Thomas N. Helm, MD

We have attended grand rounds presentations at which students announce that Mohs micrographic surgery evaluates 100% of the surgical margin, whereas standard excision samples 1% to 2% of the margin; we have even fielded questions from neighbors who have come across this information on the internet.^1-5 This statement describes a best-case scenario for Mohs surgery and a worst-case scenario for standard excision. We believe that it is important for clinicians to have a more nuanced understanding of how simple excisions are processed so that they can have pertinent discussions with patients, especially now that there is increasing access to personal health information along with increased agency in patient decision-making.

Margins for Mohs Surgery

Theoretically, Mohs surgery should sample all true surgical margins by complete circumferential, peripheral, and deep-margin assessment. Unfortunately, some sections are not cut full face—sections may not always sample a complete surface—when technicians make an error or lack expertise. Some sections may have small tissue folds or small gaps that prevent complete visualization. We estimate that the Mohs sections we review in consultation that are prepared by private practice Mohs surgeons in our communities visualize approximately 98% of surgical margins on average. Incomplete sections contribute to the rare tumor recurrences after Mohs surgery of approximately 2% to 3%.⁶

Standard Excision Margins

When we obtained the references cited in articles asserting that standard excision samples less than 0.5%, 1%, or 2% of the surgical margin, we did not find evidence-based information confirming this generally accepted conclusion. We believe the assertions are derived by comparing the sum of the thickness of all microscopic sections added together against the longitudinal length of the entire specimen.Sampling less than 0.5% of a margin has been described as providing the illusion of microscopic control.⁵ We have encountered medical students, nondermatologist physicians, and patients who have come across this information and have understandably concluded that standard margin assessment must be inadequate if only such a small amount of margin is assessed.

Here is a simple example to show that more margin is accessed in some cases. Consider this hypothetical situation: If a tumor can be readily visualized grossly and housed entirely within an imaginary cuboid (rectangular) prism that is removed in an elliptical specimen with a length of 6 cm, a width of 2 cm, and a height of 1 cm (Figure), then standard sectioning assesses a greater margin.

Bread-loaf sectioning would be expected to examine the complete surface of 2 sides (faces) of the cuboid. Assessing 2 of the 5 clinically relevant sides provides information for approximately 50% of the margins, as sections in the next parallel plane can be expected to be clear after the first clear section is identified. The clinically useful information is not limited to the sum of the widths of sections. Encountering a clear plane typically indicates that there will be no tumor in more distal parallel planes. Warne et al⁶ developed a formula that can accurately predict the percentage of the margin evaluated by proxy that considers the curvature of the ellipse.

Comparing Standard Excision and Mohs Surgery

Mohs surgery consistently results in the best outcomes, but standard excision is effective, too. Standard excision is relatively simple, requires less equipment, is less time consuming, and can provide good value when resources are finite. Data on recurrence of basal cell carcinoma after simple excision are limited, but the recurrence rate is reported to be approximately 3%.^7,8 A meta-analysis found that the recurrence rate of basal cell carcinoma treated with standard excision was 0.4%, 1.6%, 2.6%, and 4% with 5-mm, 4-mm, 3-mm, and 2-mm surgical margins, respectively.⁹

Mohs surgery is the best, most effective, and most tissue-sparing technique for certain nonmelanoma skin cancers. This observation is reflected in guidelines worldwide.¹⁰ The adequacy of standard approaches to margin evaluation depends on the capabilities and focus of the laboratory team. Dermatopathologists often are called to the laboratory to decide which technique will be best for a particular case.¹¹ Technicians are trained to take more sections in areas where abnormalities are seen, and some laboratories take photographs of specimens or provide sketches for correlation. Dermatopathologists also routinely request additional sections in areas where visible tumor extends close to surgical margins on microscopic examination.

It is not simply a matter of knowing how much of the margin is sampled but if the most pertinent areas are adequately sampled. Simple sectioning can work well and be cost effective. Many clinicians are unaware of how tissue processing can vary from laboratory to laboratory. There are no uniformly accepted standards for how tissue should be processed. Assiduous and thoughtful evaluation of specimens can affect results. As with any service, some laboratories provide more detailed and conscientious care while others focus more on immediate costs. Clinicians should understand how their specimens are processed by discussing margin evaluation with their dermatopathologist.

Final Thoughts

Used appropriately, Mohs surgery is an excellent technique that can provide outstanding results. Standard excision also has an important place in the dermatologist’s armamentarium and typically provides information about more than 1% to 2% of the margin. Understanding the techniques used to process specimens is critical to delivering the best possible care.

We have attended grand rounds presentations at which students announce that Mohs micrographic surgery evaluates 100% of the surgical margin, whereas standard excision samples 1% to 2% of the margin; we have even fielded questions from neighbors who have come across this information on the internet.^1-5 This statement describes a best-case scenario for Mohs surgery and a worst-case scenario for standard excision. We believe that it is important for clinicians to have a more nuanced understanding of how simple excisions are processed so that they can have pertinent discussions with patients, especially now that there is increasing access to personal health information along with increased agency in patient decision-making.

Margins for Mohs Surgery

Theoretically, Mohs surgery should sample all true surgical margins by complete circumferential, peripheral, and deep-margin assessment. Unfortunately, some sections are not cut full face—sections may not always sample a complete surface—when technicians make an error or lack expertise. Some sections may have small tissue folds or small gaps that prevent complete visualization. We estimate that the Mohs sections we review in consultation that are prepared by private practice Mohs surgeons in our communities visualize approximately 98% of surgical margins on average. Incomplete sections contribute to the rare tumor recurrences after Mohs surgery of approximately 2% to 3%.⁶

Standard Excision Margins

When we obtained the references cited in articles asserting that standard excision samples less than 0.5%, 1%, or 2% of the surgical margin, we did not find evidence-based information confirming this generally accepted conclusion. We believe the assertions are derived by comparing the sum of the thickness of all microscopic sections added together against the longitudinal length of the entire specimen.Sampling less than 0.5% of a margin has been described as providing the illusion of microscopic control.⁵ We have encountered medical students, nondermatologist physicians, and patients who have come across this information and have understandably concluded that standard margin assessment must be inadequate if only such a small amount of margin is assessed.

Here is a simple example to show that more margin is accessed in some cases. Consider this hypothetical situation: If a tumor can be readily visualized grossly and housed entirely within an imaginary cuboid (rectangular) prism that is removed in an elliptical specimen with a length of 6 cm, a width of 2 cm, and a height of 1 cm (Figure), then standard sectioning assesses a greater margin.

Bread-loaf sectioning would be expected to examine the complete surface of 2 sides (faces) of the cuboid. Assessing 2 of the 5 clinically relevant sides provides information for approximately 50% of the margins, as sections in the next parallel plane can be expected to be clear after the first clear section is identified. The clinically useful information is not limited to the sum of the widths of sections. Encountering a clear plane typically indicates that there will be no tumor in more distal parallel planes. Warne et al⁶ developed a formula that can accurately predict the percentage of the margin evaluated by proxy that considers the curvature of the ellipse.

Comparing Standard Excision and Mohs Surgery

Mohs surgery consistently results in the best outcomes, but standard excision is effective, too. Standard excision is relatively simple, requires less equipment, is less time consuming, and can provide good value when resources are finite. Data on recurrence of basal cell carcinoma after simple excision are limited, but the recurrence rate is reported to be approximately 3%.^7,8 A meta-analysis found that the recurrence rate of basal cell carcinoma treated with standard excision was 0.4%, 1.6%, 2.6%, and 4% with 5-mm, 4-mm, 3-mm, and 2-mm surgical margins, respectively.⁹

Mohs surgery is the best, most effective, and most tissue-sparing technique for certain nonmelanoma skin cancers. This observation is reflected in guidelines worldwide.¹⁰ The adequacy of standard approaches to margin evaluation depends on the capabilities and focus of the laboratory team. Dermatopathologists often are called to the laboratory to decide which technique will be best for a particular case.¹¹ Technicians are trained to take more sections in areas where abnormalities are seen, and some laboratories take photographs of specimens or provide sketches for correlation. Dermatopathologists also routinely request additional sections in areas where visible tumor extends close to surgical margins on microscopic examination.

It is not simply a matter of knowing how much of the margin is sampled but if the most pertinent areas are adequately sampled. Simple sectioning can work well and be cost effective. Many clinicians are unaware of how tissue processing can vary from laboratory to laboratory. There are no uniformly accepted standards for how tissue should be processed. Assiduous and thoughtful evaluation of specimens can affect results. As with any service, some laboratories provide more detailed and conscientious care while others focus more on immediate costs. Clinicians should understand how their specimens are processed by discussing margin evaluation with their dermatopathologist.

Final Thoughts

Used appropriately, Mohs surgery is an excellent technique that can provide outstanding results. Standard excision also has an important place in the dermatologist’s armamentarium and typically provides information about more than 1% to 2% of the margin. Understanding the techniques used to process specimens is critical to delivering the best possible care.

We have attended grand rounds presentations at which students announce that Mohs micrographic surgery evaluates 100% of the surgical margin, whereas standard excision samples 1% to 2% of the margin; we have even fielded questions from neighbors who have come across this information on the internet.^1-5 This statement describes a best-case scenario for Mohs surgery and a worst-case scenario for standard excision. We believe that it is important for clinicians to have a more nuanced understanding of how simple excisions are processed so that they can have pertinent discussions with patients, especially now that there is increasing access to personal health information along with increased agency in patient decision-making.

Margins for Mohs Surgery

Theoretically, Mohs surgery should sample all true surgical margins by complete circumferential, peripheral, and deep-margin assessment. Unfortunately, some sections are not cut full face—sections may not always sample a complete surface—when technicians make an error or lack expertise. Some sections may have small tissue folds or small gaps that prevent complete visualization. We estimate that the Mohs sections we review in consultation that are prepared by private practice Mohs surgeons in our communities visualize approximately 98% of surgical margins on average. Incomplete sections contribute to the rare tumor recurrences after Mohs surgery of approximately 2% to 3%.⁶

Standard Excision Margins

When we obtained the references cited in articles asserting that standard excision samples less than 0.5%, 1%, or 2% of the surgical margin, we did not find evidence-based information confirming this generally accepted conclusion. We believe the assertions are derived by comparing the sum of the thickness of all microscopic sections added together against the longitudinal length of the entire specimen.Sampling less than 0.5% of a margin has been described as providing the illusion of microscopic control.⁵ We have encountered medical students, nondermatologist physicians, and patients who have come across this information and have understandably concluded that standard margin assessment must be inadequate if only such a small amount of margin is assessed.

Here is a simple example to show that more margin is accessed in some cases. Consider this hypothetical situation: If a tumor can be readily visualized grossly and housed entirely within an imaginary cuboid (rectangular) prism that is removed in an elliptical specimen with a length of 6 cm, a width of 2 cm, and a height of 1 cm (Figure), then standard sectioning assesses a greater margin.

Bread-loaf sectioning would be expected to examine the complete surface of 2 sides (faces) of the cuboid. Assessing 2 of the 5 clinically relevant sides provides information for approximately 50% of the margins, as sections in the next parallel plane can be expected to be clear after the first clear section is identified. The clinically useful information is not limited to the sum of the widths of sections. Encountering a clear plane typically indicates that there will be no tumor in more distal parallel planes. Warne et al⁶ developed a formula that can accurately predict the percentage of the margin evaluated by proxy that considers the curvature of the ellipse.

Comparing Standard Excision and Mohs Surgery

Mohs surgery consistently results in the best outcomes, but standard excision is effective, too. Standard excision is relatively simple, requires less equipment, is less time consuming, and can provide good value when resources are finite. Data on recurrence of basal cell carcinoma after simple excision are limited, but the recurrence rate is reported to be approximately 3%.^7,8 A meta-analysis found that the recurrence rate of basal cell carcinoma treated with standard excision was 0.4%, 1.6%, 2.6%, and 4% with 5-mm, 4-mm, 3-mm, and 2-mm surgical margins, respectively.⁹

Mohs surgery is the best, most effective, and most tissue-sparing technique for certain nonmelanoma skin cancers. This observation is reflected in guidelines worldwide.¹⁰ The adequacy of standard approaches to margin evaluation depends on the capabilities and focus of the laboratory team. Dermatopathologists often are called to the laboratory to decide which technique will be best for a particular case.¹¹ Technicians are trained to take more sections in areas where abnormalities are seen, and some laboratories take photographs of specimens or provide sketches for correlation. Dermatopathologists also routinely request additional sections in areas where visible tumor extends close to surgical margins on microscopic examination.

It is not simply a matter of knowing how much of the margin is sampled but if the most pertinent areas are adequately sampled. Simple sectioning can work well and be cost effective. Many clinicians are unaware of how tissue processing can vary from laboratory to laboratory. There are no uniformly accepted standards for how tissue should be processed. Assiduous and thoughtful evaluation of specimens can affect results. As with any service, some laboratories provide more detailed and conscientious care while others focus more on immediate costs. Clinicians should understand how their specimens are processed by discussing margin evaluation with their dermatopathologist.

Final Thoughts

Used appropriately, Mohs surgery is an excellent technique that can provide outstanding results. Standard excision also has an important place in the dermatologist’s armamentarium and typically provides information about more than 1% to 2% of the margin. Understanding the techniques used to process specimens is critical to delivering the best possible care.

The Diagnosis: Squamous Cell Carcinoma

The initial clinical presentation suggested a diagnosis of herpes simplex labialis. The patient reported no response to topical acyclovir, and because the plaque persisted, a biopsy was performed. Pathology demonstrated squamous cell carcinoma (SCC) that was moderately well differentiated and invasive (Figure). 

Approximately 38% of all oral SCCs in the United States occur on the lower lip and typically are solar-related cancers developing within the epidermis.¹ Oral lesions initially may be asymptomatic and may not be of concern to the patient; however, it is important to recognize SCC early, as invasive lesions have the potential to metastasize. Some factors that increase the chance for the development of metastases include tumor size larger than 2 cm; location on the ear, lip, or other sites on the head and neck; and history of prior unsuccessful treatment.² Any solitary ulcer, lump, wound, or lesion that will not heal and persists for more than 3 weeks should be regarded as cancer until proven otherwise. Although few oral SCCs are detected by clinicians at an early stage, diagnostic aids such as vital staining and molecular markers in tissues and saliva may be implemented.³ Toluidine blue is a simple, fast, and inexpensive technique that stains the nuclear material of malignant lesions, but not normal mucosa, and may be a worthwhile diagnostic adjunct to clinical inspection.⁴

Our patient presented with a lesion that clinically looked herpetic, though he reported no prodromal signs of tingling, burning, or pain before the occurrence of the lesion. Due to the persistence of the lesion and lack of response to treatment, a biopsy was indicated. The differential diagnoses include aphthous ulcers, which may occasionally extend on to the vermilion border of the lip and exhibit nondiagnostic histology.⁵ Bullous oral lichen planus is the least common variant of oral lichen planus, is unlikely to present as a solitary lesion, and is rarely seen on the lips. Histologically, the lesion demonstrated lichenoid inflammation.⁶ Solitary keratoacanthoma, though histologically similar to SCC, typically presents as a rapidly growing crateriform nodule without erosion or ulceration.⁷ The differential diagnoses are summarized in the Table.

The patient underwent wide excision with repair by mucosal advancement flap. He continues to be regularly seen in the clinic for monitoring of other skin cancers and is doing well. Clinicians encountering any wound or ulcer that does not show signs of healing should be wary of underlying malignancy and be prompted to perform a biopsy.

The Diagnosis: Squamous Cell Carcinoma

The initial clinical presentation suggested a diagnosis of herpes simplex labialis. The patient reported no response to topical acyclovir, and because the plaque persisted, a biopsy was performed. Pathology demonstrated squamous cell carcinoma (SCC) that was moderately well differentiated and invasive (Figure). 

Approximately 38% of all oral SCCs in the United States occur on the lower lip and typically are solar-related cancers developing within the epidermis.¹ Oral lesions initially may be asymptomatic and may not be of concern to the patient; however, it is important to recognize SCC early, as invasive lesions have the potential to metastasize. Some factors that increase the chance for the development of metastases include tumor size larger than 2 cm; location on the ear, lip, or other sites on the head and neck; and history of prior unsuccessful treatment.² Any solitary ulcer, lump, wound, or lesion that will not heal and persists for more than 3 weeks should be regarded as cancer until proven otherwise. Although few oral SCCs are detected by clinicians at an early stage, diagnostic aids such as vital staining and molecular markers in tissues and saliva may be implemented.³ Toluidine blue is a simple, fast, and inexpensive technique that stains the nuclear material of malignant lesions, but not normal mucosa, and may be a worthwhile diagnostic adjunct to clinical inspection.⁴

Our patient presented with a lesion that clinically looked herpetic, though he reported no prodromal signs of tingling, burning, or pain before the occurrence of the lesion. Due to the persistence of the lesion and lack of response to treatment, a biopsy was indicated. The differential diagnoses include aphthous ulcers, which may occasionally extend on to the vermilion border of the lip and exhibit nondiagnostic histology.⁵ Bullous oral lichen planus is the least common variant of oral lichen planus, is unlikely to present as a solitary lesion, and is rarely seen on the lips. Histologically, the lesion demonstrated lichenoid inflammation.⁶ Solitary keratoacanthoma, though histologically similar to SCC, typically presents as a rapidly growing crateriform nodule without erosion or ulceration.⁷ The differential diagnoses are summarized in the Table.

The patient underwent wide excision with repair by mucosal advancement flap. He continues to be regularly seen in the clinic for monitoring of other skin cancers and is doing well. Clinicians encountering any wound or ulcer that does not show signs of healing should be wary of underlying malignancy and be prompted to perform a biopsy.

The Diagnosis: Squamous Cell Carcinoma

The initial clinical presentation suggested a diagnosis of herpes simplex labialis. The patient reported no response to topical acyclovir, and because the plaque persisted, a biopsy was performed. Pathology demonstrated squamous cell carcinoma (SCC) that was moderately well differentiated and invasive (Figure). 

Approximately 38% of all oral SCCs in the United States occur on the lower lip and typically are solar-related cancers developing within the epidermis.¹ Oral lesions initially may be asymptomatic and may not be of concern to the patient; however, it is important to recognize SCC early, as invasive lesions have the potential to metastasize. Some factors that increase the chance for the development of metastases include tumor size larger than 2 cm; location on the ear, lip, or other sites on the head and neck; and history of prior unsuccessful treatment.² Any solitary ulcer, lump, wound, or lesion that will not heal and persists for more than 3 weeks should be regarded as cancer until proven otherwise. Although few oral SCCs are detected by clinicians at an early stage, diagnostic aids such as vital staining and molecular markers in tissues and saliva may be implemented.³ Toluidine blue is a simple, fast, and inexpensive technique that stains the nuclear material of malignant lesions, but not normal mucosa, and may be a worthwhile diagnostic adjunct to clinical inspection.⁴

Our patient presented with a lesion that clinically looked herpetic, though he reported no prodromal signs of tingling, burning, or pain before the occurrence of the lesion. Due to the persistence of the lesion and lack of response to treatment, a biopsy was indicated. The differential diagnoses include aphthous ulcers, which may occasionally extend on to the vermilion border of the lip and exhibit nondiagnostic histology.⁵ Bullous oral lichen planus is the least common variant of oral lichen planus, is unlikely to present as a solitary lesion, and is rarely seen on the lips. Histologically, the lesion demonstrated lichenoid inflammation.⁶ Solitary keratoacanthoma, though histologically similar to SCC, typically presents as a rapidly growing crateriform nodule without erosion or ulceration.⁷ The differential diagnoses are summarized in the Table.

The patient underwent wide excision with repair by mucosal advancement flap. He continues to be regularly seen in the clinic for monitoring of other skin cancers and is doing well. Clinicians encountering any wound or ulcer that does not show signs of healing should be wary of underlying malignancy and be prompted to perform a biopsy.

Localized cutaneous argyria often presents as asymptomatic black or blue-gray pigmented macules in areas of the skin exposed to silver-containing compounds.¹ Silver may enter the skin by traumatic implantation or absorption via eccrine sweat glands.² Our patient witnessed a gun fight several years ago while on a mission trip and sustained multiple shrapnel wounds.

As in our patient, hyperpigmentation may appear years following initial exposure. Over time, incident light reduces colorless silver salts and compounds to black elemental silver.³ It also has been suggested that metallic silver granules stimulate tyrosine kinase activity, leading to locally increased melanin production.⁴ Together, these processes result in the clinical appearance of a blue-black macule. Despite its long-standing association with silver, this appearance also has been noted with deposition of other metals.⁵ Histologically, metal deposits can be seen as black granules surrounding eccrine glands, blood vessels, and elastic fibers on higher magnification.⁶ Granules also may be found in sebaceous glands and arrector pili muscle fibers. These findings do not distinguish from generalized argyria due to increased serum silver levels; however, some cases of localized cutaneous argyria have demonstrated spheroid black globules with surrounding collagen necrosis,¹ which have not been reported with generalized disease. Localized cutaneous argyria also may be associated with ocher pigmentation of thickened collagen fibers, resembling changes typically found in alkaptonuria, an inherited deficiency of homogentisic acid oxidase (an enzyme involved in tyrosine metabolism).⁷ The resulting buildup of metabolic intermediates leads to ochronosis, a deposition of ocher-pigmented intermediates in connective tissue throughout the body. In the skin, ocher pigmentation occurs in elastic fibers of the reticular dermis.¹ Grossly, these changes result in a blue-gray discoloration of the skin due to a light-scattering phenomenon known as the Tyndall effect. Exogenous ochronosis also can occur, most commonly from the topical application of hydroquinone or other skin-lightening compounds.^1,5 Ocher  pigmentation occurring in the setting of localized cutaneous argyria is referred to as pseudo-ochronosis, a finding first described by Robinson-Bostom et al.¹ The etiology of this condition is poorly understood, but Robinson-Bostom et al¹ noted the appearance of dark metal granules surrounding collagen bundles and hypothesized that metal aggregates surrounding collagen bundles in pseudo-ochronosis cause a homogenized appearance under light microscopy. Yellow-brown, swollen, homogenized collagen bundles can be visualized in the reticular dermis with surrounding deposition of metal granules (Figures 1 and 2).¹ Typical patterns of granule deposition in localized argyria also are present.

A blue nevus is a collection of proliferating dermal melanocytes. Many histologic subtypes exist and there may be extensive variability in the extent of sclerosis, cellular architecture, and tissue cellularity between each variant.⁸ Blue nevi commonly present as blue-black hyperpigmentation in the dermis and subcutaneous tissue.⁹ Histologically, they are characterized by slender, bipolar, dendritic melanocytes in a sclerotic stroma (Figure 3).⁸ Melanocytes are highly pigmented and contain small monomorphic nuclei. Lesions are relatively homogenous and typically are restricted to the dermis with epidermal sparing.⁹ Dark granules and ocher fibers are absent.

Long-term use of hydroxychloroquine or other antimalarials may cause a macular pattern of blue-gray hyperpigmentation.¹⁰ Biopsy specimens typically reveal coarse, yellow-brown pigment granules primarily affecting the superficial dermis (Figure 4). Granules are found both extracellularly and within macrophages. Fontana-Masson silver staining may identify melanin, as hydroxychloroquine-melanin binding may contribute to patterns of hyperpigmentation.¹⁰ Hemosiderin often is present in cases of hydroxychloroquine pigmentation. Preceding ecchymosis appears to favor the deposition of hydroxychloroquine in the skin.¹¹ The absence of dark metal granules helps distinguish hydroxychloroquine pigmentation from argyria.

Regressed melanomas may appear clinically as gray macules. These lesions arise in cases of malignant melanoma that spontaneously regress without treatment. Spontaneous regression occurs in 10% to 35% of cases depending on tumor subtype.¹² Lesions can have a variable appearance based on the degree of regression. Partial regression is demonstrated by mixed melanosis and fibrosis in the dermis (Figure 5).^13,14 Melanin is housed within melanophages present in a variably expanded papillary dermis. Tumors in early stages of regression can be surrounded by an inflammatory infiltrate, which becomes diminished at later stages. However, a few exceptional cases have been noted with extensive inflammatory infiltrate and no residual tumor.¹⁴ Completely regressed lesions typically appear as a band of dermal melanophages in the absence of inflammation or melanocytic atypia.¹⁵ The finding of regressed melanoma should prompt further investigation including sentinel lymph node biopsy, as it may be associated with metastasis.

Tattooing occurs following traumatic penetration of the skin with impregnation of pigmented foreign material into deep dermal layers.¹⁶ Histologic examination usually reveals clumps of fine particulate material in the dermis (Figure 6). The color of the pigment depends on the agent used. For example, graphite appears as black particles that may be confused with localized cutaneous argyria. Distinction can be made using elemental identification techniques such as energy-dispersive X-ray spectroscopy.¹ The intensity of the pigment in granules found in tattoos or localized cutaneous argyria will fail to diminish with the application of melanin bleach.⁶

Localized cutaneous argyria often presents as asymptomatic black or blue-gray pigmented macules in areas of the skin exposed to silver-containing compounds.¹ Silver may enter the skin by traumatic implantation or absorption via eccrine sweat glands.² Our patient witnessed a gun fight several years ago while on a mission trip and sustained multiple shrapnel wounds.

As in our patient, hyperpigmentation may appear years following initial exposure. Over time, incident light reduces colorless silver salts and compounds to black elemental silver.³ It also has been suggested that metallic silver granules stimulate tyrosine kinase activity, leading to locally increased melanin production.⁴ Together, these processes result in the clinical appearance of a blue-black macule. Despite its long-standing association with silver, this appearance also has been noted with deposition of other metals.⁵ Histologically, metal deposits can be seen as black granules surrounding eccrine glands, blood vessels, and elastic fibers on higher magnification.⁶ Granules also may be found in sebaceous glands and arrector pili muscle fibers. These findings do not distinguish from generalized argyria due to increased serum silver levels; however, some cases of localized cutaneous argyria have demonstrated spheroid black globules with surrounding collagen necrosis,¹ which have not been reported with generalized disease. Localized cutaneous argyria also may be associated with ocher pigmentation of thickened collagen fibers, resembling changes typically found in alkaptonuria, an inherited deficiency of homogentisic acid oxidase (an enzyme involved in tyrosine metabolism).⁷ The resulting buildup of metabolic intermediates leads to ochronosis, a deposition of ocher-pigmented intermediates in connective tissue throughout the body. In the skin, ocher pigmentation occurs in elastic fibers of the reticular dermis.¹ Grossly, these changes result in a blue-gray discoloration of the skin due to a light-scattering phenomenon known as the Tyndall effect. Exogenous ochronosis also can occur, most commonly from the topical application of hydroquinone or other skin-lightening compounds.^1,5 Ocher  pigmentation occurring in the setting of localized cutaneous argyria is referred to as pseudo-ochronosis, a finding first described by Robinson-Bostom et al.¹ The etiology of this condition is poorly understood, but Robinson-Bostom et al¹ noted the appearance of dark metal granules surrounding collagen bundles and hypothesized that metal aggregates surrounding collagen bundles in pseudo-ochronosis cause a homogenized appearance under light microscopy. Yellow-brown, swollen, homogenized collagen bundles can be visualized in the reticular dermis with surrounding deposition of metal granules (Figures 1 and 2).¹ Typical patterns of granule deposition in localized argyria also are present.

A blue nevus is a collection of proliferating dermal melanocytes. Many histologic subtypes exist and there may be extensive variability in the extent of sclerosis, cellular architecture, and tissue cellularity between each variant.⁸ Blue nevi commonly present as blue-black hyperpigmentation in the dermis and subcutaneous tissue.⁹ Histologically, they are characterized by slender, bipolar, dendritic melanocytes in a sclerotic stroma (Figure 3).⁸ Melanocytes are highly pigmented and contain small monomorphic nuclei. Lesions are relatively homogenous and typically are restricted to the dermis with epidermal sparing.⁹ Dark granules and ocher fibers are absent.

Long-term use of hydroxychloroquine or other antimalarials may cause a macular pattern of blue-gray hyperpigmentation.¹⁰ Biopsy specimens typically reveal coarse, yellow-brown pigment granules primarily affecting the superficial dermis (Figure 4). Granules are found both extracellularly and within macrophages. Fontana-Masson silver staining may identify melanin, as hydroxychloroquine-melanin binding may contribute to patterns of hyperpigmentation.¹⁰ Hemosiderin often is present in cases of hydroxychloroquine pigmentation. Preceding ecchymosis appears to favor the deposition of hydroxychloroquine in the skin.¹¹ The absence of dark metal granules helps distinguish hydroxychloroquine pigmentation from argyria.

Regressed melanomas may appear clinically as gray macules. These lesions arise in cases of malignant melanoma that spontaneously regress without treatment. Spontaneous regression occurs in 10% to 35% of cases depending on tumor subtype.¹² Lesions can have a variable appearance based on the degree of regression. Partial regression is demonstrated by mixed melanosis and fibrosis in the dermis (Figure 5).^13,14 Melanin is housed within melanophages present in a variably expanded papillary dermis. Tumors in early stages of regression can be surrounded by an inflammatory infiltrate, which becomes diminished at later stages. However, a few exceptional cases have been noted with extensive inflammatory infiltrate and no residual tumor.¹⁴ Completely regressed lesions typically appear as a band of dermal melanophages in the absence of inflammation or melanocytic atypia.¹⁵ The finding of regressed melanoma should prompt further investigation including sentinel lymph node biopsy, as it may be associated with metastasis.

Tattooing occurs following traumatic penetration of the skin with impregnation of pigmented foreign material into deep dermal layers.¹⁶ Histologic examination usually reveals clumps of fine particulate material in the dermis (Figure 6). The color of the pigment depends on the agent used. For example, graphite appears as black particles that may be confused with localized cutaneous argyria. Distinction can be made using elemental identification techniques such as energy-dispersive X-ray spectroscopy.¹ The intensity of the pigment in granules found in tattoos or localized cutaneous argyria will fail to diminish with the application of melanin bleach.⁶

Localized cutaneous argyria often presents as asymptomatic black or blue-gray pigmented macules in areas of the skin exposed to silver-containing compounds.¹ Silver may enter the skin by traumatic implantation or absorption via eccrine sweat glands.² Our patient witnessed a gun fight several years ago while on a mission trip and sustained multiple shrapnel wounds.

As in our patient, hyperpigmentation may appear years following initial exposure. Over time, incident light reduces colorless silver salts and compounds to black elemental silver.³ It also has been suggested that metallic silver granules stimulate tyrosine kinase activity, leading to locally increased melanin production.⁴ Together, these processes result in the clinical appearance of a blue-black macule. Despite its long-standing association with silver, this appearance also has been noted with deposition of other metals.⁵ Histologically, metal deposits can be seen as black granules surrounding eccrine glands, blood vessels, and elastic fibers on higher magnification.⁶ Granules also may be found in sebaceous glands and arrector pili muscle fibers. These findings do not distinguish from generalized argyria due to increased serum silver levels; however, some cases of localized cutaneous argyria have demonstrated spheroid black globules with surrounding collagen necrosis,¹ which have not been reported with generalized disease. Localized cutaneous argyria also may be associated with ocher pigmentation of thickened collagen fibers, resembling changes typically found in alkaptonuria, an inherited deficiency of homogentisic acid oxidase (an enzyme involved in tyrosine metabolism).⁷ The resulting buildup of metabolic intermediates leads to ochronosis, a deposition of ocher-pigmented intermediates in connective tissue throughout the body. In the skin, ocher pigmentation occurs in elastic fibers of the reticular dermis.¹ Grossly, these changes result in a blue-gray discoloration of the skin due to a light-scattering phenomenon known as the Tyndall effect. Exogenous ochronosis also can occur, most commonly from the topical application of hydroquinone or other skin-lightening compounds.^1,5 Ocher  pigmentation occurring in the setting of localized cutaneous argyria is referred to as pseudo-ochronosis, a finding first described by Robinson-Bostom et al.¹ The etiology of this condition is poorly understood, but Robinson-Bostom et al¹ noted the appearance of dark metal granules surrounding collagen bundles and hypothesized that metal aggregates surrounding collagen bundles in pseudo-ochronosis cause a homogenized appearance under light microscopy. Yellow-brown, swollen, homogenized collagen bundles can be visualized in the reticular dermis with surrounding deposition of metal granules (Figures 1 and 2).¹ Typical patterns of granule deposition in localized argyria also are present.

A blue nevus is a collection of proliferating dermal melanocytes. Many histologic subtypes exist and there may be extensive variability in the extent of sclerosis, cellular architecture, and tissue cellularity between each variant.⁸ Blue nevi commonly present as blue-black hyperpigmentation in the dermis and subcutaneous tissue.⁹ Histologically, they are characterized by slender, bipolar, dendritic melanocytes in a sclerotic stroma (Figure 3).⁸ Melanocytes are highly pigmented and contain small monomorphic nuclei. Lesions are relatively homogenous and typically are restricted to the dermis with epidermal sparing.⁹ Dark granules and ocher fibers are absent.

Long-term use of hydroxychloroquine or other antimalarials may cause a macular pattern of blue-gray hyperpigmentation.¹⁰ Biopsy specimens typically reveal coarse, yellow-brown pigment granules primarily affecting the superficial dermis (Figure 4). Granules are found both extracellularly and within macrophages. Fontana-Masson silver staining may identify melanin, as hydroxychloroquine-melanin binding may contribute to patterns of hyperpigmentation.¹⁰ Hemosiderin often is present in cases of hydroxychloroquine pigmentation. Preceding ecchymosis appears to favor the deposition of hydroxychloroquine in the skin.¹¹ The absence of dark metal granules helps distinguish hydroxychloroquine pigmentation from argyria.

Regressed melanomas may appear clinically as gray macules. These lesions arise in cases of malignant melanoma that spontaneously regress without treatment. Spontaneous regression occurs in 10% to 35% of cases depending on tumor subtype.¹² Lesions can have a variable appearance based on the degree of regression. Partial regression is demonstrated by mixed melanosis and fibrosis in the dermis (Figure 5).^13,14 Melanin is housed within melanophages present in a variably expanded papillary dermis. Tumors in early stages of regression can be surrounded by an inflammatory infiltrate, which becomes diminished at later stages. However, a few exceptional cases have been noted with extensive inflammatory infiltrate and no residual tumor.¹⁴ Completely regressed lesions typically appear as a band of dermal melanophages in the absence of inflammation or melanocytic atypia.¹⁵ The finding of regressed melanoma should prompt further investigation including sentinel lymph node biopsy, as it may be associated with metastasis.

Tattooing occurs following traumatic penetration of the skin with impregnation of pigmented foreign material into deep dermal layers.¹⁶ Histologic examination usually reveals clumps of fine particulate material in the dermis (Figure 6). The color of the pigment depends on the agent used. For example, graphite appears as black particles that may be confused with localized cutaneous argyria. Distinction can be made using elemental identification techniques such as energy-dispersive X-ray spectroscopy.¹ The intensity of the pigment in granules found in tattoos or localized cutaneous argyria will fail to diminish with the application of melanin bleach.⁶

A 76-year-old man presented with a rapidly growing, indurated, crusted nodule on his lower lip (Figure 1). This combination—a rapidly growing nodule on a sun-exposed surface in an older patient—pointed to a diagnosis of squamous cell carcinoma, and biopsy study of the affected area confirmed this diagnosis (Figure 2). Clinical examination, computed tomography, and ultrasonography of the neck revealed no lymph node involvement; the tumor was staged as T2N0M0. Mohs microscopically controlled surgery was performed to remove the tumor with clear margins, and the patient has done well.

DIFFERENTIAL DIAGNOSIS

Malignant melanoma, Merkel cell carcinoma, and deep fungal infection can also cause a rapidly growing crusted nodule on the lower lip, but this typically is not an initial presentation for these conditions.

Malignant melanoma

Malignant melanoma should be considered for any rapidly growing cutaneous tumor, especially on sun-damaged skin. Most melanoma lesions have variations in pigment and may contain shades of blue, brown, red, pink, and white. Amelanotic melanomas may mimic squamous cell carcinomas, but the histologic features of atypical keratinocytes in this patient ruled out that diagnosis. Biopsy of amelanotic melanoma reveals nests of melanocytes, usually associated with an in situ component in the overlying epithelium.

Merkel cell carcinoma

Merkel cell carcinoma can mimic squamous cell carcinoma or can even arise in association with squamous cell carcinoma. Histologic examination allows for differentiation. In difficult cases, cytokeratin staining with cytokeratin 20 and CAM 5.2 can clarify the diagnosis, because Merkel cell carcinomas exhibit a characteristic paranuclear dot-like pattern not evident in squamous cell carcinoma.

Deep fungal infection

Colonization by Candida organisms was noted within the overlying crust in this patient’s lesion, but fungal organisms were not noted in the epidermis or dermis. Pseudoepitheliomatous hyperplasia can be prominent in deep fungal infection, but the marked cytologic atypia in this case excluded deep fungal infection.

Mucosal neuroma

Mucosal neuromas are typically smooth-surfaced, soft lesions on the lip. They may be associated with multiple endocrine neoplasia syndromes. Biopsy study reveals that they are composed of delicate spindle cells that lack atypia.

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma is one of the most common types of nonmelanoma skin cancer and is associated with increased sun exposure and light skin pigmentation.¹ Unlike basal cell carcinoma, squamous cell carcinoma has a considerable potential to metastasize.^2–4 The current cancer staging manual of the American Joint Commission on Cancer refects recent evidence-based information on staging and prognosis.^5–7 Squamous cell carcinoma of the lip carries an increased risk of metastasis,⁸ and an increase in the number or the size of involved lymph nodes carries a worse prognosis.⁹ The lower lip is most commonly involved because of increased sun exposure. The most common route for the spread of squamous cell carcinoma of the head and neck is via lymphatics, so careful evaluation of the head and neck is indicated.¹⁰

STAGING OUR PATIENT’S LESION

Current staging of cutaneous squamous cell carcinoma takes into account a variety of different features. Our patient’s tumor was not associated with invasion of the maxilla, mandible, orbit, or temporal bone. This alone would have qualified the tumor as a T1 lesion, but its size of 3 cm indicated a higher risk and qualified it as a T2 lesion.

The histologic features of our patient’s lesion also indicate higher risk according to the current staging system.⁵ The Breslow thickness on histologic examination (measured from the granular cell layer of the epidermis to the deepest portion of the tumor) was 4 mm and the Clark’s level was IV (extension to the reticular dermis). The high-risk features and the location on the lip warrant a classification as T2 and carry a worse prognosis.

Wedge excision of the lower lip and Mohs surgery are accepted treatment options. The patient chose Mohs surgery and has done well, with excellent cosmetic and functional outcome. Radiation therapy can be useful as an adjuvant when lymph nodes are involved,¹¹ but this was not necessary in our patient. Careful long-term follow up is warranted, as these patients are at higher risk of developing other, separate tumors.

A 76-year-old man presented with a rapidly growing, indurated, crusted nodule on his lower lip (Figure 1). This combination—a rapidly growing nodule on a sun-exposed surface in an older patient—pointed to a diagnosis of squamous cell carcinoma, and biopsy study of the affected area confirmed this diagnosis (Figure 2). Clinical examination, computed tomography, and ultrasonography of the neck revealed no lymph node involvement; the tumor was staged as T2N0M0. Mohs microscopically controlled surgery was performed to remove the tumor with clear margins, and the patient has done well.

DIFFERENTIAL DIAGNOSIS

Malignant melanoma, Merkel cell carcinoma, and deep fungal infection can also cause a rapidly growing crusted nodule on the lower lip, but this typically is not an initial presentation for these conditions.

Malignant melanoma

Malignant melanoma should be considered for any rapidly growing cutaneous tumor, especially on sun-damaged skin. Most melanoma lesions have variations in pigment and may contain shades of blue, brown, red, pink, and white. Amelanotic melanomas may mimic squamous cell carcinomas, but the histologic features of atypical keratinocytes in this patient ruled out that diagnosis. Biopsy of amelanotic melanoma reveals nests of melanocytes, usually associated with an in situ component in the overlying epithelium.

Merkel cell carcinoma

Merkel cell carcinoma can mimic squamous cell carcinoma or can even arise in association with squamous cell carcinoma. Histologic examination allows for differentiation. In difficult cases, cytokeratin staining with cytokeratin 20 and CAM 5.2 can clarify the diagnosis, because Merkel cell carcinomas exhibit a characteristic paranuclear dot-like pattern not evident in squamous cell carcinoma.

Deep fungal infection

Colonization by Candida organisms was noted within the overlying crust in this patient’s lesion, but fungal organisms were not noted in the epidermis or dermis. Pseudoepitheliomatous hyperplasia can be prominent in deep fungal infection, but the marked cytologic atypia in this case excluded deep fungal infection.

Mucosal neuroma

Mucosal neuromas are typically smooth-surfaced, soft lesions on the lip. They may be associated with multiple endocrine neoplasia syndromes. Biopsy study reveals that they are composed of delicate spindle cells that lack atypia.

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma is one of the most common types of nonmelanoma skin cancer and is associated with increased sun exposure and light skin pigmentation.¹ Unlike basal cell carcinoma, squamous cell carcinoma has a considerable potential to metastasize.^2–4 The current cancer staging manual of the American Joint Commission on Cancer refects recent evidence-based information on staging and prognosis.^5–7 Squamous cell carcinoma of the lip carries an increased risk of metastasis,⁸ and an increase in the number or the size of involved lymph nodes carries a worse prognosis.⁹ The lower lip is most commonly involved because of increased sun exposure. The most common route for the spread of squamous cell carcinoma of the head and neck is via lymphatics, so careful evaluation of the head and neck is indicated.¹⁰

STAGING OUR PATIENT’S LESION

Current staging of cutaneous squamous cell carcinoma takes into account a variety of different features. Our patient’s tumor was not associated with invasion of the maxilla, mandible, orbit, or temporal bone. This alone would have qualified the tumor as a T1 lesion, but its size of 3 cm indicated a higher risk and qualified it as a T2 lesion.

The histologic features of our patient’s lesion also indicate higher risk according to the current staging system.⁵ The Breslow thickness on histologic examination (measured from the granular cell layer of the epidermis to the deepest portion of the tumor) was 4 mm and the Clark’s level was IV (extension to the reticular dermis). The high-risk features and the location on the lip warrant a classification as T2 and carry a worse prognosis.

Wedge excision of the lower lip and Mohs surgery are accepted treatment options. The patient chose Mohs surgery and has done well, with excellent cosmetic and functional outcome. Radiation therapy can be useful as an adjuvant when lymph nodes are involved,¹¹ but this was not necessary in our patient. Careful long-term follow up is warranted, as these patients are at higher risk of developing other, separate tumors.

A 76-year-old man presented with a rapidly growing, indurated, crusted nodule on his lower lip (Figure 1). This combination—a rapidly growing nodule on a sun-exposed surface in an older patient—pointed to a diagnosis of squamous cell carcinoma, and biopsy study of the affected area confirmed this diagnosis (Figure 2). Clinical examination, computed tomography, and ultrasonography of the neck revealed no lymph node involvement; the tumor was staged as T2N0M0. Mohs microscopically controlled surgery was performed to remove the tumor with clear margins, and the patient has done well.

DIFFERENTIAL DIAGNOSIS

Malignant melanoma, Merkel cell carcinoma, and deep fungal infection can also cause a rapidly growing crusted nodule on the lower lip, but this typically is not an initial presentation for these conditions.

Malignant melanoma

Malignant melanoma should be considered for any rapidly growing cutaneous tumor, especially on sun-damaged skin. Most melanoma lesions have variations in pigment and may contain shades of blue, brown, red, pink, and white. Amelanotic melanomas may mimic squamous cell carcinomas, but the histologic features of atypical keratinocytes in this patient ruled out that diagnosis. Biopsy of amelanotic melanoma reveals nests of melanocytes, usually associated with an in situ component in the overlying epithelium.

Merkel cell carcinoma

Merkel cell carcinoma can mimic squamous cell carcinoma or can even arise in association with squamous cell carcinoma. Histologic examination allows for differentiation. In difficult cases, cytokeratin staining with cytokeratin 20 and CAM 5.2 can clarify the diagnosis, because Merkel cell carcinomas exhibit a characteristic paranuclear dot-like pattern not evident in squamous cell carcinoma.

Deep fungal infection

Colonization by Candida organisms was noted within the overlying crust in this patient’s lesion, but fungal organisms were not noted in the epidermis or dermis. Pseudoepitheliomatous hyperplasia can be prominent in deep fungal infection, but the marked cytologic atypia in this case excluded deep fungal infection.

Mucosal neuroma

Mucosal neuromas are typically smooth-surfaced, soft lesions on the lip. They may be associated with multiple endocrine neoplasia syndromes. Biopsy study reveals that they are composed of delicate spindle cells that lack atypia.

SQUAMOUS CELL CARCINOMA

Squamous cell carcinoma is one of the most common types of nonmelanoma skin cancer and is associated with increased sun exposure and light skin pigmentation.¹ Unlike basal cell carcinoma, squamous cell carcinoma has a considerable potential to metastasize.^2–4 The current cancer staging manual of the American Joint Commission on Cancer refects recent evidence-based information on staging and prognosis.^5–7 Squamous cell carcinoma of the lip carries an increased risk of metastasis,⁸ and an increase in the number or the size of involved lymph nodes carries a worse prognosis.⁹ The lower lip is most commonly involved because of increased sun exposure. The most common route for the spread of squamous cell carcinoma of the head and neck is via lymphatics, so careful evaluation of the head and neck is indicated.¹⁰

STAGING OUR PATIENT’S LESION

Current staging of cutaneous squamous cell carcinoma takes into account a variety of different features. Our patient’s tumor was not associated with invasion of the maxilla, mandible, orbit, or temporal bone. This alone would have qualified the tumor as a T1 lesion, but its size of 3 cm indicated a higher risk and qualified it as a T2 lesion.

The histologic features of our patient’s lesion also indicate higher risk according to the current staging system.⁵ The Breslow thickness on histologic examination (measured from the granular cell layer of the epidermis to the deepest portion of the tumor) was 4 mm and the Clark’s level was IV (extension to the reticular dermis). The high-risk features and the location on the lip warrant a classification as T2 and carry a worse prognosis.

Wedge excision of the lower lip and Mohs surgery are accepted treatment options. The patient chose Mohs surgery and has done well, with excellent cosmetic and functional outcome. Radiation therapy can be useful as an adjuvant when lymph nodes are involved,¹¹ but this was not necessary in our patient. Careful long-term follow up is warranted, as these patients are at higher risk of developing other, separate tumors.