Granulomatous slack skin: More than one type of mimicry
By Warren R. Heymann, MD
November 18, 2020
Vol. 2, No. 46
My chief resident presented a case to me enamored with his clinical diagnosis of granulomatous slack skin (GSS). Although I was delighted that he considered the disorder, I explained why I thought these inguinal and submammary pink-white subtly atrophic plaques were more likely lichen sclerosus. If I have learned anything over the years, however, is that cutaneous T cell lymphoma (CTCL) and its variants can mimic anything. In this case, the biopsy proved me right — having been fooled so many times before, I did not gloat (admittedly, holding back the temptation).
If Sir William Osler was alive today, he would need to modify his oft-quoted comment to: “He who knows syphilis, sarcoidosis, and CTCL, knows medicine.” What do all three disorders have in common? Granulomatous inflammation.
In their excellent review, Hodak and Amitay-Laish summarize the variants of mycosis fungoides (MF) that can imitate other disorders, leading to diagnostic dilemmas and confusion. Alphabetically, these presentations include bullous, folliculotropic, figurate erythema-like, granulomatous, hyperpigmented, hypopigmented, ichthyosiform, interstitial, other (non-specific), Pagetoid reticulosis, palmaris et plantaris, pigmented purpura-like, pityriasis lichenoides chronica-like, poikilodermatous, psoriasiform, pustular, and verrucous.
For improving the odds of diagnosing atypical cases of MF, the authors offer sage advice:
Maintain a high index of suspicion;
Perform a meticulous full body skin examination;
Discontinue topical steroids at least two weeks prior to obtaining skin biopsies;
Perform multiple biopsies from a variety of lesions;
If feasible, in equivocal cases, utilize the newly introduced high-throughput sequencing of the T cell receptor (TCR);
If necessary, continue to follow the patient and repeat biopsies periodically. (1)
GSS is an extremely rare type of CTCL, with approximately 60 reported cases. It characteristically affects adolescents and adults, predominantly in men. Clinically, GSS is characterized by circumscribed areas of pendulous lax skin with a predilection for the axillae and groin. In approximately one-third of the reported patients, an association with Hodgkin lymphoma was observed. Most patients have an indolent clinical course. (2)
According to Wang et al: “Histopathologically, GSS presents with non-caseating granulomas with macrophagic and lymphocytic infiltrations. The distinction between GSS and granulomatous MF (GMF) can be challenging with merely pathological analysis. Elastophagocytosis occurs only in GSS and not GMF. However, it is rare finding in GSS and often missed by pathologists. Elastophagocytosis causes decreased or absence of elastic fibers in the dermis and results in clinically apparent skin laxity. Thus, elastophagocytosis is both a pathological feature and a key player in GSS pathogenesis.” The authors used electron microscopy (EM) to demonstrate that elastin fibers appear as amorphous masses. They observed fragmented elastin fibers in macrophages, indicating elastophagocytosis. These findings correlate with the disorganized elastin fibers characteristically observed with the Weigert elastic stain. (3)
Granulomatous tissue responses can have systemic implications beyond the skin, notably hypercalcemia. I was intrigued by the case of Bettuzzi et al who presented the case of GSS in a 33-year-old man who developed asymptomatic hypercalcemia. The patient had received oral 25‐OH‐D‐vitamin supplementation one month earlier and there was no other imputable medication. The corrected calcemia was 3.5 mmol/L (2.20–2.60), phosphoremia was 1.17 mmol/L (0.87–1.45), parathormone (PTH) was <5 ng/mL (9–50), 25‐OH‐vit‐D was <7.5 nmol/L (75–200), 1,25‐OH‐vit‐D was 100 ng/mL (30–80), and angiotensin‐converting enzyme (ACE) was 232 UI/L (20–70). The authors concluded, in the absence of any other cause, that hypercalcemia was caused by the granulomatous disease. They noted that their case was the third reported observation of GSSD‐associated hypercalcemia. In the two previously published cases, the same granulomatous mechanism was described with elevated ACE, undetectable PTH, low 25‐OH‐vit‐D and elevated 1,25‐OH‐vit‐D. (4)
The poster child for granulomatous disorders is sarcoidosis. Increased production of 1,25(OH)2D3 is considered to be the main cause of calcium homeostasis disorders in sarcoidosis and other granulomatous disorders (tuberculosis, nontuberculous mycobacterial infection, silicone injections, etc.), although other factors may be at play. Studies in patients with tuberculosis have revealed that macrophages activated via toll-like receptor (TLR) present increased expression of a-1-hydroxylase (CYP27B1) and vitamin D receptor. Additionally, it is known that JAK-STAT, NF kB, and p38 MAPK pathways play a role in the activation of a-1-hydroxylase. (5) In neoplasia, hypercalcemia is generally due to the secretion of parathyroid hormone (PTH)-related peptide (PTHrP) by a wide variety of nonmetastatic solid tumors, including squamous cell tumors, and also hematologic tumors. Additionally, lymphomas may also produce 1,25-dihyroxyvitamin D. (6)
If viewed in the broad context of granulomatous inflammation, the surprise is not that hypercalcemia is a complication, but why it is not observed more frequently. What protective mechanisms limit this complication in GSS and other granulomatous diseases to a minority of patients?
Point to Remember: Granulomatous slack skin is a rare variant of mycosis fungoides that may be complicated by hypercalcemia, as noted in other forms of granulomatous inflammation. Dermatologists should not be slack in systemic evaluation of patients with granulomatous disease.
Our Expert’s Viewpoint
Emmilia Hodak, MD
Chair, Division of Dermatology
Rabin Medical Center, Beilinson Hospital
Sackler Faculty of Medicine
Tel Aviv University
The David and Inez Myers Chair for Cancer Genetics
GSS is one of the many faces of mycosis fungoides (MF). Indeed, as Dr Heymann drew to our attention, all the three great imitators (syphilis, sarcoidosis, and MF) have in common granulomatous inflammation. However, in fact, granulomatous reaction is just one of all the other major histopathologic patterns encountered in inflammatory skin diseases (described by A. Bernard Ackerman, the greatest dermatopathologist of the 20th century), which can also be found in MF. The plethora of clinicopathological variants of MF is not unexpected, especially in the early stage; the number of malignant T cells is small and the dermal infiltrate consists mainly of reactive T lymphocytes, producing inflammatory cytokines that are partly responsible for the large repertoire of the histologic patterns observed in MF.
Various degrees of granulomatous reaction, as part of the inflammatory microenvironment, can be found in histopathological sections in about 4% of all cases of MF. This may be observed either at the time of the initial diagnosis or years later. Granulomatous MF is a rare variant defined by the European Organization for Research and Treatment of Cancer as MF which includes prominent granuloma formation, numerous histiocytic giant cells, or a histiocyte-rich infiltrate defined by histiocytes, accounting for more than 25% of the entire infiltrate. I have seen only two such patients in my entire career. Granulomatous MF is usually a histopathological variant detected in otherwise clinically conventional lesions of MF, and very rarely is a clinicopathological variant mimicking clinically benign granulomatous skin diseases, such as granuloma annulare, sarcoidosis, or granulomatous rosacea. GSS is a distinct clinicopathological subtype of granulomatous MF. In the very early stage, the clinical features may be misleading, as in the case presented above. However, in the course of disease the unique clinical features characteristic of GSS, with evolution to hanging skin folds, become apparent, and the clinical suspicion is quite straightforward.
The pathogenesis of granuloma formation in MF is unknown; however, it is recognized that macrophages are a major component of the infiltrate in the tumor microenvironment, playing a role in tumor development and progression in several cancers, including lymphoproliferative disorders. In MF it was found that the infiltration of macrophages typically increases during tumor progression from early to advanced stage. In line with these observations, there are some reports suggesting that patients with granulomatous MF experience more frequent disease progression than patients with classic MF. For some reason not yet investigated, this seems to be not the case in GSS, as the experience with such patients is that they usually have an indolent clinical course.
Hodak E, Amitay-Laish I. Mycosis fungoides: A great imitator. Clin Dermatol 2019; 37: 255-267.
Variants of mycosis fungoides. In Bolognia JL, Schaffer JV, Cerroni L, et al (eds). Dermatology, 4th edition, pp 2135.
Wang B, Zheng J, Wang HW. Granulomatous slack skin: Case report with electron microscopic features. Dermatol Online J 2019; 15: 25 (7).
Bettuzzi T. Ram-Wolff C, Hau E, de Masson A, et al. Severe hypercalcemia complicating granulomatous slack skin disease: An exceptional case. J Eur Acad Dermatol Venereol 2019; 33: e354-356.
Gwadera Ł, Białas AJ, Iwański MA, Górski P, Piotrowski WJ. Sarcoidosis and calcium homeostasis disturbances – Do we know where we stand? Chron Respir Dis 2019; 16:1479973119878713
Goltzman D. Nonparathyroid hypercalcemia. Front Horm Res 2019; 51: 77-90.
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