Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1999-04-09
2001-07-17
Arthur, Lisa B. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
Reexamination Certificate
active
06261775
ABSTRACT:
BACKGROUND OF THE INVENTION
The melanocyte can give rise to a plethora of morphologically different tumors. Most of them are biologically benign and are referred to as melanocytic nevi. Examples of melanocytic nevi are congenital nevi, Spitz nevi, dysplastic or Clark's nevi, blue nevi, lentigo simplex, and deep penetrating nevus. Pigmented spindle cell nevus is regarded as a subset of Spitz nevi.
Spitz nevi are benign melanocytic neoplasms that can have considerable histological resemblance to melanoma. They were first described as “juvenile melanoma” by Sophie Spitz in 1948 and initially regarded as a subset of childhood melanoma that follows a benign course (Spitz, S.,
Am. J. Pathol
. 24, 591-609 (1948)). Spitz nevi are common and account for about 1% of surgically removed nevi (Casso et al.,
J Am Acad Dermatol
., 27, 901-13 (1992)). Although in general the pathological diagnosis of Spitz nevus is straightforward, there is a subset of cases in which it is difficult to impossible to differentiate Spitz nevi from melanoma. The diagnostic difficulties are explained by overlapping histological features. Both Spitz nevi and melanoma can be composed of melanocytes with abundant cytoplasm and large nuclei. Nuclei can be pleomorphic and contain macronucleoli. Mitotic figures, sometimes numerous, occur in both neoplasms.
Melanoma refers to malignant neoplasms of melanocytes. Its proper diagnosis and early treatment is of great importance because advanced melanoma has a poor prognosis, but most melanomas are curable if excised in their early stages. While clinicians make the initial diagnosis of pigmented lesions of the skin, pathologists make the final diagnosis. Although, in general the histopathological diagnosis of melanoma is straightforward, there is a subset of cases in that it is difficult to differentiate melanomas from benign neoplasm of melanocytes, which have many variants that share some features of melanomas (LeBoit, P. E. S
TIMULANTS OF MALIGNANT MELANOMA
: A
ROGUE'S GALLERY OF MELANOCYTIC AND NON
-
MELANOCYTIC IMPOSTERS
, In
Malignant Melanoma and Melanocytic Neoplasms
, P. E. Leboit, ed. (Philadelphia: Hanley & Belfus), pp. 195-258 (1994)). Even though the diagnostic criteria for separating the many simulators of melanoma are constantly refined, a subset of cases remains, where an unambiguous diagnosis cannot be reached (Farmer et al., D
ISCORDANCE IN THE HISTOPATHOLOGIC DIAGNOSIS OF MELANOMA AND MELANOCYTIC NEVI BETWEEN EXPERT PATHOLOGISTS
, Human Pathol
. 27: 528-31 (1996)). The most frequent and important diagnostic dilemma is the differential diagnosis between Spitz nevus, a neoplasm composed of large epithelioid or spindled melanocytes, and melanoma.
Misdiagnosis of Spitz nevus as melanoma and vice versa has been repeatedly reported in the literature (Goldes et al.,
Pediatr. Dermatol
., 1: 295-8 (1984); Okun, M. R.
Arch. Dermatol
. 115: 1416-1420 (1979); Peters et al.,
Histopathology
, 10, 1289-1302 (1986)). A retrospective study of 102 melanomas of childhood found that only 60 cases were classified as melanoma by a panel of experts, the majority of the remainder being classified as Spitz nevi (Spatz, S.,
Int. J. Cancer
68, 317-24 (1996)). The hazard of mistaking a Spitz nevus for melanoma can be severe and traumatic: The patients may be subjected to needless surgery, unable to plan for the future, and psychologically traumatized. For obvious reasons, the misdiagnosis of a melanoma as a benign nevus can have even more dramatic consequences. The presence of this diagnostic gray zone has even led the authors of a review article in the “Continuing Medical Education” section of the
Journal of the American Association of Dermatology
to conclude that Spitz nevus and melanoma may “actually exist on a continuum of disease” (Casso et al.,
J. Am. Acad. Dermatol
., 27, 901-13 (1992)). The authors recommended that “treatment include complete excision of al Spitz nevi followed by reexcision of positive margins if present.” The need for improved diagnostics for melanocytic neoplasms has led to numerous attempts to improve diagnostic accuracy by the use of markers that could be detected by immuno-histochemistry. While there have been prior efforts aimed at resolving this problem, none have been satisfactory. For example, even though tests employing markers such as S 100, HMB45 are useful in establishing that a poorly differentiated tumor is of melanocytic lineage, adjunctive techniques have been of little help in separating benign from malignant melanocytic lesions.
Thus, there exists a great need for improved and accurate diagnostic methods to distinguish Spitz nevi from malignant melanoma. The present invention addresses these and other needs.
SUMMARY OF THE INVENTION
The present invention provides for methods of distinguishing melanocytic nevi, such as Spitz nevi, from malignant melanoma. The methods comprise detecting a target polynucleotide sequence on a chromosomal region such as 11p, particularly 11p15.5, which is usually amplified in Spitz nevi. The nucleic acid sample is typically taken from skin tumor tissue located within a tumor lesion on the skin of the patient. The methods can also be used to determine whether the tumor cells lack changes in chromosomal regions associated with melanoma (e.g., 1q, 6p, 7p, or 10q). Usually, the copy number of the target region is measured.
The nucleic acid sample can be extracted from an interphase nucleus. Typically, the probe is labeled e.g. with a fluorescent label. The label may be a direct label. Usually, a reference probe to a second chromosomal region is used in the methods as an internal control. In these embodiments, the second probe is labeled with a fluorescent label distinguishable from the label on the probe that selectively hybridizes to the target polynucleotide sequence.
In some embodiments, the probe may include repetitive sequences. In this case, the methods may further comprising the step of blocking the hybridization capacity of repetitive sequences the probe Unlabeled blocking nucleic acids comprising repetitive sequences (e.g. Cot-1 DNA) can be contacted with the sample for this purpose.
The nucleic acid hybridization can be carried out in a number of formats. For instance, the hybridization may be an in situ hybridization. In some embodiments, the probe is bound to a solid substrate, e.g. as a member of a nucleic acid array.
Definitions
To facilitate understanding the invention, a number of terms are defined below.
The terms “melanoma” or “cutaneous melanoma” refer to malignant neoplasms of melanocytes, which are pigment cells present normally in the epidermis and sometimes in the dermis. There are four types of cutaneous melanoma: lentigo maligna melanoma, superficial spreading melanoma (SSM), nodular melanoma, and acral lentiginous melanoma (AM). Melanoma usually starts as a proliferation of single melanocytes at the junction of the epidermis and the dermis. The cells first grow in a horizontal manner and settle an area of the skin that can vary from a few millimeters to several centimeters. As noted above, in most instances the transformed melanocytes produce increased amounts of pigment so that the area involved can easily be seen by the clinician.
The terms “Spitz nevi” or “Spitz nevus” refer to benign melanocytic neoplasms that can have considerable histological resemblance to melanoma. They were first described as “juvenile melanoma” and initially were thought of as a subset of childhood melanoma that follows a benign course. Spitz nevi are common and account for about 1% of surgically removed nevi.
The terms “tumor” or “cancer” in an animal refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. Often, cancer cells will be in the form of a tumor, but such cells may exist alone within an animal, or may be a non-tumorigenic cancer cell, such as a leukemia cell. Cancers include, but are not
Bastian Boris
Pinkel Daniel
Arthur Lisa B.
Goldberg Jeanine
The Regents of the University of California
Townsend and Townsend / and Crew LLP
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