Trial Information

Conservative Management With Isolated Sentinel Lymph Node Biopsy in Vulvar Cancer Patients With Sentinel Lymph Nodes Determined to be Negative for Metastatic Disease.

Conservative Management with Isolated Sentinel Lymph Node Biopsy in Vulvar Cancer Patients
with Sentinel Lymph Nodes Determined to be Negative for Metastatic Disease.

Introduction The American Cancer Society estimates there will be 4000 new cases of vulvar
cancer for the year 2003(1). The majority of these patients will undergo surgical therapy
with groin node dissection to assess the inguinal nodal chain for evidence of metastatic
disease. For many years there has been a search for a less radical surgical approach to
evaluating the inguinal lymphatic basin. The classic approach to vulvar cancer was an
en-bloc resection of the vulva and groins with a single incision. This approach led to
complication rates as high as 69% for chronic leg edema and 85 % for wound breakdown(2). In
an effort to reduce the morbidity of groin node dissections, the triple incision technique
was introduced(3). A GOG study evaluating limited surgery with wide local excision and
superficial groin node dissection reported rates of chronic lymphedema of 19% and wound
infection and or separation of 29%(4). In their report on penile carcinoma the concept of a
sentinel node as the first group of nodes in the inguinal lymphatic chain was put forth by
Cabanas et al.(5). Morton and colleagues advanced the technique of sentinel node lymphatic
mapping in patients with cutaneous melanoma(6). In 1994 Levenback et al, described of the
use of isosulfan blue dye for the detection of sentinel nodes in the inguinal lymphatic
chain(7). To date, a number of studies have been performed evaluating the utility of
sentinel node technology and its application in vulvar malignancies (Table 1)(7-20). For
melanoma, the sentinel node dissection has become the standard of care for the evaluation of
the lymphatic basins. Many cancer centers, including Women and Infants' Hospital, use
sentinel node dissection for the evaluation of axillary nodes in breast cancer patients as
their standard of care. This technology has decreased the rate of chronic arm edema in
breast cancer patients.

Inguinal node metastasis in patients with squamous cell carcinoma of the vulva is reported
to be as high as 27%(21). Consequently, a large number of patients may undergo a
potentially morbid procedure without any gain. Non-invasive methods for the evaluation of
the inguinofemoral nodes such as CT, MRI and PET scans have not yet been proven reliable.
Sentinel node biopsy utilizing Tc-99m sulfur colloid and isosulfan blue dye allows for
evaluation of nodal status in patients with vulvar malignancies through minimally invasive
surgery. Our study, at Women and Infants' Hospital, employed Tc-99m sulfur colloid and
isosulfan blue dye to identify sentinel nodes in the inguinal lymphatic chain of patients
with primary squamous cell carcinoma of the vulva. Twenty nine patients were enrolled and
107 sentinel nodes were studied with no false negative SLN being reported(22) There are
over 175 patients in the reported literature who have undergone a SLN dissection for the
evaluation of the inguinal lymphatic basin for metastatic disease. To date there have been
no false negative SLN reported. We feel the SLN dissection has been proven to be reliable
and safe procedure both at our institution and others around the world. Further studies
need to be performed in order to evaluate the use of SLN dissection alone in patients with
pathologic negative sentinel nodes for metastasis. This study will evaluate the use of
sentinel node dissection alone and management of these patients who potentially do not need
or will benefit from a full inguinal node dissection.

Sentinel Node Concept Sentinel node dissection was first applied for the evaluation of
inguinal nodal basins in patients with penile cancer(23). The sentinel node concept is
based on the belief that certain anatomical areas are drained by individual nodal chains
with the first lymph node in this chain being the sentinel node. It has been shown the
sentinel node is predictive of the status of the lymphatic basin for the presence of
metastatic disease to non-sentinel nodes. The use of both lymphazurin blue dye and
technetium-99m sulfur colloid has been shown to reliably identify sentinel nodes in many
cancers such ad melanoma, breast and colon. This technology has also been studied in
patients with vulvar malignancies and has been shown to detect a sentinel node 100% of the
time(22). With a limited number of sentinel nodes obtained from a lymphatic basin a more
complete pathologic evaluation of the lymph node can be performed. The use of ultra-staging
(serial sectioning) allows for smaller metastasis and micrometastasis to be reliably
detected. Sentinel lymph node technology will allow for a more complete surgical and
pathologic evaluation of the inguinal lymphatic basins with a potential benefit of avoiding
a complete inguinal node dissection for patients with a SLN determined to be negative for
metastatic disease.

Study Design

This is a prospective trial examining conservative management of patients with inguinal
sentinel nodes that have been deemed negative for metastatic disease in patients with
primary squamous cell carcinoma of the vulva.

Number of Patients:

The goal of this study is to enroll 100 patients over a 5 year period and follow each for a
total of three years.

Sentinel Lymph Node Technique:

Each patient will undergo two intradermal peritumoral injections with a total of 2-3 mCi of
unfiltered technetium-99m sulfur colloid in a volume of 1cc, within 24 hours prior to
surgery. These injections will take place in the nuclear medicine suite at Rhode Island
Hospital under Dr. Richard Noto's supervision. Following the injection of the Tc-99m sulfur
colloid a lymphoscintigram will be performed to detect the presence of a sentinel node.
Intra-operatively, 5 to 10 minutes prior to the groin dissection, 3 cc of isosulfan blue dye
will be injected at the peritumoral edge in a manner and location similar to the Tc-99m
sulfur colloid injection. An inguinal dissection will then performed before the radical
excision of the vulvar tumor. Prior to the groin node incision, a hand held collimated
gamma counter will be used to identify the location of the sentinel node. This area will be
marked with ink on the skin surface. An inguinal incision will be made and the inguinal
lymphatic beds will be dissected to identify blue afferent lymphatic tracts and/or blue
stained lymph nodes. A hand held collimated gamma counter will be used to detect any lymph
nodes with increased activity, defined as a count greater than 5 % of that at the injection
site, through the groin incision. Also, any lymph node with a blue lymphatic tract leading
to it or stained blue will be considered a sentinel node. As well, any lymph node identified
with the hand held gamma counter as taking up the Tc-99m sulfur colloid will be considered a
hot sentinel node. Each sentinel node will be evaluated with a 10 second gamma count and
labeled as hot and blue, hot and non-blue or cold and blue. With completion of the sentinel
node groin node dissection, the lymphatic beds will be re-scanned with the gamma counter to
ensure all sentinel nodes have been removed. Once the SLN groin dissection is complete the
incision will be closed and a full groin dissection will be done at a separate sitting
pending the pathologic evaluation of the sentinel lymph node. The remainder of the surgery
for the treatment of the primary tumor will then be completed with a current standard of
care procedure depending on the size and location of the tumor.

Pathologic Analysis of Sentinel Lymph Nodes:

Each sentinel lymph node will be serially sectioned at 2mm intervals parallel to the long
axis and totally submitted for histologic evaluation in one or more blocks. From each
block, five slides will be cut at 100 micron intervals and stained with hematoxylin and
eosin. A parallel slide at each level will be cut and held for batch cytokeratin AE1/AE3
immunohistochemical staining if negative for metastasis by initial H&E staining. The
largest dimension of each metastasis will be measured and recorded in order to track the
presence of micrometastasis defined as a metastatic focus less than 2mm in size.

Patient Management Protocol:

Patients enrolled on to the sentinel lymph node protocol will undergo a sentinel lymph node
dissection as described above followed by a radical excision of the primary tumor. Patients
with sentinel nodes found to contain metastatic disease from the primary vulvar malignancy
will under go a complete inguinal lymph node dissection as per standard care. Patients with
sentinel lymph nodes deemed negative for metastatic disease based on ultra-staging and H&E
staining will be followed with conservative management (no further groin node dissection).
Each of these patients will be followed clinically at 3 month intervals for the first three
years for a total study follow up period of three years. Any patient determined to have a
groin recurrence will be treated with current standard of care modalities as appropriate for
their recurrence. Published data documenting a 5-7% unanticipated groin failures in
patients with negative lymphadenectomies will be used as the comparative outcomes (25).