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 Table of Contents  
Year : 2018  |  Volume : 5  |  Issue : 2  |  Page : 120-123

Interstitial pattern of cutaneous metastases and its diagnostic pitfalls: A report of three cases

Department of Pathology, St. John's Medical College, Bengaluru, Karnataka, India

Date of Web Publication19-Dec-2018

Correspondence Address:
Dr. Rajalakshmi Tirumalae
Department of Pathology, St. John's Medical College, Sarjapur Road, Bengaluru - 560 034, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijdpdd.ijdpdd_29_18

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Cutaneous metastases are rare and indicate a poor prognosis. Occasionally, these may be the only presenting sign, with clinically inapparent primary source of the malignancy. Of the various histologic patterns of cutaneous metastases, interstitial pattern is very uncommon and mimics inflammatory diseases such as granuloma annulare. This article illustrates three such cases and underscores the role of morphology and immunohistochemical markers in establishing the correct diagnosis.

Keywords: Cutaneous metastases, granuloma annulare, interstitial pattern

How to cite this article:
Panjwani PK, Tirumalae R, Yeliur IK, Ananthamurthy A. Interstitial pattern of cutaneous metastases and its diagnostic pitfalls: A report of three cases. Indian J Dermatopathol Diagn Dermatol 2018;5:120-3

How to cite this URL:
Panjwani PK, Tirumalae R, Yeliur IK, Ananthamurthy A. Interstitial pattern of cutaneous metastases and its diagnostic pitfalls: A report of three cases. Indian J Dermatopathol Diagn Dermatol [serial online] 2018 [cited 2020 Oct 31];5:120-3. Available from: https://www.ijdpdd.com/text.asp?2018/5/2/120/247868

  Introduction Top

Skin, although the largest human organ, is not a very common site for harboring metastases from internal malignancies. The incidence of cutaneous metastases reported in literature varies from 0.6 to around 10.4%.[1],[2],[3],[4] While the index of suspicion may be high in a patient with documented malignancy, it is often unsuspected and may be the first sign. In such a case, the pathologist has to overrule a wide list of inflammatory conditions and take the help of ancillary techniques to prove its neoplastic nature. This report highlights three cases wherein clinically silent visceral malignancies were suggested based on the evaluation of cutaneous lesions.

  Case Reports Top

Case 1

A 65-year-old woman presented with multiple indurated skin lesions, some showing ulceration, over the right side of the chest, back, shoulder, and axilla. The treating physician had differentials of Herpes zoster or possible metastatic disease. There was no palpable breast lump and no lung lesion on chest X-ray. A skin biopsy was done.

Histopathology showed the presence of neoplastic cells arranged in nodular as well as interstitial pattern [Figure 1]a in the dermis. The neoplastic cells were seen dissecting between collagen fibers [Figure 1]b. The epidermis was also involved in a Pagetoid manner, with nests of tumor cells [Figure 1]a. The cells showed glandular differentiation and were also present in cords and in an Indian file pattern. Marked nuclear atypia was noted, along with a few vascular emboli. There was a sparse plasma cell infiltrate in the dermis along with fibrosis. On immunohistochemistry, the cells were positive for pancytokeratin, cytokeratin-7 (CK-7) [Figure 1]c, and gross cystic disease fluid protein-15 (GCDFP-15), which pointed toward an underlying breast malignancy.
Figure 1: (a) Biopsy showing neoplastic cells in a nodular and interstitial pattern in the deep dermis. In addition, note the nests of tumor cells within the epidermis in a Pagetoid fashion (H and E, ×40). (b) Neoplastic cells with nuclear atypia seen dissecting between collagen fibers in the reticular dermis with a stromal response (H and E, ×100). (c) Neoplastic cells showing strong expression of cytokeratin-7 (×100)

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Case 2

This was a 45-year-old man with multiple skin nodules over the left side of the neck and upper limb for 6 months. These nodules were gradually increasing in size. The patient also had low backache and bilateral hip pain over the same period of time. Local examination revealed lymphedema over the left side of the face, neck, and breast, with nipple retraction. There was no breast lump palpable and no breast lesion detectable on radiology. Magnetic resonance imaging of the spine showed cystic lesions in the spine which were very suspicious for metastases. The patient had a skin biopsy done from one of the neck nodules.

The epidermis was uninvolved, and the dermis showed an interstitial infiltrate of cells arranged in cords and Indian file pattern [Figure 2]a and [Figure 2]b. Minimal nuclear atypia was observed. There was a sparse lymphocytic infiltrate in the dermis. Keloidal collagen was noted [Figure 2]a.
Figure 2: (a) Neoplastic cells in an interstitial pattern with negligible atypia. Note the keloidal nature of collagen fibers (H and E, ×100). (b) The Indian file pattern and subtly cytologic atypia (H and E, ×400). (c) Neoplastic cells in an interstitial pattern expressing cytokeratin-7 (×100)

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Immunohistochemistry showed positivity for pancytokeratin and CK-7 [Figure 2]c. Staining for GCDFP-15 was negative. The possibility of a primary neoplasm in the upper gastrointestinal tract, lung, or breast was suggested.

Case 3

A 57-year-old man presented with nodules over the scalp and supraclavicular region. Radiological examination showed cystic lesions in the skull, and the possibility of multiple myeloma was considered; the patient was subjected to further investigations. Both the scalp and supraclavicular nodules were biopsied. The laboratory workup for myeloma was negative.

This case also showed an unremarkable epidermis and an interstitial infiltrate of cells in cords and Indian file pattern [Figure 3]a. Cellular atypia was inconspicuous, and the cells were closely interspersed with lymphocytes and histiocytes [Figure 3]b. Keloidal collagen was noted.
Figure 3: (a) Cells in an interstitial pattern with no nuclear atypia (H and E, ×100). (b) Cells with no atypia admixed with lymphohistiocytes (H and E, ×400). (c) Neoplastic cells positive for cytokeratin-7. Note that the eccrine glands are also stained (CK-7, ×100)

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The cells were positive for pancytokeratin and CK-7 [Figure 3]c. Positivity for GCDFP-15 was also seen in some cells. A possible primary in the breast or lung was suggested, but the patient deferred further investigations.

Interestingly, the second biopsy from case 3, which was a supraclavicular nodule, showed a dermatofibroma (DF) and no evidence of metastasis.

[Table 1] and [Table 2] summarize the salient histological and immunohistochemical findings in all the three cases.
Table 1: Histological features noted in the skin biopsies

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Table 2: Results of panel of immunohistochemistry

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  Discussion Top

The incidence of skin metastases, as reported in literature, varies from around 0.6% to 10.4%.[1],[2],[3],[4] Lung and breast, by far, form the most common sources of primary malignancies in men and women, respectively.[1],[2],[3],[4],[5] Usual sites involved are head and neck and anterior chest in men, while in women, anterior chest and abdomen are the preferred sites.[1] Most of these metastases are seen in late stages of disease and herald a poor prognosis. The median survival is reported to be as low as 6.5 months in patients with skin metastasis, with the worst survival rate in patients of lung carcinoma.[6],[7]

Clinically, cutaneous metastases may be seen as nodules, papules, plaques, tumors, or ulcers.[8] Rare presentations include carcinoma en cuirasse, erysipelas-like, telangiectatic, and alopecia.[8] In many instances, the histological finding of metastasis may be incidental and the underlying malignancy may actually not be apparent.[2],[9] Skin metastasis as the first manifestation of an internal malignancy is seen mostly in tumors arising from the lungs, kidneys, and ovaries.[10]

Histologically, four patterns of cutaneous involvement have been described as follows: nodular, infiltrative (interstitial), diffuse, and intravascular.[8] While the nodular and diffuse patterns are relatively easier to identify on morphology, it is the interstitial or the infiltrative pattern which poses a common diagnostic problem to the histopathologist.

In all the three cases in our series, the infiltrate was seen insinuating between bundles of collagen accompanied by lymphohistiocytes. An Indian file pattern was also discerned, where the cells were seen in a single-file-like linear pattern. This subtly differs from the interstitial pattern where a more dissecting or insinuating pattern in between collagen bundles was seen.

The most common inflammatory condition with this interstitial pattern is granuloma annulare (GA). Although classically described as an example of palisading granuloma, interstitial GA is more common in our experience.[11] Two of our cases had negligible cytologic atypia, making GA a plausible diagnosis. Mucin is commonly found in GA and may be an additional confounding factor. This was not seen in our cases. Degenerative changes in collagen seen in GA have also been recorded in metastases.[12],[13],[14] The clues that may help in distinguishing the two are a more cellular dermis and presence of atypia in the metastatic lesions.[13]

Keloidal collagen was noted in two of three cases in this series. In combination with an interstitial infiltrate, this brings into play another common entity, DF. DF is characterized by interstitial or diffuse infiltrates of histiocytes with angulated fibroblasts and keloidal bundles of collagen at the periphery. The margins are ill-defined. There are a variable number of giant cells, siderophages, and foam cells that aid in the distinction. Another helpful clue is the phenomenon of induction of follicular/sebaceous structures in the epidermis overlying a DF.[15] It is fortuitous that case 3 had a DF at a site different from the metastasis.

The first case showed epidermal involvement by tumor cells in a Pagetoid pattern. Alcaraz et al. observed this commonly in the perianal or genital skin.[8] They prefer to designate these as epidermotropic metastases, in order to distinguish them from authentic extramammary Paget's disease. They have been reported in carcinomas from breast, hypopharynx, and stomach.[8]

In a patient with documented malignancy, the index of suspicion for metastases is higher. In all three of our cases, there was no known primary and we had to rely on ancillary diagnostic tests. Immunohistochemistry is a valuable tool that comes to the pathologist's aid in these instances.[16] Selection of markers should be based on malignancies common in particular age groups, sites, and geographic distribution. Two of our cases were positive for CK-7 and GCDFP, indicating that the likely primary was in the breast. The third case showed only CK-7 expression. The panel we have used is not exhaustive. The panel should also include markers for melanoma such as S100 and Melan-A. Desmoplastic melanoma is an important mimic.

Although rare, the classical form of epithelioid sarcoma can resemble cutaneous metastases both clinically and histologically, especially in cases with minimal cellular atypia. Demonstration of co-expression of CK and Vimentin stains, along with a positive stain for CD34, can distinguish these two entities in a majority of cases.[17]

Immunohistochemistry not only helps in determining the possible primary tumor but also is useful to highlight morphologic patterns of the infiltrate and the depth of infiltration. These features may often be difficult to assess on histology due to the presence of a dense inflammatory component. Nevertheless, one has to keep in mind the sensitivity and specificity of various markers selected and understand that a negative result does not completely exclude a diagnosis, which can be particularly vexing in unknown primary sites.

  Conclusion Top

The interstitial pattern of cutaneous metastases on histology has a high likelihood of being mislabeled as an inflammatory condition. Careful histologic examination, appropriate clinical information, imaging, and prudent use of immunohistochemistry help in determining the probable primary source of malignancy in most cases. The overall patient survival may be poor, but pinpointing the possible primary can direct specific treatment modalities.


The authors wish to sincerely thank Dr. Almut Boer-Auer, Dermatologikum Hamburg, for the immunohistochemical stains.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Hussein MR. Skin metastasis: A pathologist's perspective. J Cutan Pathol 2010;37:e1-20.  Back to cited text no. 1
Lookingbill DP, Spangler N, Helm KF. Cutaneous metastases in patients with metastatic carcinoma: A retrospective study of 4020 patients. J Am Acad Dermatol 1993;29:228-36.  Back to cited text no. 2
Hu SC, Chen GS, Wu CS, Chai CY, Chen WT, Lan CC, et al. Rates of cutaneous metastases from different internal malignancies: Experience from a Taiwanese medical center. J Am Acad Dermatol 2009;60:379-87.  Back to cited text no. 3
Schwartz RA. Cutaneous metastatic disease. J Am Acad Dermatol 1995;33:161-82.  Back to cited text no. 4
Bansal R, Naik R. A study of 70 cases of cutaneous metastases from internal carcinoma. J Indian Med Assoc 1998;96:10-2.  Back to cited text no. 5
Schoenlaub P, Sarraux A, Grosshans E, Heid E, Cribier B. Survival after cutaneous metastasis: A study of 200 cases. Ann Dermatol Venereol 2001;128:1310-5.  Back to cited text no. 6
Wollina U, Graefe T, Konrad H, Schonlebe J, Koch A, Hansel G, et al. Cutaneous metastases of internal cancer. Acta Dermatoven 2004;13:79-84.  Back to cited text no. 7
Alcaraz I, Cerroni L, Rütten A, Kutzner H, Requena L. Cutaneous metastases from internal malignancies: A clinicopathologic and immunohistochemical review. Am J Dermatopathol 2012;34:347-93.  Back to cited text no. 8
Resnik KS, DiLeonardo M, Gibbons G. Clinically occult cutaneous metastases. J Am Acad Dermatol 2006;55:1044-7.  Back to cited text no. 9
Schwartz RA. Histopathologic aspects of cutaneous metastatic disease. J Am Acad Dermatol 1995;33:649-57.  Back to cited text no. 10
Chaitra V, Inchara YK, Rajalakshmi T, Antony M. Granuloma annulare – Histology reconsidered. Indian J Dermatol Venereol Leprol 2010;76:568-9.  Back to cited text no. 11
[PUBMED]  [Full text]  
Hawryluk EB, Izikson L, English JC 3rd. Non-infectious granulomatous diseases of the skin and their associated systemic diseases: An evidence-based update to important clinical questions. Am J Clin Dermatol 2010;11:171-81.  Back to cited text no. 12
Hartman RI, Chu EY, Acker SM, James WD, Elenitsas R, Kovarik CL, et al. Cutaneous metastases from visceral malignancies mimicking interstitial granulomatous processes: A report of 3 cases. Am J Dermatopathol 2013;35:601-5.  Back to cited text no. 13
Deal T, Mishra V, Duong B, Andea A. Pitfalls in Dermatopathology. When things are not what they seem. Expert Rev Dermatol 2012;7:579-88.  Back to cited text no. 14
Ackerman AB, Boer A, Bennin B, Gottlieb GJ. Histologic Diagnosis of Inflammatory Skin Diseases. An algorithmic method based on pattern analysis. 3rd ed. New York: Ardor Scribendi; 2005. p. 375-408.  Back to cited text no. 15
Sariya D, Ruth K, Adams-McDonnell R, Cusack C, Xu X, Elenitsas R, et al. Clinicopathologic correlation of cutaneous metastases: Experience from a cancer center. Arch Dermatol 2007;143:613-20.  Back to cited text no. 16
Armah HB, Parwani AV. Epithelioid sarcoma. Arch Pathol Lab Med 2009;133:814-9.  Back to cited text no. 17


  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2]


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