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Table of Contents

Published May 30, 2002

Rebecca C.
Tung, MD

Department of
Dermatology

Allison T.
Vidimos, RPh, MD

Department of
Dermatology

Print Chapter

Copyright 2002
The Cleveland Clinic Foundation

INTRODUCTION

Introduction

Definition

Incidence
and Prevalence

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy

Prognosis

References

National Guidelines American Academy of Dermatology

 

More than one million cases of skin cancer will be diagnosed in the United States this year. About 80% of these new skin cancer cases will be basal cell carcinoma, 16% will be squamous cell carcinoma, and 4% will be melanoma. On a preventive health note, it has been estimated that regular application of sunscreen with sun protection factor of 15 or greater for the first 18 years of life would reduce the lifetime incidence of non-melanoma skin cancers by 78%. While non-melanoma skin cancers (basal and squamous cell carcinoma) are the most common types of malignancies in humans, melanoma ranks as the 6th and 7th most common cancer in men and women, respectively. Although the number of non-melanoma skin cancers is staggering, both basal cell and squamous cell carcinomas have a better than 95% cure rate if detected and treated early. Unfortunately, there is a higher mortality associated with melanoma—an estimated 7,800 deaths will be due to melanoma in 2001. Since it has been shown that early detection has led to overall increased survival rates for melanoma patients, it is of utmost importance for all physicians to possess the clinical diagnostic skills necessary to identify early melanoma lesions and then refer cases for further appropriate evaluation and treatment.

Cutaneous malignant melanoma is a neoplasm arising from the melanocytes that can occur de novo, or from a pre-existing lesion such as a congenital, acquired, or atypical (dysplastic) nevus. Non-cutaneous primary sites of melanocytes also include the mucosal epithelium, retina, and leptomeninges. As melanoma is potentially curable with surgical excision of early, thin lesions, prompt detection, diagnosis, and adequate removal of such lesions is of utmost importance. Education of the public with regard to the technique of routine self-examination and proper methods of sun protection can greatly improve the chances for early detection and adequate treatment of melanoma. (See American Academy of Dermatology Sun Safety Tips). A multidisciplinary approach, including primary care physicians, dermatologists, surgeons, oncologists, immunologists, radiologists, pathologists, and epidemiologists is necessary to optimize detection and treatment of this increasingly common cancer.

Recent U.S. incidence figures estimate that there will be about 51,400 cases of melanoma in 2001—29,000 men and 22,400 women. In 2001, at current rates, 1 in 71 Americans will develop melanoma over a lifetime. It is an alarming fact that one person dies of melanoma every hour. In 2001, 7,800 deaths will be attributed to melanoma—5,000 men and 2,800 women. Older Caucasian males have the highest mortality rates from melanoma. Melanoma is the 6th most common cancer in men and the 7th most common cancer in women. Melanoma is the #1 cancer in women ages 25 to 29 in the U.S. and the second most common, behind breast cancer, in women ages 30 to 34.

Evidence from epidemiologic studies show that exposure to solar irradiation is the main cause of cutaneous melanoma in fair-complected persons.^2,3 This causal relationship is supported by anatomic differences by sex, migration studies, difference in latitude of residence, and racial differences. The most common site for melanoma in men is the upper back while in women, the most common sites are the lower legs and upper back.² Studies have also shown that persons who immigrated to countries with higher levels of ambient solar irradiation have increased rates of melanoma compared to similar people who did not move. Likewise, melanoma incidence and mortality rates in white persons were inversely correlated with distance from the equator. Racial differences also exist with respect to melanoma. It is cited that the lower rate of melanoma in darkly pigmented people is due to the protective effect of melanin and fewer number of nevi that may serve as precursor lesions for melanoma. Main risk factors for cutaneous melanoma include phenotype (blue eyes, blond or red hair, and fair complexion), cutaneous reaction to sun exposure (freckling, inability to tan, sunburn tendency), upper socioeconomic status, family history of melanoma, nevi number and subtype, history of prior melanoma, and immunosuppression.² Genetic studies have also shown that 50% of familial melanomas and 25% of sporadic melanomas may be due to mutation in the tumor suppressor gene p16.¹ Linkage studies have identified chromosome 9p21 as the familial melanoma gene.¹ About 8% to 12% of all melanoma patients are cases of familial melanoma. The familial melanoma syndrome (also known as the dysplastic nevus syndrome) has been defined as: 1) melanoma in one or more first- or second-degree relatives, 2) large numbers of melanocytic nevi (often 50 to > 100), some of which are atypical and variable in size, 3) melanocytic nevi demonstrating certain histologic features. The mode of inheritance is most likely polygenic. The cumulative risk of developing cutaneous melanoma among persons with a history of familial melanoma is estimated to be approximately 50% by 50 years of age.¹ Mutations in the gene CDKN2A within the 9p21 region have been demonstrated in familial melanoma kindreds. The CDKN2A gene is complex and codes for p16 and p14ARF which both function to suppress cellular growth. An intact p16 inhibits cyclin-dependent kinases, a critical class of enzymes, whose function is to promote cellular proliferation by inhibiting the retinoblastoma protein. Therefore, an intact p16 is essential to arrest the cell cycle. p14ARF may be important in enhancing the effect of another tumor suppressor, p53.¹

Five stages of tumor progression have been suggested:

1. benign melanocytic nevi;
2. melanocytic nevi with architectural and cytologic atypia (dysplastic nevi);
3. primary malignant melanoma, radial growth phase;
   
4. primary malignant melanoma, vertical growth phase; and
5. metastatic malignant melanoma.

Each step in tumorigenesis is marked by a new clone of cells with growth advantages over the surrounding tissues.

Early signs of melanoma include ABCDEs: asymmetry of lesion; border irregularity, bleeding, or crusting; color change or variegation (some lesions are amelanotic—non-pigmented); diameter over 6 mm or growing lesion; elevated area (or palpable papule) in a previously flat nevus. About 1% to 2% of primary melanomas arise from mucous membrane melanocytes. Approximately 5% to 10% of patients present with metastatic disease (usually in the lymph node basin) without an identifiable primary lesion. Less than 2% of patients present with visceral metastases in the absence of an unknown primary lesion.

Precursor Lesions
Acquired dysplastic nevi (Figure 1) are atypical-appearing melanocytic tumors which are histologically characterized by intraepidermal melanocytic dysplasia. Dysplastic nevi are important because they are potential histogenic precursors of melanoma and markers of increased melanoma risk., Dysplastic nevi are fairly common—in the U.S., 1.8% to 4.9% of white adults have dysplastic nevi. Dysplastic nevi start as rather large moles during the first decade of life. Almost 40% of children from dysplastic nevi-melanoma families have dysplastic nevi and all children in whom melanoma eventually develops have dysplastic nevi. At least 17% of white adults with melanoma outside the familial melanoma setting have one or more dysplastic nevi, illustrating that dysplastic nevi are markers of risk, as well as potential precursors.

Clinically, dysplastic nevi appear by age 20 as 2 or more disorderly distributed shades of brown and black. They may be round, oval, or misshapen with an irregular or fuzzy outline. Any site may be affected, even sun-protected sites. The "horse-collar" area is usually most heavily involved.⁴

Management for people who have dysplastic nevi, with or without a personal or family history of melanoma, is controversial. Pathologic confirmation of the clinical diagnosis provides a more solid basis for making further management decisions. For people who have one or 2 suspected dysplastic nevi, excision is reasonable, but periodic examinations should be offered for a lifetime.⁴ Prophylactic removal of suspected dysplastic nevi is not feasible for people who have numerous dysplastic nevi. In patients with many dysplastic nevi, excision for hard-to-monitor areas (scalp, perineum, etc.) should be considered and serial clinical photography of other lesions should be performed to detect new or changing lesions. Persons with dysplastic nevi should also be instructed on how to practice the self-skin examination every 4 to 6 weeks at home.

For the removal of dysplastic nevi, lateral margins of about 2-3 mm should be taken to ensure complete removal.⁴ Dysplastic nevi may remain unchanged, progress to melanoma, or even regress over time. Only a small proportion of dysplastic nevi ever progress to melanoma, even in the familial melanoma setting. It is probable that both environmental and genetic factors play a role in the transition from dysplastic nevus to melanoma. In Greene et al's. study of dysplastic nevi-melanoma kindreds, they found the actuarial probability of melanoma developing in individuals who have dysplastic nevi in the familial melanoma setting may be as high as 56% from age 20 to 59 years, and 100% by age 76 years.⁵

In summary, dysplastic nevi should be considered potential precursor lesions to melanoma and deserve careful surveillance and prompt treatment when required.

A short discussion on congenital nevi (Figure 2) will be presented here because patients often are concerned with the malignant potential of these lesions. A congenital nevus is defined as a melanocytic nevus that is present at birth or appears within the first few months of life. They are classified by size as small (< 1.5 cm), medium (1.5-20.0 cm), and large (> 20.0 cm). The risk of developing cutaneous melanoma within small- and medium-sized lesions is low, but can be 1% over a lifetime. Conversely, large congenital nevi have an increased incidence of melanoma of up to 10% over a lifetime. Approximately 50% of the melanomas that develop within large congenital nevi do so by age 3 to 5, and patients have a melanoma risk of approximately 5% during the first 5 years of life.⁶ Therefore, while smaller congenital nevi can be followed clinically, early and complete surgical excision of large congenital nevi is usually recommended. If complete removal is not possible, the lesion should be closely observed and any nodules or suspicious changes should be biopsied.

Subtypes of Melanoma:

The subtypes of melanoma are distinguished by clinical and pathologic growth patterns: superficial spreading, lentigo maligna, nodular, and acral lentiginous.

Lentigo Maligna and Lentigo Maligna Melanoma
(LM, LMM)
Lentigo maligna (melanoma in situ) (Figure 3) begins as a tan irregular macule that extends peripherally, with differing shades throughout, which occurs on sun-damaged atrophic skin in elderly people. Lentigo maligna occurs equally in men and women, usually in the 7th and 8th decades.⁴ The exact percentage of lentigo maligna which progress to invasive lentigo maligna melanoma is unknown, but is estimated to be less than 30% to 50%. The lesion may grow slowly for 5-15 years in the precursor form prior to invasion.⁴ While lentigo maligna has a prolonged radial growth phase, when invasion occurs the result can be lethal. Long-term cumulative rather than intermittent sun exposure is thought to confer the greatest risk for developing lentigo maligna.

Lentigo maligna melanoma arises from lentigo maligna, a melanoma in situ (within the epidermis). Lentigo maligna melanoma is the least common subtype of melanoma (accounting for 4-15% of all melanoma patients).⁴ Lentigo maligna melanoma occurs almost exclusively on the sun-exposed skin of the head and neck, with the nose and cheek being the most common sites.⁷ Median age of diagnosis is 65 years old. The lesion is usually quite large (3-6 cm or greater) with a variable nodular area from one mm to 2 cm in width.⁷ Rarely lentigo maligna and lentigo maligna melanoma can be amelanotic.

Superficial Spreading Melanoma (SSM) (Figure 4)
Superficial spreading melanoma represents approximately 70% of all melanomas and is the most common type of cutaneous melanoma occurring in light-complicated people. It affects adults of all ages with the peak incidence in the 4th and 5th decade of life. SSM, not uncommonly, can arise in a pre-existing melanocytic nevus. The usual history is that of a slowly changing mole over 1-5 years.⁴ SSM most commonly affects intermittently sun-exposed areas with the greatest nevus density, such as the upper backs of men and women and lower legs of women. Clinically, SSM starts as a deeply pigmented macule or plaque with intact skin markings. The earliest change in SSM can be a focal area of darkening within a pre-existing nevus. Pigment variegation in a SSM ranges from black, blue-gray to pink, or gray-white color., The absence of pigmentation within a SSM may represent regression of the melanoma often, and the borders are often extremely irregular. The superficial spreading melanoma subtype usually presents with the classic early signs of melanoma (ABCDEs) mentioned earlier.

Nodular Melanoma (NM) (Figure 5)
The second most common subtype of melanoma is nodular melanoma (NM). NM represents 15% of all melanomas. The median age of onset is 53 years. Clinically NM presents as a uniform blue-black, blue-red, or amelanotic nodule. About 5% of nodular melanomas lack pigment (amelanotic melanoma). The most common sites for nodular melanoma are the trunk, head, and neck. It is more common for NM to begin in normal skin rather than in a pre-existing lesion. Rapid growth is also a hallmark of nodular melanoma.

Acral Lentiginous Melanoma (ALM) (Figure 6)
Acral lentiginous melanoma accounts for 10% of melanomas overall; however, they are the most common types among Japanese, African-Americans, Latinos, and native Americans. The median age for occurrence is 65 years with equal sex distribution. The most common site of melanoma in African-Americans is the foot with 60% of patients having subungual or plantar lesions.⁴ Overall, ALM can occur on the palms, soles, or beneath the nail plate with the sole being the most common site in all races. The average size at diagnosis is 3 cm, which may be related to delayed diagnosis. Clinically, the lesion is characterized by a tan, brown-to-black, flat macule with color variegation and irregular borders. Unlike lentigo maligna melanoma, development of acral lentiginous melanoma does not seem to be associated with sun exposure. Subungual melanoma (Figure 7) is a rare variant of acral lentiginous melanoma. The majority of subungual melanomas involves the great toe or thumb and generally arise from the nail matrix. Hutchinson's sign is the finding of pigmentation on the posterior nail fold and is associated with advanced subungual melanoma.⁴

Other more uncommon variants of melanoma include melanoma of the mucosa (Figure 8) and desmoplastic melanoma. When melanoma occurs on the mucosa, it usually develops on the mucosal surfaces of the head and neck (nasal and oral cavities), genital, or anorectal mucosa. Patients may present with bleeding or a mass lesion.

Desmoplastic Melanoma (Figure 9)
Desmoplastic melanoma is a rare subtype of melanoma, which is locally aggressive and has a high rate of local recurrence. It most commonly develops on sun-exposed skin of the head and neck of elderly persons in the 6th or 7th decade of life. Desmoplastic melanoma has a male predominance ratio of approximately 2:1. Approximately one half of desmoplastic melanomas develop in association with a lentigo maligna. Desmoplastic melanoma may present clinically as a pigmented macule with or without a nodular component or a flesh-colored nodule without any surrounding pigmentation. Desmoplastic melanomas often invade perineurally and are, therefore, frequently symptomatic to the patient. Most desmoplastic melanomas are deeply invasive at the time of diagnosis—at least 5-6 mm thick. They have a propensity to recur and deeply invade locally.

As with non-melanoma skin cancers, biopsy is indicated for all suspicious pigmented lesions. Surface epiluminescence microscopy (dermatoscopy) and ultrasound are evolving adjunctive noninvasive diagnostic techniques.³ According to the American Academy of Dermatology (AAD) Guidelines, whenever possible the lesion should be excised with narrow margins for diagnostic purposes. An incisional biopsy technique is appropriate when suspicion for melanoma is low, when the lesion is large, or it is impractical to perform a complete excision. A repeat biopsy should be performed if the initial biopsy specimen is inadequate for accurate histological diagnosis or staging. Fine needle aspiration cytology should not be used to assess the primary tumor. Histologic interpretation should be performed by a pathologist experienced in the microscopic diagnosis of pigmented lesions.³

Staging
Determination of melanoma stage is important for planning appropriate treatment and assessing prognosis. The American Joint Commission on Cancer (AJCC) recently published a revised four-stage system in 2002, which reflects new findings that Clark's Level (level of invasion according to depth of penetration of the dermis) offer little prognostic information for tumors thicker than 1 mm; whereas histologic ulceration consistently worsens prognosis across all tumors depths. Overall, 8 different T (tumor) criteria for primary tumors will now exist: T1a, T1b, T2a, T2b, T3a, T3b, T4a, and T4b. A new stage called IIC has been added, which represents clinically localized melanoma with the worst prognosis (thick, ulcerated primary tumors).

Eighty-five percent of melanoma patients have localized disease (stage I and II) on presentation. About 15% of patients have regional nodal disease, and only about 2% of patients have distant metastases at diagnosis. Prognosis for Stage I and II melanoma sites can be affected by many factors. Factors, which are associated with an improved prognosis, include: younger age, female sex, extremity lesions, and histologically negative nodes. Histologic variables which have been associated with a less favorable prognosis include: increasing tumor thickness, deeper level of invasion, increased mitotic rate, presence of ulceration, diminished lymphoid response, evidence of tumor regression, microscopic satellites, vascular invasion and non-spindle-cell type tumors.

The presence of regional lymph node metastases impart an overall 5-year survival of 37% and a 10-year survival of 32%.⁸ The most important prognostic factor for Stage III melanoma is the number of positive lymph nodes. Patients with nodal micrometastases have an improved survival compared to patients with clinically palpable nodes. Melanoma location on an extremity and younger age at diagnosis have been shown to have a better prognosis.

If there are distant metastases in a patient, median survival is about 6-9 months.⁹ For Stage IV patients, the prognostic variables suggesting worse prognosis include increasing number of metastatic sites, visceral location of metastases (lung, liver, brain, bone), absence of "resectable metastases," male sex, and shorter duration of remission.⁹ Of note, patients with non-visceral disease (eg, skin, subcutaneous tissue, lymph nodes) have a better median survival, ranging from 12-15 months, and are more likely to respond to chemotherapy.⁹

According to the AAD's updated 2001 Guidelines for care of primary cutaneous melanoma, surgical management should focus on obtaining excision margin based on histologic confirmation of tumor-free margins.³

• For melanoma in situ—0.5 cm margins.
• Melanoma with Breslow's thickness < 2 mm—1.0 cm margins.
• Melanoma with Breslow's thickness > or equal to 2.0 mm—2.0 cm margins.

In certain circumstances, surgical management may need to be tailored to the individual case. Primary melanomas near a vital structure may require a reduced margin, while aggressive histologic features may suggest a more worrisome tumor and warrant a wider margin. Surgical excision at sites like the fingers, toes, and sole of the foot, and ear also need separate surgical considerations. While Mohs micrographic surgery may prove useful for excision of melanoma, especially those located on the head, neck, hands, and feet—there are no formal recommendations pending additional studies.³ Despite adequate surgical resection of the primary melanoma, approximately 15% to 36% of patients with stage I and II melanoma will have some form of recurrence or metastasis during their clinical course.

Routine laboratory tests and imaging studies are not required for asymptomatic patients with primary cutaneous melanoma 4 mm or less in thickness for initial staging or routine follow-up.³ Indications for such studies are directed by a thorough medical history and complete physical examination. However, some studies have suggested that a chest x-ray and serum lactate dehydrogenase (LDH) might help detect occult metastases and alter further clinical management.^10,11

Elective Lymph Node Dissection (ELND)
ELND is defined as the removal of regional lymph nodes draining the site of the primary melanoma in absence of any clinical evidence of nodal metastases. Performing ELND is a much-debated topic in the management of melanoma. Proponents of ELND have cited retrospective studies demonstrating improved prognosis for patients with intermediate thickness (1-4 mm) lesions.^12-14 Conversely, opponents of ELND have cited prospective randomized trials, which fail to show a statistically significant difference in survival rates following ELND.^15-17

Sentinel Lymph Node Biopsy (SLNB)
Initially, lymphoscintigraphy is used to precisely map the draining nodal basin.¹⁸ The sentinel lymph node biopsy is based on the premise that the first node draining a lymphatic basin (sentinel lymph node), would be expected to predict the absence or presence of melanoma in that area.¹⁸ One percent isosulfan blue (Lymphazurin) dye is injected around the cutaneous lesion to allow intraoperative localization of this sentinel lymph node. Alternately, a radioactive tracer, technetium-99, can also be injected at the lesion site. A gamma probe is used to pinpoint the radiolabeled lymph node, which is then removed for histopathologic review. If no melanoma cells are found, no further surgery is done. However, if the node does have involvement, the remainder of the nodes in this area are removed.¹⁸ Determination of the status of the sentinel lymph node is relevant because: 1) it has been shown to be an important independent prognostic factor, with a positive result predictive of high risk of treatment failure, 2) it is a relatively low-risk procedure that can help identify high-risk patients who might benefit from additional therapy like selective complete lymphadenectomy or adjuvant interferon alpha-2b, 3) it provides a psychologic benefit for the patient whose sentinel lymph node biopsy does not reveal metastases.² Because positivity rates for sentinel lymph node biopsy are less than 5% for AJCC T1 melanomas, SLNB is viewed to be a low-yield procedure in most thin melanomas. Currently, the ideal Breslow criteria for selection of this technique are not yet established.²

Adjuvant Therapy Interferon
In the Eastern Cooperative Oncology Group (ECOG) 1684 study, high-dose interferon alpha-2b was initially reported to improve the survival of patients with melanoma > 4 mm thick; however, the follow-up trial ECOG 1690 did not show an overall survival benefit. Another major study reported by the Austrian Malignant Melanoma Cooperative Group did show that adjuvant treatment with low-dose interferon alpha-2b diminished the occurrence of metastases and prolonged the disease-free survival in patients with melanoma > 1.5 mm. All of these studies suggest that the role of interferon in the treatment of melanoma is evolving and needs further study.

Chemotherapy
Systemic chemotherapy is primarily used in patients with advanced Stage III (unresectable regional metastases) or Stage IV (distant metastases) melanoma. Although most chemotherapy is not that effective, dacarbazine remains the most active drug and is the only FDA-approved chemotherapeutic agent for the treatment of advanced melanoma in the United States.⁹ The response rate is in the range of 10% to 20%, and patients with metastases in the skin, subcutaneous tissues, or lymph nodes respond most frequently. Other combination chemotherapy and biochemotherapy regimens could achieve higher response rates, but do not appear to lead to durable remission.⁹

Biologic Therapy
Therapy directed toward modulating or inducing the immune system against melanoma has gathered considerable interest in recent years. Interleukin-2 (IL-2) as a single agent has been utilized in metastatic melanoma. In one study, there was a complete response in 7% of patients, which was durable with patients remaining disease-free for up to 8 years after initiating therapy.¹⁹ Another study also showed positive results treating patients with their own tumor-infiltrating lymphocytes and IL-2. Monoclonal antibody therapies are, as of yet, experimental and may be of potential use in melanoma. Likewise, melanoma vaccines have been developed to stimulate a specific response against melanoma-associated antigens. Vaccines are currently undergoing clinical trials.

Perfusion Chemotherapy
Isolated limb perfusion (ILP) has been used for melanoma of the extremities. ILP is a technique that involves isolating a limb from the systemic circulation with a tourniquet, using arterial and venous cannulation, and infusing a chemotherapeutic agent by means of a pump oxygenator, then removing the medication from the limb.²⁰ It has been developed into the most effective method of treatment for local recurrent or intransit metastases of an extremity.²⁰ Medications which are used for infusion include melphalan, dacarbazine, cisplatin, carboplatin, thiotepa, and cytokine tumor necrosis factor alpha.²⁰

Radiation
Radiation therapy is indicated in certain patients with Stage IV disease with the purpose of palliation. Specific indications include brain metastases, pain associated with bone metastases, and skin and subcutaneous metastases that are superficially located.

The prognosis for a patient with Stage I or II melanoma is mainly related to tumor thickness:⁴ (Table 1)

• Melanoma in situ — 100% survival at 5 years and 10 years
• Lesions < or = to 1 mm — 91%-95% at 5 years; 83%-88% at 10 years
• Lesions 1.01 mm to 2 mm — 77%-89% at 5 years; 64%-79% at 10 years
• Lesions 2.01- 4 mm — 63% to 79% at 5 years; 51%-64% at 10 years
• Lesions > 4 mm — 45% to 67% at 5 years; 32%-54% at 10 years

If grouped according to stage for localized primary melanoma, the overall survival rate is 80%.⁴ For patients with regional lymph node metastases (Stage III disease), survival rates were 27% to 69% at 5 years and 18% to 63% at 10 years. Unfortunately, when there is evidence of distant metastases (Stage IV disease), the 5-year survival rate is only 9%-19% and 10-year survival rate is 6%-16%. (Table 1) However, spontaneous regression has been documented in melanoma cases, even those with metastatic disease.⁴

Follow-up Evaluation
The goal of regular follow-up evaluation of patients with melanoma is the detection of melanoma recurrence or development of a second primary melanoma. Each visit should include a detailed history and physical examination. For most patients with Stage I and II melanoma, it is recommended that follow-up appointments be scheduled initially every 3 months for 2 years, then every 6 months for 3 years, then once yearly thereafter. If the patient has dysplastic nevi, the interval may be continued at every 6 months indefinitely. Photography may be helpful in following multiple clinically atypical nevi. Patients should also be taught and encouraged to practice monthly self-skin examination. Since most experts attribute the rising trend in the overall 5-year melanoma survival rate (some 40% in the 1940s to the current rate of 86%) to improved early detection, it is very important for both physicians and the public to be aware of the early warning signs of melanoma and to get appropriate dermatologic evaluation and treatment as soon as possible.

Return to Medicine Index

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