Continuing Education Activity

Granular cell tumors are rare neoplasms derived from Schwann cells with characteristic pathologic findings. They can exhibit either benign or malignant behavior and most commonly occur in the oral cavity, skin, and gastrointestinal tract. They must be appropriately treated to avoid recurrence or metastasis of malignant lesions. This activity reviews the diagnosis, management, and prognosis of granular cell tumors and highlights the role of the interprofessional team in evaluating and treating patients with this neoplasm.

Objectives:

• Describe the typical clinical presentation of patients with granular cell tumors.
• Identify the histologic features required to differentiate benign from malignant granular cell tumors.
• Outline the management of patients with granular cell tumors.

Introduction

Granular cell tumors were described as early as 1926 by the Russian pathologist Abrikossoff. They were initially coined granular cell myoblastomas, as they were believed to be of muscular origin. With the advent of immunohistochemical stains and electron microscopy, they are now believed to be Schwannian derivation.[1][2] Notably, a subset of S100-negative “non-neural” granular cell tumors have been identified which may not derive from neural tissue.[3][4][5]

These rare tumors are most commonly reported in the skin, oral cavity, digestive tract, and subcutaneous tissue. However, they can occur anywhere in the body, including breast, bladder, nervous system, respiratory and genitourinary tracts. All age groups and genders can be affected, but it is classically found in women in their 4th to 6th decades of life.[6][7][8][9][10] Granular cell tumors typically present as solitary, painless nodules less than 3-4 cm large and may be found incidentally.[7][11][12]

The vast majority behave indolently. Based on histologic criteria or the presence of metastasis, however, 1% to 2% of these lesions can be malignant, with poor prognosis and few curative options beyond surgical excision.[13][14][11]

Etiology

The etiology of granular cell tumors to-date is poorly described, and its genetic underpinnings and pathophysiology are not well understood. Although it is known that these tumors may demonstrate recurrent genetic mutations in the setting of specific syndromes, the mutations driving sporadic tumorigenesis have only recently become evident with the use of whole-genome sequencing.

Syndrome Associations

It is known that the clinical finding of multiple granular cell tumors is associated with Noonan syndrome, neurofibromatosis I, and LEOPARD syndrome.[15][16][17][18][19][20] Authors have reported PTPN11 gene mutations in granular cell tumors associated with LEOPARD and Noonan syndromes.[15] It has also been proposed that the etiology of multiple granular cell tumors may be linked to abnormal RAS/MAPK pathway cell signaling, given that this mutation is a shared feature in all 3 syndromes. In another study, granular cell tumor was also associated with germline PTEN mutations in patients with PTEN hamartoma tumor syndrome.[21]

It is important to note that many of these syndrome-associated gene mutations have not yet been tested in large studies and are mostly derived from case studies or small case series. To the contrary, one small follow-on study attempting to confirm the importance of PTEN and PTPN11 mutations in granular cell tumors could not detect either of them and instead found KDR, GNAQ, and ATM mutations in a small sample of granular cell tumors, none of which were recurrent within the sample.[22]

Non-Neural Tumors

Although the question of shared cell lineage with conventional granular cell tumors is debated, there is also a subset of non-neural, S100-negative granular cell tumors which reportedly harbor an ALK gene fusion and which stain positively for Anaplastic Lymphoma Kinase immunohistochemistry.[23]

ATP6AP1 and ATP6AP2 Mutations

Recently, whole-genome sequencing and targeted sequencing analysis have been used to identify mutations in granular cell tumors. In 2018, Pareja et al. used whole-exome sequencing and targeted sequencing analysis to identify recurrent ATP6AP1 and ATP6AP2 inactivating somatic mutations in 72% of their sampled granular cell tumors.[24] Subsequent in-vitro impairment of these pH regulators in Schwann cells not only spurred oncogenesis via increased phosphorylation of PDGFR-B, SFK, and STAT-5, but it also resulted in impaired vesicle acidification, impaired endocytosis, and build-up of intracytoplasmic granules. This re-created the characteristic histologic finding of eosinophilic granules in the cytoplasm. The authors suggest that these 2 mutations are pathognomonic for granular cell tumors, as they are each found in less than 0.3% of other common cancer types. Impairment of ATP6AP1 and ATP6AP2 resulted in impairment of the V-ATPase (H+ ATPase) complex with a subsequent decrease in lysosomal activity. Not only does this correlate with the characteristic cytoplasmic findings, but it also explains the tumor’s positive immunohistochemical staining for TFE3 and wild-type MITF, as lysosomal inhibition induces activation of transcription factors MITF, TFE3, and TFEB. A larger follow-on study in 2019 verified the presence of truncating or splice site mutations in ATP6AP1 and ATP6AP2 as well as ATP6V0C, which also codes for a V-ATPase accessory protein.[25]

Malignant Tumors

Further studies have sought to specifically characterize malignant granular cell tumors via whole-genome sequencing, finding mutations in the new tumor suppressor candidate BRD7 and in GFRA2 of the tyrosine kinase receptor pathway.[26] Other studies have reported potential driver mutations in ATM, ASXL1, NOTCH2, and PARP4 pathways in malignant granular cell tumors, as well as the loss of heterozygosity in chromosomes 9p and 17p in oral granular cell tumors.[27][28][29]

Epidemiology

Granular cell tumors can appear in all age groups but are thought to arise most commonly in the 4th to 6th decades.[8] These tumors are most often seen in women (ranging from 1.8 to 2.4 female: male).[30] While two-thirds of the benign lesions are reported in African-American patients, recent cohort analysis of 113 patients found that over 70% of the patients with malignant cutaneous tumors were Caucasian.[31][32]

These are rare tumors. According to a study by Lack et al. at a single institution over 32 years, the overall incidence of granular cell tumors in surgical specimens was 0.03%.[6]

Although most are solitary, 7% to 29% of patients can have multiple lesions on presentation, 30% of which involve the skin and subcutaneous tissue.[33] In 45 to 65% of cases, they are found in the head and neck region.[30][34][35][36]

Overall, they involve the cutis and subcutaneous tissue in 30% of patients, involve the breasts in 15% of cases, the respiratory tract in 10% of cases, and the gastrointestinal tract in 5% to 11%. 1% to 2% of them are malignant based on histology or clinical presentation.[11][32][37]

Histopathology

Morphology

Granular cell tumors are characterized by infiltrative, non-encapsulated nests, cords, or sheets of polygonal and occasionally spindled cells with abundant eosinophilic, finely granular cytoplasm. Many of the tumors have Pustulo-ovoid bodies of Milian, which are large granules with clear halos.[38] The granules are period acid-Schiff (PAS) positive and diastase resistant, and they are thought to represent lysosomes.[8] The nests are often separated by fibrous tissue and located in the dermis, subcutis, or submucosa.[39] Nuclei have dense chromatin, are relatively small, and are centrally placed. 

Malignant Features

These lesions can be sub-classified into benign, atypical, and malignant categories based on histologic features. The first system was developed in 1998 by Fanburg-Smith et al. using these six features: necrosis, increased mitotic count (greater than 2 per 10 high power fields), spindled tumor cells, nuclear pleomorphism, prominent nucleoli, and vesicular nuclei, and high nuclear to cytoplasmic ratio.[40] Lesions with none of these features are categorized as benign, and those with 1 or 2 features are categorized as atypical. Tumors with 3 or more are called malignant and have a considerably worse prognosis. 

Immunohistochemistry

Both benign and malignant tumor cells typically stain positively for S-100, CD68, neuron-specific enolase, CD57, inhibin, calretinin, TFE3, SOX10, CD56, PGP9.5, and vimentin.[1][41][42][43] There is a rare non-neural variant which stains negatively for S-100 but is positive for CD68, CD10, and occasionally neuron-specific enolase.[5][44] In some studies, proliferation markers ki-67 and PHH3 were shown to be good predictors of atypical histology.[45]

Additional Features

Although benign granular cell tumors are readily identified morphologically, there are some features that can be mistaken for malignancy. Benign lesions located deep to the skin or deep to a mucosal surface can induce reactive pseudoepitheliomatous hyperplasia, which closely mimics squamous cell carcinoma in superficial biopsies and is found in over half of cases.[7][46] Benign tumors can also demonstrate both vascular and perineural invasion, but these histologic features do not confer malignancy or an adverse prognosis.[39]

History and Physical

General

Granular cell tumors typically present as skin-colored or brown-red, solitary, painless, and slow-growing nodules in the head and neck area that are less than 3-4 cm in diameter.[11][47] They are rarely painful or pruritic. They are most reported in the skin, oral cavity, gastrointestinal tract, breast, and respiratory tract. It is postulated that their high frequency in the tongue and skin parallels the large concentration of peripheral nerves in those areas. They have also been reported in every organ system, including the genitourinary tract, thyroid, neurohypophysis, and pancreaticobiliary system.[8]

They may present as multiple nodules, which should prompt an exam for other findings associated with Noonan syndrome, neurofibromatosis type I, and LEOPARD syndrome.[18][48]

Breast

In the breast, granular cell tumors can arise in any location, including all 4 quadrants, the axilla, and nipple. Some authors previously argued that they might arise predominantly in the upper inner quadrant in the distribution of the supraclavicular nerve, although this is debated in recent literature. 70% of these present as palpable masses and others are found incidentally or during screening without a palpable mass on the exam. Most of them are painless, although some patients have reported pain, pruritis, skin retraction, thickening or dimpling, and reactive lymphadenopathy on presentation.[49]

Gastrointestinal Tract

In the gastrointestinal tract, these tumors are often found incidentally during screening, and patients are usually asymptomatic. They occur most frequently in the distal esophagus, followed by the duodenum, anus, and stomach, although cases in the colon, biliary tract, and rectum have also been reported. Some patients present with non-specific symptoms such as belching, dysphagia, abdominal distension, or hematochezia. Endoscopy typically reveals a hard, isolated grey-white submucosal or mucosal nodule with normal overlying mucosa, and the lesions generally do not have unique features to set them apart from other etiologies of gastrointestinal polyps.[50][51][52][53][54][55]

Oral Cavity

In the oral cavity, these are known to occur most frequently on the anterior tongue and are seen as a firm yellow or pink, non-painful, solitary nodule.[56] Although these are also seen on the lip, palate, and buccal mucosa, some studies have found that these locations account for less than 20% of oral cavity granular cell tumors.[57]

Neurohypophysis

In the neurohypophysis, they are most often asymptomatic and found incidentally at autopsy. However, they may rarely present with bitemporal visual impairment due to mass effect, headache, or hyperprolactinemia with hypogonadism. Given their rarity, they are often initially diagnosed with radiology as pituitary adenomas or craniopharyngiomas.[58]

Malignant Tumors

As for the malignant counterpart, the tumors often present as subcutaneous masses, most commonly in the lower extremities.[59] They are usually larger than benign lesions and are known to present with metastatic lesions in the lung, lymph nodes, and bones.[60] Clinical findings associated with malignant lesions include rapid growth, ulceration, invasion of adjacent structures by radiology, and diameter greater than 5 cm.[13][60]

Evaluation

Radiology

Imaging is typically not pursued prior to excisional biopsy for small, benign-appearing nodules in the skin or oral cavity. However, tumors in the gastrointestinal tract, breast, extremity soft tissue, or other uncommon locations are often imaged because they cannot be distinguished clinically from other benign or malignant lesions.

Intramuscular

Although no radiologic findings are unique to granular cell tumors, MRI is the best imaging modality to differentiate benign from malignant lesions. In the muscle, benign granular cell tumors appear iso-intense or brighter than muscle on T1-weighted imaging. On T2-weighted sequences, the center of the lesion is also iso-intense to muscle or suppressed fat, but there is peripheral enhancement. They are round- or oval-shaped, less than 4 cm in diameter, and superficial. By comparison, the malignant counterparts often show high signal intensity on T2-weighted sequences, have the same iso-intensity to muscle on T1-weighted images, are larger than 4 cm in diameter, and may show the invasion of adjacent structures.[35][61]

Breast

In the breast, imaging findings can be difficult to distinguish from carcinoma. They can be seen on mammography as small, round, well-circumscribed lesions that are less than 3 cm in diameter, but they have also been reported to be indistinct, stellate, heterogeneous with hypodense rims, poorly circumscribed, and spiculated without calcifications. Ultrasound findings are also non-specific in the breast. They are the most commonly heterogeneous, solid, and poorly defined masses featuring posterior shadowing and high depth to width ratio. Some series have described them as predominantly hyperechoic, while others have described them as hypoechoic. Rarely, however, they can be well-circumscribed with weak internal echoes and acoustic enhancement.[49][62][63][64][65] On MRI, breast lesions demonstrate similar findings as compared to intramuscular lesions, with the intermediate signal in T1-weighted sequences and peripheral enhancement in T2-weighted images with iso-intensity to muscle.[49][66]

Esophagus

In the esophagus, granular cell tumors are more often hypoechoic, homogeneous, and smooth-edged by ultrasound, although hyperechoic, heterogeneous, and irregular lesions have been described.[37] On MRI, esophageal lesions have been described as having low T1 signal intensity with homogeneous enhancement and high T2 intensity.[67]

Pathology

Given the similar clinical and radiologic findings between granular cell tumors and other benign and malignant entities, diagnosis via biopsy for microscopic analysis is required for all lesions.[49][66]. Both benign and malignant tumors have characteristic histologic findings such that excisional biopsies are readily diagnosed by morphology in combination with immunohistochemical stains. For lesions amenable to it, excisional biopsy is preferred to core biopsy or shave biopsy. This will minimize the likelihood of sampling error, whereby the tumor underlying reactive squamous atypia is missed or where portions of the tumor showing malignant histology are missed.[68]

Treatment / Management

Surgery

Complete excision to negative margins with close clinical follow-up is recommended for granular cell tumors in nearly all locations, whether benign or malignant.[47][49] In the skin, wide local excision is performed for the diagnosis of smaller lesions, but larger lesions may require a biopsy followed by excision. Given the propensity of these tumors to recur with positive margins, Mohs surgery is occasionally employed to ensure complete removal of the tumor, particularly in cosmetically and functionally important locations.[47][69] Sentinel lymph node biopsy is only recommended for lesions suspected to be malignant by clinical impression or histology. Lymph node dissection is generally only suggested for palpable lymph nodes or biopsy-proven metastatic disease, although some authors recommend lymph node dissection upfront in malignant breast tumors.[70][49][65]

Chemotherapy and Radiation Therapy

The current understanding is that there is a limited role for chemotherapy and radiation therapy. There have been rare case reports of these modalities being used with some success on patients with malignant tumors and metastatic disease on presentation.[13][71][72] A handful of case reports have shown that the sarcoma treatment pazopanib can treat some recurrent malignant granular cell tumors, but there is no current standard chemotherapy regimen for malignant or metastatic disease given the lack of randomized clinical trials with this specific lesion. The use of adjuvant radiation therapy has been similarly controversial and ill-defined, with scattered reports recommending its use in recurrent malignant lesions or inoperable metastases.[72][73][74][75] In the United States, only 11.3% of patients with malignant granular cell tumors receive radiation therapy.[31]

Management in the Gastrointestinal Tract

In the gastrointestinal tract, it is important to follow up on the initial endoscopy with endoscopic ultrasound in order to assess tumor size, location, and anatomic depth of invasion. This will determine treatment modality. In contrast to other locations, asymptomatic esophageal granular cell tumors less than 1 cm can be monitored with follow-up endoscopic ultrasounds. Tumors greater than 1 cm, lesions causing symptoms, rapidly growing nodules, or those suspicious for malignancy are resected. Endoscopic mucosal resection is used to resect benign tumors under 2 cm, while submucosal endoscopic resection is used for benign tumors between 2 to 3 cm in the submucosa. Conventional open surgery or video-assisted thoracoscopic surgery are pursued tumors located in the muscularis propria, large or malignant lesions, and in the presence of other contraindications to endoscopic resection.[76][77]

In the colon, endoscopic mucosal resection or endoscopic submucosal dissection are also the best strategies for benign tumors under 2 cm. Some authors recommend endoscopic submucosal excavation for benign tumors up to 5 cm with traditional surgery reserved for those greater than 5 cm and for malignant lesions. Others recommend polypectomy for anything under 4 cm, while some recommend colectomy for any lesion greater than 2 cm.[55][78][79]

Differential Diagnosis

Clinical Differential

The clinical differential diagnosis for granular cell tumors is extensive and varies by the location of the tumor. It may include alveolar soft parts sarcoma, adnexal tumors, apocrine carcinoma, basal cell carcinoma, cholangiocarcinoma, colonic adenoma, cystic lesions, dermatofibroma, dermoid cyst, desmoid tumor, duct ectasia, fat necrosis, fibroadenoma, fibrosarcoma, gastrointestinal stromal tumor, granulomatous mastitis, hidradenoma, hypertrophic scar, invasive mammary carcinoma, irritation fibroma, keloid, leiomyoma, leiomyosarcoma, lipoma, malignant fibrous histiocytoma, neurofibroma, nodular fasciitis, oncocytic renal cell carcinoma, prurigo nodularis, regressing verruca, rhabdomyosarcoma, sclerosing adenosis, schwannoma, steatoma, and traumatic neuroma. 

Histologic Differential[80]

The histologic differential largely includes tumors that have similar morphologic findings and those with granular variants. It includes alveolar soft parts sarcoma, ameloblastoma, angiosarcoma, atypical fibroxanthoma, basal cell carcinoma, congenital granular cell epulis, dermatofibroma, dermatofibrosarcoma protuberans, epithelioid histiocytoma, fibroxanthoma, granular cell dermatofibroma, hibernoma, leiomyoma, leiomyosarcoma, lobomycosis, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, melanocytic nevus, melanoma, neurofibroma, non-neural granular cell tumor, primitive polypoid granular cell tumor, reactive granular cell change, reticulohistiocytoma, rhabdomyoma, rhabdomyosarcoma, schwannoma, squamous cell carcinoma, trichoblastoma, and xanthoma.

Staging

Currently, no clear staging system exists for malignant granular cell tumors.[31] Nonetheless, for lesions expected to be malignant by clinical presentation or by histology, sentinel lymph node biopsies, and possible lymph node dissection are recommended to evaluate for regional metastasis.[49][65][70]

Prognosis

Benign

The prognosis for benign granular cell tumors is excellent, as complete surgical resection is considered curative.[81] There have only been sporadic case reports of metastatic lesions arising from histologically benign primaries.[82] With wide local excision, the recurrence rate has been reported to be as low as 2% to 8%, although that increases to 21% to 50% with incomplete excision.[83]

Malignant

By contrast, patients with malignant granular cell tumors have a substantially worse prognosis, with 74% and 65% survival rates at 5 years and 10 years, respectively. They see a 32% to 41% rate of recurrence and 11 to 62% rate of metastasis between 3 to 37 months after diagnosis.[11][82][84] Notably, patients with tumors greater than 5 cm see decreased 5-year survival rates of 51% compared to 90% in those with tumors less than 5 cm. Similarly, those with distant metastases at diagnosis have 0% survival at 5 years compared to 81% in those without metastases.

Complications

Complications include the following

• Surgical site infection
• Recurrence
• Metastasis, regional and distant
• Poor aesthetics of surgical scar
• Local invasion and tissue destruction
• Discomfort due to mass effect (dysphagia, nerve impingement, constipation, abdominal fullness, bitemporal hemianopsia, hyperprolactinemia)

Deterrence and Patient Education

Following the resection of granular cell tumors, patients should monitor for metastatic and recurrent lesions. This is especially true with malignant tumors. They should also be reminded to keep their follow-up appointments for appropriate surveillance imaging of metastatic lesions or nodules which were not excised (small esophageal tumors). This will allow for the proper treatment of any newly discovered tumors.

Patients with multiple granular cell tumors should also be educated about the possible association with neurofibromatosis I, Noonan syndrome, and LEOPARD syndrome (lentigines, electrocardiogram (ECG) conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness). They will likely need a thorough exam and additional studies to rule these out.

Pearls and Other Issues

Non-Representative Biopsy

Numerous pitfalls exist in the work-up and diagnosis of granular cell tumors. One well-known pitfall involves a shave biopsy of the superficial skin or mucosa overlying a granular cell tumor. Granular cell tumors are commonly associated with superficial pseudoepitheliomatous hyperplasia, which has a morphologic appearance that is strikingly similar to squamous cell carcinoma. If only the epidermis overlying a deep dermal or subcutaneous nodule is shaved, the patient will be misdiagnosed and receive inappropriate therapy. Similarly, needle biopsies are discouraged for lesions amenable to complete excisional biopsies. Some granular cell tumors may have patchy foci of malignant histology such that a single core may not be representative of the entire tumor.

Incomplete Excision

Another pitfall is not obtaining broad margins on local excisions of lesions where it is feasible. Clinically benign-appearing lesions may still have malignant histology, so wide local excision with negative margins is recommended for all lesions suspected or proven to be granular cell tumors to minimize the possibility of recurrence.

Lymph Node Dissection

Although it is debated in the literature, performing a lymph node dissection for benign or malignant tumors before a sentinel lymph node biopsy may result in unnecessary surgery and morbidity associated with lymph node dissections. Many authors recommend sentinel lymph node biopsies only for malignant tumors before a full lymph node dissection.

Poor Communication

Finally, if there is poor communication between the clinician and the pathologist, the patient may mistakenly be diagnosed with a benign granular cell tumor rather than a malignant one. The history of rapid growth, size over 5 cm, ulceration, and prominent lymphadenopathy, for example, may prompt the diagnosis of a malignant lesion regardless of histologic findings. Failure to communicate that to the pathologist may result in a benign diagnosis and, subsequently, inappropriate follow-up and under-investigation for metastatic lesions.

Enhancing Healthcare Team Outcomes

Granular cell tumors are rare neoplasms whose clinical and radiologic findings are often indistinguishable from other, more common lesions. These tumors, whether malignant or benign, typically present as solitary masses in a wide range of organ systems without any unique features until examined microscopically. Furthermore, while some of the malignant lesions present as such with nodal or distant metastases, many are not found to be malignant until the histology is worked up. Subsequently, while a single physician may be initiating the care of a patient with a granular cell tumor, it is important to consult with an interdisciplinary team of specialists promptly to expedite workup and treatment.

A dermatologist who diagnoses a malignant granular cell tumor of the skin by biopsy or excision may need to order additional imaging and rely on radiology to identify metastatic lesions. An interventional pulmonologist may need to be consulted for biopsy of lung lesions, with the subsequent engagement of thoracic surgery, surgical oncology, medical oncology, and radiation oncology to discuss and pursue management options for metastatic lesions with the patient.

Radiology

Radiologists play an important role in determining the etiology of the lesion, as they can advise the primary physician to keep benign tumors in mind, such as benign granular cell tumors, even when the imaging demonstrates malignant features such as spiculation. If the patient has a prior history of other benign granular cell tumors, it is important to relay that history to the radiologists to ensure they consider multiple foci of such tumors in the differential even if the lesion appears malignant. The radiologist may also be able to discern features suggestive of a malignant versus benign granular cell tumor. 

Pathology

Pathologists are also a vital part of the team, as they identify the diagnostic morphologic and immunohistochemical findings in this tumor. They will ultimately communicate with the team whether the lesion is benign or its malignant counterpart. It is important to provide appropriate clinical history and imaging findings to the pathologist when tissue is sent, as this will impact diagnosis as well as classification of the tumor as malignant or benign. Failing to impart the information that lymphadenopathy was noted near the tumor or the fact that synchronous liver lesions were noticed in addition to a skin primary, for example, may lead the pathologist to call a lesion benign or atypical rather than malignant. Alternatively, if it is not communicated to the pathologist that a biopsy was just a superficial shave of a deep dermal lesion, the reactive pseudoepitheliomatous hyperplasia overlying a benign granular cell tumor may be erroneously called squamous cell carcinoma.[46] (Level V)

Nursing and Pharmacy

Leading up to and following surgical excision of the lesion, the nurses play an essential role in the interprofessional group, as they monitor the patient’s pre-operative, intra-operative, and post-operative vital signs and symptoms concerning for infection, and they assist with the education of the patient and family. Pharmacists will ensure the patient is sent home on the appropriate pain medication.

Outcomes

The outcomes of granular cell tumors depend in part on whether the lesions are malignant or benign. Benign tumors have excellent outcomes with wide local excision and rarely recur or metastasize. On the other hand, patients with large, malignant lesions and metastatic disease have dismally poor outcomes. Some studies report up to 41% recurrence after excision and a 62% rate of metastasis in malignant lesions. Another recent study demonstrated that patients with metastatic disease at diagnosis have 0% survival at 5 years.[84] (Level V) It is therefore important to maintain clear communication with diagnostic specialists and to promptly consult with an inter-disciplinary group of sub-specialists. This will decrease the time to treatment and will reduce the likelihood that any given malignant lesion will metastasize or cause further morbidity for the patient.