After participating in this activity, physicians should be better able to:
- Assess the presence of the line sign. (1)
- Identify the line sign when present in histologic sections of skin disorders. (1, 2, 3)
- Compare the line sign with other diagnostic “tests” for morphea and other sclerosing disorders. (4)
- Recognize that subcutaneous fat tissue is required to assess the line sign. (3)
Morphea, also known as localized scleroderma, is characterized by discrete plaques of thickened, indurated skin, and sometimes, subcutaneous tissue. Although morphea can be recognized by its usual clinical findings of indurated, smooth-surfaced, whitish to dusky appearing plaques, and/or sclerotic plaques with a “lilac ring,”1 the diagnosis is typically confirmed histologically.2 Thus, recognition of histologic clues may facilitate diagnosis.
Histopathologic features of morphea that can be rapidly assessed at scanning magnification include square biopsy sign (SBS), cookie cutter sign (CCS), and high eccrine glands (HEGs). However, these simple and useful diagnostic clues have not been systematically evaluated or defined, largely being handed down as teaching pearls for trainees, with documentation limited to unreferenced statements or depictions in textbooks.3–5 In 2005, one of us (M.D.) coined the term “line sign” (LS) to describe the prominent and straight or linear interface produced by subcutis and adjacent sclerotic collagen, especially when viewed at low magnification. In a previous analysis of 37 patients, we (M.D., M.A.F.) reported the diagnostic sensitivity of LS to be higher than CCS (81% vs. 41%); specificity was comparable (87% vs. 90%).6
In clinical practice over the past decade, we continue to define LS as a prominent, straight interface between subcutis, and adjacent collagen, including the reticular dermis, subcutaneous fascia, and/or subcutaneous septa (Fig. 1). Previous allusion to what essentially seems to be the LS in the literature is scant, but comments by key opinion leaders spanning many decades support its usefulness as a diagnostic clue. In 1973, Reed, Clark, and Mihm referred to morphea as the prototype of a group of “substitutive hyperplastic collagenoses,” which produces a “straight interface between the dermis and the panniculus adiposus.”7 Weedon described morphea in Weedon's Skin Pathology, “Note…the straight edge of the dermal-subcutaneous interface” in 2002 and in subsequent editions to date.8,9 In 2010, Harvell and Barnhill10 described necrobiosis lipoidica: “In many instances, the interface between the dermis and subcutis is well demarcated, linear and parallel to the skin surface.” In this study, we further evaluated the sensitivity and specificity of LS in the diagnosis of morphea within a larger, clinically relevant database.
MATERIALS AND METHODS
In this case–control study, we performed a natural language search of our institution's laboratory information system from January 1992 through May 2017 as well as personal teaching files (M.A.F.) for cases of morphea as well as other disorders characterized by sclerosis involving the deep dermis, namely, sclerodermoid graft versus host disease and necrobiosis lipoidica. Inclusion required clinical confirmation of diagnosis by review of electronic medical records (when available). Exclusion criteria included absence of subcutaneous fat in the available tissue sections.
We reviewed existing hematoxylin- and eosin-stained sections using a light microscope to assess 5 histopathologic features: LS, CCS, SBS, HEGs, and interstitial mucin. We defined LS as a prominent and straight or linear interface produced by subcutis and adjacent sclerotic collagen of the reticular dermis and/or subcutaneous septa (Fig. 1). We defined CCS as the presence of straight and parallel lateral edges of the punch biopsy specimen, such as that made by a cookie cutter in cookie dough (Fig. 1). We defined SBS as a biopsy in which the 4 corners of the tissue sections each formed approximately 90 degree angles, that is, a rectangle or square (Fig. 1). HEG was defined as eccrine glands present in the upper 2/3 of the dermis. Interstitial mucin (present, absent) was assessed on H&E. The LS, SBS, CCS, and HEG were evaluated at 40× magnification. Mucin was evaluated at 100× magnification.
Two investigators (S.Y., M.A.F.), including an experienced dermatopathologist (M.A.F.), evaluated the microscopic features independently. Discordant scores were resolved by consensus achieved by concomitant review. The sensitivity for LS, CCS, and SBS in morphea was calculated. The diagnostic specificity of LS was determined by comparing morphea against a control group consisting of necrobiosis lipoidica and sclerodermoid graft versus host disease. We also calculated efficiency, positive predictive value, and negative predictive values for LS to further assess its utility as a diagnostic tool.
Institutional Review Board approval was obtained.
We analyzed 115 cases, including 73 cases of morphea. The sensitivity for LS, CCS, SBS, HEG, and mucin in morphea is shown in Table 1. HEG was the most sensitive feature (86%), followed by LS (82%). CCS and SBS were less than 50 percent sensitive for morphea (20% and 13%, respectively). The presence of mucin was the least sensitive feature.
The diagnostic specificity for selected features in morphea versus other sclerosing disorders is shown in Table 2. Comparing 73 cases of morphea with 42 cases of necrobiosis lipoidica or sclerodermoid graft versus host disease, the presence of mucin was the most specific feature (95%), whereas LS was least specific (27%).
The efficiency of LS was 64%. The positive predicative value of LS was 70%. Negative predictive value was calculated to be 42%.
We analyzed a variety of rapid and efficient “low-power” histologic clues for the diagnosis for morphea. Our results indicate that LS is a sensitive feature in morphea, substantially more sensitive than SBS and CCS, although LS seems to be less well known compared with SBS and CCS. However, LS is not specific for morphea and may be seen in other sclerosing disorders.
We suspect that the higher sensitivity and positive predictive value of LS (vs. CCS and SBS) reflects the fact that LS is not dependent on procedure type or specimen type. Rather, LS reflects a pathologic alteration created by the disease process itself, whereas SBS and CCS are dependent on the choice of biopsy instrument or else on the surgeon's technique (beveling or antibeveling). Our study shows that any type of specimen can show LS (Fig. 2), whereas SBS and CCS are generally only ascertainable in punch biopsy specimens—thus SBS and CCS are less likely to be useful markers in shave biopsies or most incisional or excisional biopsy specimens.
Although LS was significantly more sensitive than CCS and SBS in morphea, specificity and negative predictive value were low compared with CCS and SBS in this series. This is likely attributable to the fact that the number of control cases was smaller (42 cases vs. 73 cases), combined with the fact that, within our group of control cases, 30% could not be assessed for LS versus only 15% in the morphea cases. The number of cases that could not be assessed was high in both groups, which seemed to be due to having biopsies that did not have adequate depth to assess LS, although we excluded cases that were completely devoid of subcutis (Fig. 3). LS was thus shown in our study to be more likely to confirm true morphea cases than to confirm that the biopsy was not morphea. We hypothesize that if all biopsies in the control group were taken at an adequate depth, then LS would have demonstrated specificity comparable with CCS and SBS, similar to our previous analysis.6 Thus, a limitation in the assessment of LS is that the specimen must contain subcutis, whereas subcutis is not required for CCS or SBS (Fig. 3). It seems likely that LS, SBS, CCS, and HEG are all useful clues for assessing sclerosis involving the deep dermis, but that none of them are specific for morphea versus other sclerosing disorders.
In conclusion, we have studied LS in comparison with other histologic clues for morphea that can be rapidly assessed at scanning magnification. Our results demonstrate that LS is a useful feature for identifying morphea and other disorders characterized by deep dermal sclerosis such as necrobiosis lipoidica or sclerodermoid graft versus host disease. Compared with CCS or SBS, assessment of LS is independent of procedure or specimen type but does require a specimen of sufficient depth to assess the dermal-subcutaneous junction.
1. Burg G, Kempf W, Kutzner H. Connective tissue: sclerosis
. In: Burg G, Kempf W, Kutzner H, eds. Atlas of Dermatopathology
: Practial Differential Diagnosis by Clinicopathologic Pattern. Hoboken, NJ: John Wiley and Sons; 2015:205.
2. Leitenberger JJ, Cayce RL, Haley RW, et al. Distinct autoimmune syndromes in morphea
: a review of 245 adult and pediatric cases. Arch Dermatol. 2009;145:545–550.
3. Fung MA. Inflammatory diseases of the dermis and epidermis. In: Busam KJ, ed. Dermatopathology
. 2nd ed. Philadelphia, PA: Elsevier Saudners; 2015:71–72.
4. Winfield H, Jaworsky C. Connective tissue diseases. In: Elder DE, ed. Lever's Histopathology of the Skin. 11th ed. Alphen aan den Rijn: Wolters Kluwer; 2015:348–349.
5. Ferringer T. Alterations in collagen and elastin. In: Elston DM, Ferringer T, ed. Dermatopathology
. 2nd ed. Philadelphia, PA: Elsevier Saunders; 2014:214–215.
6. Draznin M, Fung M. The line sign. J Cutan Pathol. 2006;33:80–81.
7. Reed RJ, Clark WH, Mihm MC. Disorders of the panniculus adiposus. Hum Pathol. 1973;4:219–229.
8. Weedon D. Weedon's Skin Pathology. 3rd ed. London, United Kingdom: Churchill Livingstone Elsevier; 2010.
9. Patterson JW. Weedon's Skin Pathology. 4th ed. London, United Kingdom: Churchill Livingston Elsevier; 2016.
10. Harvell JD, Barnhill RL. Nodular and diffuse cutaneous infiltrates. In: Barnhill RL, Crowson AN, Magro CM, et al, eds. Dermatopathology
. 3rd ed. New York, NY: McGraw Hill; 2010:108.
The American Journal of Dermatopathology includes CME-certified content that is designed to meet the educational needs of its readers.
An annual total of 12 AMA PRA Category 1 Credits™ is available through the twelve 2018 issues of The American Journal of Dermatopathology. This activity is available for credit through November 30, 2020.
Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
Credit Designation Statement
Lippincott Continuing Medical Education Institute, Inc., designates this journal-based CME activity for a maximum of one (1) AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
To earn CME credit, you must read the article in The American Journal of Dermatopathology and complete the quiz, answering at least 80 percent of the questions correctly. Mail the Answer Sheet along with a check or money order for the $15 processing fee, to Lippincott CME Institute, Inc., Wolters Kluwer Health, Two Commerce Square, 2001 Market Street, 3rd Floor, Philadelphia, PA 19103. Only the first entry will be considered for credit and must be postmarked by the expiration date. Answer sheets will be graded and certificates will be mailed to each participant within 6 to 8 weeks of participation. Visit http://cme.lww.com for immediate results, other CME activities, and your personalized CME planner tool.
CME EXAM INSTRUCTIONS FOR OBTAINING AMA PRA CATEGORY 1 CREDITSTM CME EXAMINATION
Please mark your answers on the ANSWER SHEET.
After participating in this activity, physicians should be better able to assess the presence of the line sign (1), identify the line sign when present in histologic sections of skin disorders (1, 2, 3), compare the line sign with other diagnostic “tests” for morphea and other sclerosing disorders (4), recognize that subcutaneous fat tissue is required to assess the line sign. (3)
- 1. The “line sign” is defined as:
- a. prominent, straight line produced by the interface of subcutis and sclerotic collagen
- b. a punch biopsy wherein all 4 corners of the tissue section form a 90 degree angle
- c. a punch biopsy exhibiting straight and parallel lateral edges
- d. equidistant lines between “high” eccrine glands and the surface and underlying biopsy base
- 2. The line sign may be detected in which of the following types of specimens?
- a. Incisional biopsy
- b. Punch biopsy
- c. Excisional biopsy
- d. All of the above
- 3. Which of the following is a limitation of the line sign?
- a. the line sign and cookie cutter sign may co-exist in the same case
- b. the line sign and square biopsy sign may co-exist in the same case
- c. the line sign is dependent upon the type of biopsy performed
- d. the line sign cannot be assessed if subcutis is not present
- 4. In this study, which of the following was most often present in morphea?
- a. Cookie cutter sign
- b. Increased mucin
- c. Line sign
- d. Square biopsy sign
- 5. In addition to morphea, the line sign can be seen in which of the following?
- a. Acute graft versus host disease
- b. Erythema multiforme
- c. Granuloma annulare
- d. Necrobiosis lipoidica