node with macrometastasis)

M0

OR

N2b or N2c (2–3 lymph nodes with macrometastases or in transit metastases/satellites without lymph node involvement)

IIIC

Any T

N3 (4 or more 4 lymph nodes with metastases or in transit metastases/satellites with lymph node metastases)

M0

IV

Any T

Any N

M1 (distant metastases)


Data from Ref. [19]

Micrometastases are diagnosed after sentinel lymph node biopsy

Macrometastases are defined as clinically detectable nodal metastases confirmed pathologically

NA not applicable, LDH lactate dehydrogenase

Parameters that correlate strongly with the prognosis and should be always mentioned in the report include tumor thickness, number of mitoses per square millimeter, as well as presence or absence of ulceration, lymphovascular, perineural invasion, satellitosis, and regression. In addition, it is recommended to include Clark level (only for vulvar melanomas affecting the cutaneous aspect of the vulva). It is important to emphasize that according to literature, most of the vulvar melanomas at the time of diagnosis are Clark level IV, reach a Breslow thickness ranging between 3.2 and 4.4 mm, have an average of six mitoses per square mm, and a large proportion may be ulcerated [8, 21].


Therapy


The treatment of choice consists of surgical removal or vulvectomy (hemivulvectomy or radical vulvectomy). There is a trend toward less extensive resection, since there have not been found a difference of survival rates between patients treated with radical vulvectomy and conservative surgery [23] which yields results as good as radial vulvectomies. Obtaining tumor-free resection margins is critical to prevent local recurrence. However, due to the multifocality commonly seen in vulvar melanomas, their frequent amelanotic nature and highly subclinical peripheral extension, complete resection was proven to be a difficult task. Moreover, in up to 20 % of cases, there is a background of atypical junctional melanocytic hyperplasia that makes the assessment of resection margins even more challenging. Frozen section analysis is neither specific nor sensitive for histological evaluation of margins of resection and is not generally indicated. Chemotherapy and radiation therapy add little to overall survival.

The sentinel lymph node biopsy (SLNB) is a less invasive alternative to elective lymph node dissection. The SLNB has a lower associated morbidity and higher sensitivity in detecting lymph node metastases. According to 2009 AJCC recommendations for melanoma staging, immunohistochemical studies have to be performed if tumor is not identified in the routine H&E sections (Fig. 8.7a, b). Up to date the studies analyzing the potential role of SLNB in vulvar melanomas are relatively small but appears that the procedure is capable of identifying patients who have occult lymph node metastases and may benefit from local lymphadenectomy performed in order to prevent distant metastases [24, 25].
Nov 11, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Malignant Melanoma of the Vulva

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