—  SPECIALTY CONFERENCE  —

Dermatopathology

Case 8 - Metastatic Papillary Thyroid Carcinoma to the Skin

Lori Erickson
Mayo Clinic College of Medicine
Rochester, MN





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History:
42 year old male with "Lesion on nose, ?BCC"

Microscopic:
The tumor is located in the dermis and composed of lobules of polygonal cells with clear cytoplasm.


Case 8 - Slide 1
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Case 8 - Figure 1
Dermal based nodule comprised of pale staining epithelial aggregates.
Case 8 - Figure 2
Epithelial islands demonstrate cells with abundant cytoplasm and central nuclei with nuclear clearing.

Case 8 - Figure 3
Clear cells with abundant cytoplasm, large irregular nuclei with nuclear grooves.
Case 8 - Figure 4
Clear cells forming follicular structures surrounding areas of eosinophilic material.


Immunophenotype:
Immunoperoxidase studies performed on paraffin embedded tissue show the tumor cells are positive for keratin 7, TTF1, and thyroglobulin. The tumor cells are negative for vimentin, MelanA, and S100.

Diagnosis:
Metastatic papillary thyroid carcinoma to the skin.

Discussion
Approximately 1-5% of visceral carcinomas metastasize to the skin. The number would approach 10% if melanoma, sarcoma, and hematolymphoid tumors were included. [1] Cutaneous metastases from visceral tumors often present in the region of the skin near the primary tumor, but visceral carcinomas may metastasize to a variety of unusual cutaneous sites. The scalp is a particularly common site of cutaneous site of metastases, [2, 3, 4, 5, 6, 7, 8] particularly for thyroid carcinoma [4, 6, 9, 10, 11, 12, 13, 14] and renal cell carcinoma. [8, 15, 16, 17] Scalp metastasis may present as areas of alopecia (alopecia neoplastica). [18, 19, 20, 21, 22, 23, 24] Alopecia neoplastica is seen most often with breast cancer. [18, 23, 24] Metastasis to the skin of the umbilicus are also a relatively common site. [25, 26, 27, 28, 29, 30, 31, 32, 33] This tumor has been referred to as Sister Mary Joseph's nodule. [34] Sister Mary Joseph Dempsey was the superintendent of nursing at Saint Mary's Hospital, Mayo Clinic in Rochester, MN. Sister Mary Joseph noted that a nodule in the umbilicus was often associated with advanced cancer. She shared her observations with W. J. Mayo, for whom she was first surgical assistant, and he published the observation in 1928 as the "pants button umbilicus." [35] In 1949 the Dr. Bailey used the term "Sister Joseph's nodule" in the text Demonstration of Physical Signs in Clinical Surgery. [34] A variety of carcinomas have metastasized to the skin of the umbilicus, but gastric, colon, ovary, and pancreas are most common. [36]

The most carcinomas to metastasize to the skin are the most common primary visceral carcinomas. [33] Breast cancer, colon cancer, and ovarian cancer are most common in women, and lung cancer and colon cancer are most common in men. [33, 37, 38, 39] Although cutaneous involvement by a visceral tumor usually occurs in the setting of disseminated disease, visceral carcinomas may present as cutaneous metastasis in about 0.8% of cases. [40] The most common internal malignancies to present as a cutaneous metastasis are lung, kidney, and ovary. [33] When tumors metastasize to the skin they generally present as cutaneous nodules, however they can present as inflammatory lesions, cicatricial lesions, and bullous lesions. [39] The tumors may be single, but are often multiple discrete nodules. [39] Unusual presentations of cutaneous metastases can resemble granuloma annulare, condyloma, ulcer, and epidermal inclusion, as well as in zosteriform patterns. [41, 42, 43, 44]

Cutaneous metastases of renal cell carcinoma are well known to occur. [8, 15, 16, 17, 33, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56] In one study renal cell carcinoma was the fourth most common carcinoma to metastasize to the skin. [37] In a recent review of cutaneous metastases from genitourinary tumors, renal cell carcinoma metastasizes to the skin more frequently than other urologic tumor including bladder, prostate, and testes. [44] Of the 456 cutaneous metastases from genitourinary carcinomas, renal cell carcinoma accounted for 302 cases (66%), followed by urothelial cell carcinoma of the bladder (17%), prostatic adenocarcinoma (12%), and testicular germ cell tumors (4%). [44] Renal cell carcinoma can also present as a cutaneous metastasis. [16, 40, 50, 51, 53, 55, 57] Cutaneous metastases from renal cell carcinoma often occur on the head and neck, [15, 16, 17, 53] but a variety of unusual sites may be involved such as the scrotum [45] and acral sites, [17]

The differential diagnosis is particularly difficult for cutaneous metastases of renal cell carcinomas as there are a number of both primary and metastatic tumors that show prominent clear cell change that can be mistaken for renal cell carcinoma. Cutaneous metastases of renal cell carcinomas are often highly vascular can mimic pyogenic granulomas, both clinically and histologically. [47] Clear cell hidradenoma can mimic conventional renal cell carcinomas. [58] Features helpful in the identifying clear cell hidradenoma include ductular lumens and apocrine and squamoid change and the lack of a prominent vascular pattern. [58] Clear cell hidradenoma is positive for cytokeratins to simple epithelia such as CK6/18, CK7, and CK8/18, [59] as well as CK5/6. [60] The squamoid and tubule lining cells show the most prominent keratin positivity. [59] The clear cells themselves were positive for CK10/17/18 and negative for S100. [59] Other keratins noted to be positive in a proportion of hidradenomas include AE1/AE3, CK19, 34BE12, and CAM5.2. [61, 62, 63] EMA, CEA, S100, muscle specific actin and vimentin have also been noted to be positive in some cases. [62, 63] Renal cell carcinoma is positive for vimentin and CD10. [58] A recent study showed 2 (6.5%) of 31 eccrine, 1 (6%) of 16 apocrine, and 4 (40%) of 10 sebaceous neoplasms, and 4 of 4 (100%) were positive for CD10. [64] Thus, CD10 was found to be a useful addition to differentiate renal cell carcinoma metastases to the skin from adnexal neoplasms with eccrine and apocrine differentiation, but not with sebaceous differentiation. [64]

Clear cell dermatofibroma has also been considered in the differential diagnosis of metastatic renal cell carcinoma. [65] A review of 1,496 dermatofibromas revealed 12 cases (1%) with areas of clear cell change. [65] However, these additional tumors showed clear cell change only in a minor component of the tumor. [65] The clear cell dermatofibroma described by Zelger et al was "richly vascularized with numerous partially ecstatic capillaries." [65] Prominent vascularity is a feature classically seen in cutaneous metastases of renal cell carcinoma. However, metastases of renal cell carcinoma are reported to show more atypia and mitoses than clear cell dermatofibroma. [65] Clear cell dermatofibroma is also negative for epithelial markers, a feature that helps differentiate it from metastatic renal cell carcinoma.

Clear cell sarcoma (melanoma of soft parts) is uncommon in the dermis as it is a deep tumor often involving tendon sheaths or aponeuroses. Clear cell or balloon cell variants of conventional cutaneous malignant melanoma, however, are more superficially located and involve the dermis. Also, this variant is more common on the extremities as compared to metastatic renal cell carcinoma which is most common on the head and neck. Melanomas with prominent clear cell or balloon cell change often show areas of more conventional melanoma. Melanomas with prominent clear or balloon cell change usually show involvement of the overlying epidermis, whereas cutaneous metastases from renal cell carcinoma lack involvement of the overlying epidermis. Also melanomas are positive for S100, MelanA, and HMB45 and negative for keratin.

Cutaneous metastases from well differentiated thyroid carcinoma are uncommon, but there are a number of case reports and small series in the literature. [4, 9, 10, 11, 12, 13, 14, 66, 67, 68, 69, 70, 71, 72, 73, 74] In a study of 91 patients with papillary thyroid carcinoma with distant metastases only six had cutaneous metastases. [74] Papillary thyroid carcinoma (PTC) is the most common thyroid carcinoma and is usually associated with an excellent prognosis even with regional lymph node metastases. [75, 76] Thus, this tumor may be overlooked as a possible site for cutaneous metastases. Patients whose tumors have metastasized to the skin have an extremely poor prognosis. [9] In a small series and review of the literature of cutaneous metastases of thyroid carcinoma, 11 of 12 patients with cutaneous metastases from PTC or FTC died or were alive with disease. [9] Only one patient was alive with no evidence of disease at follow-up of 1.5 years. Immunopositivity for TTF1 and thyroglobulin is helpful in distinguishing cutaneous metastases of well differentiated thyroid carcinomas from other tumors. [75]

Lung cancer is the most common malignancy in men to metastasize to the skin. When skin metastases of an unknown primary site appear, lung cancer is highest in the differential diagnosis in men, and breast cancer in women. [77] Cutaneous metastases are identified in 2.8-8.7% of lung cancer, often in advanced disease. [77] However, cutaneous metastases can be the first manifestation of lung cancer. [33, 57, 78, 79] A study of 63 patients, 48 of whom had primary lung cancer with subsequent cutaneous metastases and another 15 with cutaneous metastases as the initial presentation of their lung cancer, found no difference in survival between the patients who presented with cutaneous metastases versus those who developed cutaneous metastases after being diagnosed with lung cancer. [80] The median survival after being diagnosed with a cutaneous metastasis from lung cancer was 3 months. [80]

When lung cancer metastasizes to the skin, it is usually involves the skin of the chest and abdomen, [80] but some studies have found head and neck to be commonly involved. [81] The tumor can spread to unusual sites such as scrotum, lip, and perianal area. [80] Like thyroid, lung cancers, particularly lung adenocarcinoma and lung neuroendocrine tumors both small cell and carcinoid are positive for TTF1. [82, 83, 84, 85] Immunostains are less helpful when faced with cutaneous metastases from pulmonary squamous cell carcinomas, as these tumors are generally negative for TTF1. Squamous cell carcinomas are particular problem as the differential diagnosis of metastatic squamous cell carcinoma to the skin also includes primary squamous cell carcinoma of the skin. Metastases to the skin form dermal nodules with an uninvolved Grenz zone separating the dermal metastasis from the overlying benign epidermis as opposed to most primary squamous cell carcinomas which emanate from the overlying atypical epidermis.

Cutaneous metastases from pulmonary carcinoid tumors must be differentiated from other neuroendocrine tumors. There are a number of pitfalls in this differential diagnosis. Both pulmonary carcinoid tumors and medullary thyroid carcinomas are positive for TTF1 and the neuroendocrine markers synaptophysin and chromogranin. [82, 83, 84, 85] Thus, additional markers such as calcitonin must be included in the workup of these cutaneous metastases. Another pitfall is atypical laryngeal carcinoid which often presents in the skin and, like medullary thyroid carcinoma, is positive for chromogranin, synaptophysin, CEA, and calcitonin. [5, 86, 87, 88, 89, 90] However, medullary thyroid carcinoma is positive for TTF1. [91] Thus, an immunohistochemical panel including TTF1 is needed to separate cutaneous metastases of medullary thyroid carcinoma from atypical laryngeal carcinoid. CDX2 is an intestine specific transcription factor expressed in colon adenocarcinomas which is also useful in identifying cutaneous metastases of carcinoids. [82, 84, 92, 93] CDX2 is positive in greater than 90% of midgut carcinoids, but few lung, gastric, or colon carcinoids are positive for CDX2. [82, 84, 92, 93] Thus a panel of immunostains including chromogranin, synaptophysin, calcitonin, TTF1, and CDX2 is helpful to determine the primary site for cutaneous metastases of well differentiated neuroendocrine tumors.

Breast cancer is the most common tumor to metastasize to the skin in women. [33, 94]. In a retrospective study of 4020 patients with metastatic cancer, 30% of patients with metastatic breast cancer had cutaneous metastases, and cutaneous metastases were the first sign of extranodal disease in 24% of patients. [39] The chest wall is usually involved in cutaneous breast metastases, although distant metastases are also known to occur such as to the scalp as alopecia neoplastica. [18, 23, 24] Breast cancer is a common cause of carcinoma erysipeloides [95], although a variety of tumors may show this clinically "inflammatory" pattern including lung, [96] stomach, [97] colon [98], nasopharynx [99], and genitourinary [100]. Another characteristic pattern of breast cancer metastases is "en cuirasse metastatic carcinoma" in which the skin is markedly indurated. Telangiectatic metastatic breast cancer is characterized by violaceous papules resembling telangiectasia or lymphangioma circumscriptum.

Differentiating metastatic breast carcinoma from other metastases to the skin as well as from cutaneous adnexal tumors such as eccrine ductal carcinoma can be very difficult. A study from Mayo Clinic showed 30 of 42 (71%) cases of metastatic breast cancer in the skin were positive for GCDFP-15 and 30 of 41 (73%) were positive for estrogen receptor, while cutaneous metastases from other sites showed 2 of 23 (9%) were positive for GCDFP-15 and none (0/23) was positive for estrogen receptor. [101] A study from Stanford University showed 2 of 10 cases of metastatic ductal carcinoma and 4 of 4 cases of metastatic lobular carcinoma were positive for BRST-2. [102] Estrogen receptor positivity was identified in one case of metastatic ductal carcinoma, but none of the 4 lobular carcinomas was positive, while all cases of ductal and lobular carcinoma were positive for progesterone receptor. [102] A study evaluating epidermal growth factor receptor (EGFR), and estrogen and progesterone receptors in 42 primary sweat gland carcinomas and 30 breast cancer metastases to the skin found EGFR to be positive in 81% of sweat gland carcinomas and only 17% of breast cancer metastases to the skin. [103] Estrogen and progesterone receptors were positive in 21% and 19% of sweat gland carcinomas and 33% and 27% of breast cancer metastases to the skin, respectively. The authors concluded that EGFR may be diagnostically helpful in separating sweat gland carcinomas from breast cancer metastases to the skin. A study showed 85% of cutaneous metastases from breast cancer were positive for androgen receptor. [104]

Additional markers evaluated in the cutaneous metastases of breast carcinoma include CK5/6, p63, CK7, and CK20 (Table 1). [60, 105, 106] In a study of 230 adnexal neoplasms and 27 cutaneous metastases of adenocarcinoma, 97% of the adnexal neoplasms and 33% of the cutaneous adenocarcinoma metastases were positive for CK5/6. [60] A study evaluated p63 expression in 20 benign adnexal tumors, 10 malignant adnexal tumors, and 14 adenocarcinomas metastatic to the skin (12 from breast, 2 from gastrointestinal tract). [106] All of the primary benign and malignant adnexal neoplasms were positive for p63, while none of the metastatic adenocarcinomas to the skin was positive for p63. [106] Another study compared p63, CK5/6, CK7, and CK20 in 21 adnexal neoplasms with sweat gland differentiation (6 benign and 15 malignant), one sebaceous carcinoma versus15 metastatic carcinomas (14 adenocarcinomas, 1 urothelial carcinoma) to the skin. [105] Twenty of 22 adnexal neoplasm expressed p63 and CK5/6, 13 of 22 expressed CK7, and none expressed CK20. [105] Four of 15 metastatic carcinomas were positive for CK5/6, 2 of 15 expressed p63, 13 of 15 expressed CK7, and 2 of 15 expressed CK20. [105] All 6 breast cancer metastases in this study were negative for CK5/6 and p63. The staining pattern for CK7 was generally focal in the adnexal neoplasms with the exception of one hidradenocarcinoma which stained diffusely, while the metastases showed diffuse staining. The combination of p63 and CK5/6 are helpful in distinguishing primary cutaneous adnexal neoplasms from metastases. [105]

Table 1. Estrogen receptor, progesterone receptor, BRST-2, EGFR, CK5/6, p63 and CK7 in cutaneous metastases from breast carcinoma versus adnexal neoplasms. [60, 102, 103, 105, 106, 107]

Breast to skin Other mets to skin Adnexal neoplasms
Estrogen receptor 7-73% 15-21%
Progesterone receptor 27-100% 19-54%
BRST-2 43-71% 9% 9%
EGFR 17% 81%
CK5/6 0-47% 10-44% 91-97%
p63 0 0-22% 91-100%
CK7 100% (diffuse) 78% (diffuse) 59% (focal)


Conclusion
Breast, lung and colon cancers are the most common internal carcinomas to metastasize to the skin. Renal cell carcinomas are the most common genitourinary tumor to metastasize to the skin. The differential diagnosis includes both primary cutaneous adnexal tumors and melanomas with clear cell change and metastases from other sites to the skin. Transcription factors, TTF1 and CDX2, are helpful in identifying lung, thyroid, and gastrointestinal tumor metastases. A combination of CK5/6 and p63 are helpful in distinguishing primary cutaneous adnexal neoplasms from visceral metastases to the skin.

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