18 Dermatopathology

Of all organ systems, the skin has the greatest number of lesions described, perhaps because the skin is subject to a wide variety of environmental exposures and no special procedures are necessary to visualize its surface.

RELEVANT CLINICAL HISTORY (IN ADDITION TO AGE AND GENDER)

TABLE 18–1 RELEVANT CLINICAL HISTORY

HISTORY RELEVANT TO ALL SPECIMENS	HISTORY RELEVANT FOR DERMATOPATHOLOGY SPECIMENS
Organ/tissue resected or biopsied	Site, duration, and appearance of the lesion (especially for incisional biopsies)
Purpose of the procedure
Gross appearance of the organ/tissue/lesion sampled	Systemic diseases that affect the skin
Any unusual features of the clinical presentation	Clinical differential diagnosis
Any unusual features of the gross appearance	Family history (see Table 7-50)
Prior surgery/biopsies – results	Previous similar lesions
Prior malignancy
Prior treatment (radiation therapy, chemotherapy, drug use that can change the histologic appearance of tissues)
Compromised immune system

GENERAL CONSIDERATIONS

The ability to clearly visualize the entire epidermis in a perpendicular section is important for diagnosis, and at times for prognosis (e.g., malignant melanoma). Therefore, try to maintain vertical orientation at all times in sections. Any specimen that is labeled “excision,” regardless of the type of specimen, must have the margins evaluated by inking and submission of appropriate sections. Diagrams are used for any difficult or complicated specimens.

Never cut through small vesicular lesions in any type of specimen. The overlying tissue layer is important for diagnosis, but is fragile and easily detached and lost. Cut the specimen so as to leave the vesicle intact or submit small specimens whole and request that the histotechnologists bisect the specimen after processing.

SKIN - SPECIAL STUDIES

Occasionally fresh or frozen specimens (usually punch biopsies) will be submitted for special studies for the evaluation of specific disease:

• Immunofluorescence: lupus erythematosus, bullous pemphigoid, or pemphigus

• Immunofluorescence on frozen tissue: leukemias and lymphomas

• Electron microscopy: epidermolysis bullosa, other blistering diseases, some melanomas (e.g., S100 negative tumors), unusual tumors, amyloid

SKIN PUNCH BIOPSIES

Punch biopsies are performed to completely excise small lesions, to sample large lesions, or to evaluate an inflammatory process or a systemic disease (e.g., pustular psoriasis). Punches can be 2, 3, 4, 5, 6, 8, or 10 mm in diameter.

PROCESSING THE SPECIMEN

1. Describe the type of specimen (“punch biopsy”) including diameter and depth and skin color. Describe any lesions including size, type (macular, papular, vesicular, plaque), borders (well-circumscribed, irregular), color (brown, black, variegated), shape (verrucous, lobulated), and distance from the closest margin.

Ink all punch biopsies.

2. Punch biopsies 3 mm or less are submitted uncut in their entirety (Fig. 18-1). These specimens can be bisected by the histology laboratory.

Figure 18–1 Punch biopsy of the skin.

Punch biopsies greater than 4 mm are bisected or trisected, depending on size. If there is a discrete lesion, cut in a plane to demonstrate the closest margin. If the lesion is very small (i.e., leveling the block might remove the lesional tissue), cut the punch biopsy on either side of the lesion. Do not section through vesicles or blisters – submit whole and request sectioning by the laboratory.

3. Request three levels.

SAMPLE DICTATION

Received in formalin labeled with the patient’s name and unit number and “5 mm punch, left leg” is a 5 mm in diameter by 5 mm (depth) punch biopsy with tan/white skin. There is a flat homogeneously brown lesion with slightly irregular margins, 0.3 × 0.3 cm, on the skin surface. The lesion is less than 0.1 cm from the nearest margin, but does not grossly involve the margin.

Cassette: bisected, 2 frags, ESS.

SKIN SHAVE BIOPSIES

Shave biopsies are usually performed to remove nonmalignant lesions (e.g., seborrheic keratoses, actinic keratoses, or fibroepithelial polyps) or for diagnosis of basal cell carcinomas. Shave biopsies of pigmented lesions should be strongly discouraged and interpreted with caution. The diagnosis of melanoma may be difficult in such a specimen due to limited sampling and the depth of invasion may be impossible to assess. Specimens are inked if designated “excisions.”

PROCESSING THE SPECIMEN

1. Describe the specimen type (“shave biopsy”), the dimensions (including depth) and the surface appearance. The specimen is usually oval and relatively flat. The edges may curl due to retraction of the dermis. Ink the base to aid in orientation during embedding.

Specimens greater than 3 to 4 mm in diameter may be bi- or trisected. Try to maintain the vertical orientation in sections by making one or more cuts perpendicular to the surface at 2 to 3 mm intervals.

2. Submit in entirety and order three levels. Indicate that the fragments should be embedded on edge.

SKIN CURETTINGS

Skin scrapings (curettings) of seborrheic or actinic keratosis or basal cell carcinoma may be performed.

PROCESSING THE SPECIMEN

1. Describe the specimen, including number of fragments (or estimate), color, and size in aggregate.

2. Submit entirely using a nylon specimen bag or lens paper to wrap the fragments. Check the sides of the container and lid for small pieces. Orientation is usually not possible. Margins cannot be evaluated due to the specimen fragmentation.

3. Order three levels.

SKIN ELLIPSES

These specimens are excisions of malignant tumors (squamous cell carcinoma or basal cell carcinoma), typical or atypical melanocytic nevi (and to rule out melanoma), or large benign lesions (e.g., epithelial inclusion cysts). Occasionally, ellipses are submitted for the evaluation of panniculitis or large vessel vasculitis.

PROCESSING THE SPECIMEN

1. Record the dimensions (length, width, and depth) and describe the skin color.

Describe any lesions including color, borders, ulceration, shape, and distance from margins. Describe any scars from prior biopsies (length, recent or well-healed).

2. If an orienting suture is present, use the clinical designation or (lacking this) designate it 12 o’clock. Use two different colors of ink to mark the two longitudinal halves of the specimen and dictate the location of the inks (e.g., “the 12 o’clock margin is inked green and the 6 o’clock margin is inked blue”). Green and blue inks are reccommended as these colors are easier for the histotechnologists to see during embedding and sectioning the tissue (Fig. 18-2).

Figure 18–2 Skin ellipses.

Serially section the entire specimen along the short axis at 2 to 3 mm intervals.

Submit the most distal sections (“tips”) as two of the margins in two cassettes. If the ellipse is small and unoriented, both tips can be placed in one cassette. Each tip is taken as a 0.1 to 0.2 cm en face margin.

Submit the remainder of the specimen in one or more cassettes.

A simple diagram showing orientation and sections is very helpful in interpreting the sections histologically. This is especially true for large or irregularly shaped skin excisions.

For pigmented lesions, the initial cut is made through the thickest or darkest portion of the lesion (most likely area to have deep invasion). Describe the gross depth of invasion or involvement of subcutaneous tissues.

3. Very large ellipses (several centimeters) are usually re-excisions. The central scar is serially sectioned and representative sections taken including the deep margin. Representative sections are taken of the 3, 6, 9, and 12 o’clock margins.

4. The following levels are ordered:

• Non-pigmented lesions and re-excisions: One level on all blocks

• Pigmented lesions:

• Three levels on the block with the lesion

• One level on other blocks (e.g., tips without lesion)

GROSS DIFFERENTIAL DIAGNOSIS

Seborrheic Keratosis

This is a rounded, raised, lesion sharply demarcated from any surrounding skin with a “stuck on” appearance. The color is usually dark brown, black, or gray and has a dirty appearance due to the presence of horn cysts containing keratinous debris.

Epidermal Inclusion Cyst

These cysts are often received in multiple fragments. The wall of the cyst is thin (1 to 2 mm) and has a smooth inner lining. The cyst is filled with white or yellow friable, often malodorous, material corresponding to keratinaceous debris. Some are due to traumatic or iatrogenic introduction of keratinizing epithelium into deep soft tissues. If located near the nipple, the lesion may be in a lactiferous sinus (squamous metaplasia of lactiferous ducts or recurrent subareolar abscess).

Fibroepithelial Polyp (Acrochordon)

A flesh colored papule often designated “skin tag” by the clinician.

Basal Cell Carcinoma

Translucent papule or plaque with a yellow or pearly hue. Central ulceration with a rolled border is common in larger lesions. The outer margin tends to be sharply demarcated from the surrounding skin.

Squamous Cell Carcinoma

A raised irregular flesh colored lesion that is often centrally ulcerated.

Nevus

A pigmented or flesh-colored flat or raised lesion. Dysplastic nevi have some of the characteristics of melanoma such as an irregular shape and some variation in pigmentation.

Malignant Melanoma

The most common appearance is as a pigmented lesion with irregular or notched borders. The pigmentation is often variable and may be very dark. Nodules or ulcers within the lesion are usually indicative of invasion.

MICROSCOPIC SECTIONS

• Small ellipses (<2 cm): The lesion is entirely submitted in the first cassette(s). Submit tips in one cassette (if unoriented) or in two cassettes (if oriented).

• Larger ellipses (>2 cm): Representative sections of the lesion and margins submitted. Re-excisions must have the margins carefully evaluated.

SAMPLE DICTATION

Received in formalin labeled with the patient’s name, unit number, and “right shoulder” is a 2.5 × 1 × 0.8 cm (depth) skin ellipse with tan/brown skin and an orienting suture at one tip (designated by the surgeon as 12 o’clock). There is a variegated brown and black lesion (1 × 0.8 cm) with markedly irregular borders with notching located in the center of the ellipse. Within the lesion there is a raised black nodule (0.3 × 0.3 cm) that grossly appears to extend through the epidermis into the dermis and is 0.2 cm from the deep resection margin. The closest margin is the 3 o’clock margin, which is 0.1 cm from the lesion. The 3 o’clock margin is inked black and the 9 o’clock margin is inked blue.

Cassette #1: 12 o’clock margin, 1 frag, ESS.

Cassette #2: 6 o’clock margin, 1 frag, ESS.

Cassette #3: Cross sections from 3 to 9 o’clock, 4 frags, ESS.

PATHOLOGIC PROGNOSTIC/DIAGNOSTIC FEATURES SIGN-OUT CHECKLIST FOR SKIN CARCINOMAS

• Procedure: Punch biopsy, shave biopsy, curettings, excisional biopsy (ellipse)

• Tumor Site: Specify, if known

• Tumor Size: Greatest dimension (additional dimensions optional)

• Histologic Type: Squamous cell (subtypes: acantholytic, adenosquamous, basaloid, spindle cell (sarcomatoid), pseudovascular, undifferentiated (lymphoepithelioma), verrucous), basal cell, adenocarcinomas of sweat and sebaceous glands

• Histologic Grade: Well, moderate, poor, or undifferentiated (Table 18-2)

• Maximum Tumor Thickness: Thickness in millimeters

• Anatomic Level: Clark level (I to V)

• Margins: Radial (“peripheral” or non-deep): uninvolved (optional: distance form closest margin), involved (specify location if possible). Specify if carcinoma in situ or invasive carcinoma at margin.

• Deep: Uninvolved (optional: distance form closest margin), involved (specify location if possible)

• Lymph-Vascular Invasion: Not identified, present

• Perineural Invasion: Not identified, present

• Lymph Nodes: Number of nodes, number of nodes with metastases

• Optional: Size of largest metastatic deposit

• Extranodal Extension: Not identified, present

• Tumor Features: Inflammatory response, association with actinic keratosis, association with human papilloma virus (HPV), association with Bowen disease

• Adjacent Epithelium: Dysplasia, grade (mild, moderate, severe/CIS), extent (focal, multifocal, extensive), proximity to invasive carcinoma (adjacent or distant)

• Distant Metastasis: Present. If distant metastasis is not present on pathologic examination, the M category is a clinical classification.

• AJCC Classification: T, N, and M classifications should be provided, when possible (Table 18-3). M0 is conferred after clinical assessment; there is no pM0 category.

Table 18–2 HISTOLOGIC GRADE – SQUAMOUS CELL CARCINOMA

Grade 1	Well differentiated tumors are characterized by squamous epithelium that frequently shows easily recognizable and often abundant keratinization. Intercellular bridges are readily apparent. There is minimal pleomorphism, and mitotic figures are mainly basally located.
Grade 2	Moderately differentiated tumors show more structural disorganization in which squamous epithelial derivation is less obvious. Nuclear and cytoplasmic pleomorphism are more pronounced, and mitotic figures may be numerous. Keratin formation is typically limited to keratin pearls, horn cysts, and scattered individually keratinized cells.
Grade 3	In poorly differentiated tumors it may be difficult to establish squamous differentiation, usually by identification of rare intercellular bridges or small foci of keratinization.
Grade 4	Used to denote anaplastic or undifferentiated tumors.

From Protocol for the Examination of Specimens from Patients with Squamous Cell Carcinoma of the Skin (www.cap.org).

Table 18–3 AJCC (7^TH EDITION) CLASSIFICATION OF CUTANEOUS SQUAMOUS CELL CARCINOMA AND OTHER CUTANEOUS CARCINOMAS

TUMOR
TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	Tumor 2 cm or less in greatest dimension with less than two high-risk features∗
T2	Tumor greater than 2 cm in greatest dimension or Tumor any size with two or more high-risk features^∗
T3	Tumor with invasion of maxilla, mandible, orbit, or temporal bone
T4	Tumor with invasion of skeleton (axial or appendicular) or perneural invasion of skull base
^∗HIGH-RISK FEATURES FOR THE PRIMARY TUMOR (T) STAGING
	Depth/invasion	> 2 mm thickness Clark level ≥ IV Perineural invasion
	Anatomic location	Primary site ear Primary site non-hair-bearing lip
	Differentiation	Poorly differentiated or undifferentiated
REGIONAL LYMPH NODES
NX	Regional lymph nodes cannot be assessed.
N0	No regional lymph node metastasis
N1	Metastasis in a single ipsilateral lymph node, 3 cm or less in greater dimension.
N2	Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension.
N2a	Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension.
N2b	Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension.
N2c	Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension.
N3	Metastasis in a lymph node, more than 6 cm in greatest dimension
DISTANT METASTASIS
M0	No distant metastasis
M1	Distant metastasis

Note: Used for squamous cell and basal cell carcinomas of the skin and adenocarcinomas developing from sweat or sebaceous glands. The classification is not used for carcinomas of the eyelid, melanomas, or Merkel cell carcinomas.

From the AJCC Cancer Staging Manual, Seventh Edition. New York, Springer-Verlag, 2009. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.

This checklist incorporates information from the CAP Cancer Committee protocols for reporting on cancer specimens (see www.cap.org/) and the ADASP (see www.adasp.org). The underlined elements are considered to be scientifically validated or regularly used data elements that must be present in reports of cancer-directed surgical resection specimens from ACS CoC-approved cancer programs. The specific details of reporting the elements may vary among institutions.

PATHOLOGIC PROGNOSTIC/DIAGNOSTIC FEATURES SIGN-OUT CHECKLIST FOR MELANOMA OF THE SKIN

• Procedure: Punch biopsy, shave biopsy, excisional biopsy, re-excision, lymphadenectomy (sentinel or regional nodes)

• Specimen Laterality: Right, left, midline

• Tumor Site: Specify (if known)

• Tumor Size: Greatest dimension (optional: additional dimensions), if gross tumor is present

• Macroscopic Satellite Nodules: Not identified, present (specify)

• Distance from primary tumor

• Macroscopic Pigmentation: Not identified, present, diffuse, present, patchy/focal, indeterminate

• Histologic Type: Lentigo maligna, superficial spreading, nodular, acral lentiginous, desmoplastic, others

• Maximal Tumor Thickness: Measure in millimeters

Prognosis is primarily related to the depth of invasion measured vertically in millimeters from the granular cell layer of the epidermis (or the base of the ulcer, if ulcerated) to the deepest point of tumor penetration, excluding tumor surrounding skin appendages (see Breslow A, Thickness, cross-sectional areas, and depth of invasion in the prognosis of cutaneous melanoma, Ann Surg 172:902-908, 1970, Table 18-4). If satellite lesions are used in this measurement, this should be recorded. An ocular micrometer should be used for measurements.

• Anatomic Level: Clark level (I to V; Table 18-5)

• Ulceration: Not identified, present

• Post traumatic ulceration (e.g., due to prior surgery) should be distinguished from ulceration due to invasion by tumor when possible. The width of the ulcerated area should be reported.

• Ulceration includes the following features:

• Full-thickness epidermal defect (including absence of stratum corneum and basement membrane)

• Reactive changes (fibrin deposition, neutrophils)

• Surrounding epidermis is thinned or may show reactive hyperplasia

• Margins: Peripheral and deep: Involved or free, positive = ink on tumor. The distance to the closest margins should be given. Specify whether melanoma in situ or invasive melanoma.

• Mitotic Index: Mitoses per mm² < 1 mitotic figure per mm² or ≥ 1 mitotic figure per mm² is used for AJCC classification.

• Assessed in the vertical growth phase (not the intraepidermal component). The area with the greatest number of mitoses should be counted first, and then the surrounding area, until a 1 mm² area has been counted. The size of a microscopic field depends on the microscope (see “Measuring with the Microscope”).

• Microsatellitosis: Not identified, present. Defined as tumor cell nests greater than 0.05 mm in size in the reticular dermis, panniculus, or vessels beneath the principal invasive tumor but separated from it by at least 0.3 mm of normal tissue.

• Lymph-Vascular Invasion: Not identified, present

• Perineural Invasion: Not identified, present

• Tumor Infiltrating Lymphocytes (TILs): Not identified, non-brisk, brisk

• TILs absent: no lymphocytes present, or present but do not infiltrate tumor

• TILs non-brisk: lymphocytes infiltrate melanoma only focally or not along the entire base of the vertical growth phase

• TILs brisk: lymphocytes diffusely infiltrate the entire base of the vertical growth phase or the entire invasive component of the melanoma.

• Tumor Regression: Not identified, present involving < 75%, present involving 75% or more of lesion

• Partial or complete obliteration of melanoma by host response (fibrosis, telangiectasia, lymphocytes, and melanophagocytosis)

• Growth Phase: Radial growth phase: Present or not identified, type (lentigo maligna, acral-lentiginous, superficial spreading). The tumor is generally of uniform cytologic appearance and is wider than it is deep.

• Vertical growth phase: Present or not identified, type (epithelioid, spindle, or mixed). Expansile nests of tumor cells are present in the papillary and/or reticular dermis.

• Lymph Nodes: Number of nodes examined, number of sentinel nodes, number of nodes with metastases

• Extranodal invasion not identified or present

Location of metastatic tumor in sentinel node: subcapsular, intramedullary, or subcapsular and intramedullary.

Sentinel nodes may be examined by mutliple H&E levels and immunoperoxidase studies; a standard protocol for all institutions has not been established. Typically, three H&E levels and one to three immunohistochemical studies on intervening levels are examined. S100 is sensitive but other markers are more specific (Table 18-6). The significance of small metastases (< 0.2 cm) is unknown but is currently being investigated.

• Distant Metastasis: Present. If distant metastasis is not present on pathologic examination, the M category is a clinical classification.

• AJCC Classification: T, N, and M classifications should be provided, when possible (Tables 18-7 and 18-8). M0 is conferred after clinical assessment; there is no pM0 category.

TABLE 18–4 BRESLOW DEPTH OF INVASION

Nonulcerated lesions	Measure from the top of the granular layer to the deepest point of invasion
Ulcerated lesions	Measure from the ulcer base overlying the deepest point of invasion
Difficult cases	Melanocytes in junctional nests (i.e., not invasive into stroma) are not included in the measurement. This includes junctional involvement of skin appendages. Microscopic satellite lesions in reticular dermis are sometimes used in measurements. It is usually preferable to measure a contiguous area of invasion from the surface. If satellite lesions are used, this can be described in the report. If there is marked epidermal hyperplasia (resulting in a thickened granular layer), then the measurement may overestimate the thickness of the melanoma. This situation can be described in the report. Lesions with tangential sectioning or curetted lesions cannot have the depth measured accurately.

Measurements should be performed with an ocular reticule.

Adapted from Breslow A: Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg 172:902-908, 1970.

TABLE 18–5 CLARK LEVEL

Level I	Melanoma confined to the epidermis and epidermal appendages
Level II	Extension into the papillary dermis by single cells, and sometimes small clusters of cells, with, at most, only a few cells extending to the interface between the papillary and reticular dermis
Level III	Extension of tumor cells throughout the papillary dermis, filling it and impinging upon the reticular dermis but not invading it
Level IV	Invasion of the reticular dermis
Level V	Invasion of the subcutaneous fat

Adapted from Clark WH Jr, From L, Bernardino EH, et al: Histogenesis and biologic behavior of primary human malignant melanoma of the skin. Cancer Res 29:705-727, 1969.

TABLE 18–6 IMMUNOHISTOCHEMICAL MELANOMA MARKERS

TYPE OF CELL IN THE LYMPH NODE	S100	MART-1
Metastatic melanoma	POS	High∗
Nevus cells	POS	POS
Dendritic cells	POS	neg
Nerves, ganglion cells	POS	neg

∗ About 20% of metastatic melanomas are negative for HMB45 and MART-1.

Table 18–7 AJCC (7^TH EDITION) CLASSIFICATION OF MELANOMA OF THE SKIN

TUMOR
TX	Primary tumor cannot be assessed. (e.g., curettaged or severely regressed melanoma)
T0	No evidence of primary tumor
Tis	Melanoma in situ
T1	Melanomas 1.0 mm or less in thickness with or without ulceration
T1a	≤ 1.0 mm in thickness, without ulceration, and mitosis < 1/mm²
T1b	≤ 1.0 mm in thickness, with ulceration, or mitoses ≥ 1/mm²
T2	Melanomas 1.01 to 2.0 mm in thickness with or without ulceration
T2a	1.01 to 2.0 mm in thickness without ulceration
T2b	1.01 to 2.0 mm in thickness with ulceration
T3	Melanomas 2.01 to 4.0 mm in thickness with or without ulceration
T3a	2.01 to 4.0 mm in thickness without ulceration
T3b	2.01 to 4.0 mm in thickness with ulceration
T4	Melanomas more than 4.0 mm in thickness with or without ulceration
T4a	> 4.0 mm in thickness without ulceration
T4b	> 4.0 mm in thickness with ulceration
REGIONAL LYMPH NODES
NX	Patients in whom regional lymph nodes cannot be assessed (e.g., previously removed for another reason)
N0	No regional metastasis detected
N1	Metastasis in one lymph node
N1a	Clinically occult (microscopic) metastasis
N1b	Clinically apparent (macroscopic) metastasis
N2	Metastasis in two to three regional nodes or intralymphatic regional metastasis without nodal metastases
N2a	Clinically occult (microscopic) metastasis
N2b	Clinically apparent (macroscopic) metastasis
N2c	Satellite or in-transit metastasis without nodal metastasis
N3	Metastasis in four or more nodes, or matted nodes, or in transit metastasis/satellites with metastatic nodes.
Micrometastases are diagnosed after sentinel node biopsy and completion lymphadenectomy (if performed). A micrometastasis is a pathologically documented metastasis (of any size) in a node detected by clinical or radiologic examination. Metastases detected only by immunohistochemical studies (i.e., not present on H&E slides) should be confirmed by at least one melanoma-associated marker (e.g., HMB-45, Melan-A/MART-1) in addition to less specific markers such as S100 or tyrosinase. Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits extracapsular extension.
Definitions: Satellite metastases: Defined arbitrarily as grossly visible cutaneous and/or subcutaneous metastases occurring within 2 cm of the primary melanoma. Microsatellite metastases: Microscopic and discontinuous cutaneous and/or subcutaneous metastases found on pathologic examination adjacent to a primary melanoma. In transit metastases: Defined arbitrarily as clinically evident cutaneous and/or subcutaneous metastases identified at a distance greater than 2 cm from the primary melanoma in the region between the primary and the first echelon of regional lymph nodes.
DISTANT METASTASIS
M0	No detectable evidence of distant metastasis
M1	Distant metastasis
M1a	Metastasis to skin, subcutaneous tissue, or distant lymph nodes, LDH is normal
M1b	Lung metastases, LDH is normal
M1c	All other visceral metastases, LDH is normal or Any distant metastasis, LDH is elevated

Note: This classification is not used for melanomas of sites other than skin (e.g., ocular, mucosal, urethral, etc.).

From the AJCC Cancer Staging Manual, Seventh Edition. New York, Springer-Verlag, 2009. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.

Table 18–8 AJCC (7^TH EDITION) CLASSIFICATION – MERKEL CELL CARCINOMA

TUMOR
TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor (e.g., nodal/metastatic presentation without associated primary)
Tis	In situ primary tumor
T1	Less than or equal to 2 cm maximum tumor dimension
T2	Greater than 2 cm but not more than 5 cm maximum tumor dimension
T3	Over 5 cm maximum tumor dimension
T4	Primary tumor invades bone, muscle, fascia, or cartilage
REGIONAL LYMPH NODES
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
cN0	Nodes negative by clinical exam∗ (no pathologic node exam performed)
pN0	Nodes negative by pathologic exam
N1	Metastasis in regional lymph node(s)
N1a	Micrometastasis
N1b	Macrometastasis
N2	In transit metastasis
^∗ Clinical detection of nodal disease may be via inspection, palpation, and/or imaging. Micrometastases are diagnosed after sentinel or elective lymphadenectomy. A micrometastasis is a pathologically documented metastasis (of any size) in a node not detected by clinical or radiologic examination. Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or needle biopsy. In transit metastasis: a tumor distinct from the primary lesion and located either (1) between the primary lesion and the draining regional lymph nodes or (2) distal to the primary lesion.
DISTANT METASTASIS
M0	No distant metastasis
M1	Metastasis beyond regional lymph nodes
M1a	Metastasis to skin, subcutaneous tissues, or distant lymph nodes
M1b	Metastasis to lung
M1c	Metastasis to all other visceral sites

This system does not include Merkel Cell carcinoma of the eyelid.

From the AJCC Cancer Staging Manual, Seventh Edition. New York, Springer-Verlag, 2009. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.

This checklist incorporates information from the CAP Cancer Committee protocols for reporting on cancer specimens (see www.cap.org/) and the ADASP (see www.adasp.org). The underlined elements are considered to be scientifically validated or regularly used data elements that must be present in reports of cancer directed surgical resection specimens from ACS CoC-approved cancer programs. The specific details of reporting the elements may vary among institutions.

LARGE SKIN EXCISIONS

Large resections are usually carried out after the lesion has been biopsied and a diagnosis made.

PROCESSING THE SPECIMEN

1. Record the dimensions (length, width, depth), skin color, lesions, scars (presence of a prior biopsy scar), and deep margin (soft tissue, fascia, muscle). Describe the closest approach of the lesion to a margin.

2. Ink all margins, excluding skin surfaces. All sections taken must be thin to allow for adequate fixation of the fatty subcutaneous tissue.

3. There is usually an orienting suture with a designated “o’clock.” If there are no orienting sutures, try to pick an identifiable area to designate 12 o’clock. Document in the gross description that the specimen is unoriented and the o’clock designations are arbitrarily assigned. Take four perpendicular sections of the margin at 12 o’clock, 3 o’clock, 6 o’clock, and 9 o’clock but including the closest approach of tumor to the margin(s). This is adequate unless the lesion is grossly at or near the margin. More sections are taken in these areas.

Even the smallest ellipses must be cross-sectioned perpendicular to the scar (i.e., do not bisect longitudinally) in order to evaluate the closest (lateral) margins.

4. Block out the lesion or the biopsy scar and submit the entire lesion or biopsy site. If these sections do not include the deep margin, separate sections of the deep margin should be submitted.

5. Carefully section through soft tissue looking for lymph nodes. Submit all lymph nodes found.

6. Draw a diagram of the specimen that includes the location of all sections taken and a key to the corresponding cassettes in which they are submitted. This is particularly important for irregularly shaped specimens.

LIP EXCISIONS

Squamous cell carcinoma is the most common neoplasm of the lip. The specimens are more complicated because there is often both a mucosal and skin surface (Fig. 18-3). There are three margins: the side margins (lateral and medial) margins and a deep margin.

Figure 18–3 Lip resection.

PROCESSING THE SPECIMEN

1. Describe the specimen including overall dimensions and dimensions of mucosal and skin surfaces.

2. Describe any lesions including size, color, quality (exophytic, verrucous, polypoid, ulcerated), and location (with respect to skin, mucosa, and vermilion border, and distance from margins).

3. Ink the lateral, medial, and deep surgical margins.

4. Serially section the specimen. Note the depth of invasion of the tumor. Submit sections demonstrating the tumor and its deepest extent, relationship to skin and mucosa, and relationship to all margins.

5. Draw a diagram showing the location of the lesion and a key to the location of tissue sections and the corresponding cassettes.

FORESKIN

The foreskins of newborn infants are generally not submitted for histologic examination unless there are gross abnormalities. Circumcisions of older males are performed in two age groups:

• Young adults (18 to 25 years old): Usually performed for phimosis due to a subtle anatomic defect (e.g., minimal hypospadias). The only histologic finding is slight nonspecific chronic balanitis.

• Older men (>50): A specific inflammatory or neoplastic lesion is usually found. Common lesions are condylomas, balanitis xerotica obliterans (lichen sclerosus), balanitis circumscripta plasmacellularis (Zoon’s balanitis), squamous cell carcinoma in situ, and invasive squamous cell carcinomas. If no lesions are detected on the initial sections, and the clinical history is not provided, call the clinician to find out the reason for the circumcision.

PROCESSING THE SPECIMEN

1. Measure length, width, and thickness. The specimen usually consists of a rectangle of tissue including skin and mucosa on the surface with underlying loose areolar tissue. It is usually not possible to orient the specimen as to proximal and distal margins.

2. Examine the surface carefully for any epidermal lesions. If any are present, describe size, appearance (verrucous, papillary, ulcerated), depth of invasion, and distance from the nearest cut edge. Ink margins if a focal lesion is present.

Describe the uninvolved skin including color, texture (rugose, atrophic, thickened).

3. The specimen is sectioned longitudinally including both skin and mucosa. One cassette with representative sections is adequate if there are no gross lesions and the foreskin is removed in the clinical context of phimosis. Additional cassettes are submitted to document all lesions and adjacent margins.

FINGERNAILS aND TOENAILS

Clippings

Toenail clippings may be sent for the evaluation of fungal infection. Inform the histology laboratory that the specimen consists of a nail as these specimens are usually very difficult to section and may require special techniques for softening.^1,² Order a PAS stain (for fungi).

Nail bed biopsies are usually submitted for the evaluation of pigmented lesions. Do not order a PAS stain on these specimens.

Tumor

Subungual melanomas occur in all ethnic groups but are proportionately more common in persons of color. These lesions may present as linear pigmented streaks of the nail, if the melanoma cells involve the nail matrix. Specimens consisting of only the nail (and not the matrix) will not be diagnostic because melanocytes are not present. The appropriate specimen is a punch biopsy of the nail matrix. If a nail is received with a pigmented area, it is submitted for microscopic examination for evaluation of an atypical melanocytic lesion or melanoma.

REFERENCES

1. Lewin K., et al. Softening techniques for nail biopsies. Arch Dermatol. 1973;107:223-224.

2. Shapiro L. Softening hard keratin in specimens for microscopic sections. Am J Clin Pathol. 1970;54:773-774.